138 results
Search Results
2. Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1).
- Author
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Yang J, Wu Y, Zhu Q, Qu X, Ou H, Liu H, Wei Y, Ge D, Lu C, Jiang B, and Song X
- Subjects
- Humans, Animals, Molecular Structure, Mice, Structure-Activity Relationship, Apoptosis drug effects, Drug Screening Assays, Antitumor, Dose-Response Relationship, Drug, Proteolysis drug effects, Molecular Docking Simulation, Cell Line, Tumor, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis, Mice, Nude, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Proliferation drug effects, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Drug Discovery
- Abstract
The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
3. A new strategy for the treatment of Parkinson's disease: Discovery and bio-evaluation of the first central-targeting tyrosinase inhibitor.
- Author
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Qi S, Guo L, Liang J, Wang K, Liao Q, He S, Lyu W, Cheng Z, Wang J, Luo X, Yan X, Lu Z, Wang X, Wang Z, Chen X, and Li Q
- Subjects
- Animals, Structure-Activity Relationship, Mice, Molecular Structure, Neuroprotective Agents chemistry, Neuroprotective Agents pharmacology, Neuroprotective Agents chemical synthesis, Humans, Male, Molecular Docking Simulation, Blood-Brain Barrier metabolism, Monophenol Monooxygenase antagonists & inhibitors, Monophenol Monooxygenase metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemical synthesis, Parkinson Disease drug therapy, Parkinson Disease metabolism, Dose-Response Relationship, Drug, Drug Discovery
- Abstract
The high level of tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood-brain barrier (BBB). Herein, we obtained a novel tyrosinase inhibitor, 2-06 (tyrosinase: monophenolase IC
50 = 70.44 ± 22.69 μM, diphenolase IC50 = 1.89 ± 0.64 μM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting tyrosinase inhibitor, which is crucial for in-depth study on the new strategy for utilizing tyrosinase inhibitors to treat PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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4. Discovery of novel FUT8 inhibitors with promising affinity and in vivo efficacy for colorectal cancer therapy.
- Author
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Lv Y, Zhang Z, Wang M, Wang Y, Chen M, Jia J, Guo Y, Wang K, Li Z, Wang W, and Li H
- Subjects
- Humans, Animals, Structure-Activity Relationship, Mice, Molecular Structure, Drug Screening Assays, Antitumor, Dose-Response Relationship, Drug, Cell Proliferation drug effects, Mice, Nude, Cell Line, Tumor, Mice, Inbred BALB C, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Neoplasms, Experimental metabolism, Molecular Docking Simulation, Fucosyltransferases antagonists & inhibitors, Fucosyltransferases metabolism, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemical synthesis
- Abstract
As a member of glycosyltransferases, fucosyltransferase 8 (FUT8) is essential to core fucosylation and has been considered as a potential therapeutic target for malignant tumors, including colorectal cancer (CRC). Based on the identification of key binding residues and probable conformation of FUT8, an integrated strategy that combines virtual screening and chemical optimization was carried out and compound 15 was identified as a potent FUT8 inhibitor with novel chemical structure and in vitro antitumor activity. Moreover, chemical pulldown experiments and binding assays confirmed that compound 15 selectively bound to FUT8. In vivo, compound 15 showed promising anti-CRC effects in SW480 xenografts. These data support that compound 15 is a potential FUT8 inhibitor for CRC treatment and deserve further optimization studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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5. Discovery of highly potent PARP7 inhibitors for cancer immunotherapy.
- Author
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Yang J, Liu B, Yan W, Zhao X, Wang C, Zhu Q, Zou Y, Xu Y, and Gu H
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Animals, Mice, Poly(ADP-ribose) Polymerases metabolism, Cell Line, Tumor, Neoplasms drug therapy, Neoplasms pathology, Mice, Inbred BALB C, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors chemistry, Poly(ADP-ribose) Polymerase Inhibitors chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Drug Screening Assays, Antitumor, Immunotherapy, Drug Discovery, Dose-Response Relationship, Drug, Cell Proliferation drug effects
- Abstract
PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type Ⅰ interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type Ⅰ interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC
50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC50 > 1.0 μM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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6. Activity-based protein profiling in drug/pesticide discovery: Recent advances in target identification of antibacterial compounds.
- Author
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Chen K, Zhang L, Ding Y, Sun Z, Meng J, Luo R, Zhou X, Liu L, and Yang S
- Subjects
- Bacteria drug effects, Microbial Sensitivity Tests, Bacterial Proteins antagonists & inhibitors, Bacterial Proteins metabolism, Molecular Structure, Proteomics, Humans, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Drug Discovery
- Abstract
Given the escalating incidence of bacterial diseases and the challenge posed by pathogenic bacterial resistance, it is imperative to identify appropriate methodologies for conducting proteomic investigations on bacteria, and thereby promoting the target-based drug/pesticide discovery. Interestingly, a novel technology termed "activity-based protein profiling" (ABPP) has been developed to identify the target proteins of active molecules. However, few studies have summarized advancements in ABPP for identifying the target proteins in antibacterial-active compounds. In order to accelerate the discovery and development of new drug/agrochemical discovery, we provide a concise overview of ABPP and its recent applications in antibacterial agent discovery. Diversiform cases were cited to demonstrate the potential of ABPP for target identification though highlighting the design strategies and summarizing the reported target protein of antibacterial compounds. Overall, this review is an excellent reference for probe design towards antibacterial compounds, and offers a new perspective of ABPP in bactericide development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. The potential of marine natural Products: Recent Advances in the discovery of Anti-Tuberculosis agents.
- Author
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Peng X, Zeng Z, Hassan S, and Xue Y
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Microbial Sensitivity Tests, Animals, Aquatic Organisms chemistry, Tuberculosis drug therapy, Biological Products chemistry, Biological Products pharmacology, Biological Products chemical synthesis, Antitubercular Agents pharmacology, Antitubercular Agents chemistry, Antitubercular Agents chemical synthesis, Drug Discovery, Mycobacterium tuberculosis drug effects
- Abstract
Tuberculosis (TB) is an infectious airborne disease caused by Mycobacterium tuberculosis. Since the 1990 s, many countries have made significant progress in reducing the incidence of TB and associated mortality by improving health services and strengthening surveillance systems. Nevertheless, due to the emergence of multidrug-resistant TB (MDR-TB), alongside extensively drug-resistant TB (XDR-TB) and TB-HIV co-infection, TB remains one of the lead causes of death arising from infectious disease worldwide, especially in developing countries and disadvantaged populations. Marine natural products (MNPs) have received a large amount of attention in recent years as a source of pharmaceutical constituents and lead compounds, and are expected to offer significant resources and potential in the fields of drug development and biotechnology in the years to come. This review summarizes 169 marine natural products and their synthetic derivatives displaying anti-TB activity from 2013 to the present, including their structures, sources and functions. Partial synthetic information and structure-activity relationships (SARs) are also included., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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8. Discovery and development of thiazolidine-2,4-dione derivatives as Bcl-2/Mcl-1 dual inhibitors.
- Author
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Long J, Chen H, Yan Z, Zhou L, Deng R, Wang J, Tang Z, and Wan Y
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Animals, Rats, Drug Development, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Proliferation drug effects, Apoptosis drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Drug Discovery, Thiazolidinediones pharmacology, Thiazolidinediones chemistry, Thiazolidinediones chemical synthesis
- Abstract
Increasing the levels of antiapoptotic Bcl-2 proteins is an important way that cancer cells utilize to get out of apoptosis, underscoring their significance as promising targets for anticancer therapies. Lately, a primary compound 1 bearing thiazolidine-2,4-dione was discovered to exhibit comparable Mcl-1 inhibitory activity in comparison to WL-276. Herein, thirty-nine thiazolidine-2,4-dione analogs were yielded through incorporating different biphenyl moieties (R
1 ), amino acid side chains (R2 ) and sulfonamides (R3 ) on 1. The findings indicated that certain compounds exhibited favorable inhibitory effects against Bcl-2/Mcl-1, while demonstrating limited or negligible binding affinity towards Bcl-xL. In particular, compounds 16 and 20 exhibited greater Bcl-2/Mcl-1 inhibition compared to AT-101, WL-276 and 1. Moreover, they demonstrated notable antiproliferative effects and significantly induced apoptosis in U937 cells. The western blot and co-immunoprecipitation assays confirmed that 20 could induce alterations in the expression of apoptosis-associated proteins to result in apoptosis through on-target Bcl-2 and Mcl-1 inhibition. In addition, 20 exhibited favorable stability profiles in both rat plasma and rat liver microsomes. In total, 20 could be used as a promising compound to discover Bcl-2/Mcl-1 dual inhibitors with favorable therapeutic properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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9. Label-free cell phenotypic profiling of histamine H4R receptor and discovery of non-competitive H4R antagonist from natural products.
- Author
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Tang H, Hou T, Zhou H, Liao H, Xu F, Xie X, Yuan W, Guo Z, Liu Y, Wang J, Zhou W, and Liang X
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Phenanthrenes pharmacology, Phenanthrenes chemistry, Histamine Antagonists pharmacology, Histamine Antagonists chemistry, Molecular Docking Simulation, Phenotype, Biological Products chemistry, Biological Products pharmacology, Receptors, Histamine H4 antagonists & inhibitors, Receptors, Histamine H4 metabolism, Dose-Response Relationship, Drug, Drug Discovery
- Abstract
Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream G
i and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC50 value of 11.68 ± 1.30 μM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Han Zhou reports financial support was provided by Dalian Institute of Chemical Physics Chinese Academy of Sciences. Jixia Wang reports financial support was provided by Dalian Institute of Chemical Physics Chinese Academy of Sciences. Hongming Tang, Tao Hou, Weijia Zhou, Jixia Wang has patent #202311766641.3 pending to Hongming Tang, Tao Hou, Weijia Zhou, Jixia Wang. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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10. Discovery of two non-UDP-mimic inhibitors of O-GlcNAc transferase by screening a DNA-encoded library.
- Author
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Balsollier C, Bijkerk S, de Smit A, van Eekelen K, Bozovičar K, Husstege D, Tomašič T, Anderluh M, and Pieters RJ
- Subjects
- Structure-Activity Relationship, Humans, Molecular Structure, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Uridine Diphosphate metabolism, Uridine Diphosphate chemistry, N-Acetylglucosaminyltransferases antagonists & inhibitors, N-Acetylglucosaminyltransferases metabolism, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, DNA chemistry, DNA metabolism, Drug Discovery, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries chemical synthesis
- Abstract
Finding potent inhibitors of O-GlcNAc transferase (OGT) has proven to be a challenge, especially because the diversity of published inhibitors is low. The large majority of available OGT inhibitors are uridine-based or uridine-like compounds that mimic the main interactions of glycosyl donor UDP-GlcNAc with the enzyme. Until recently, screening of DNA-encoded libraries for discovering hits against protein targets was dedicated to a few laboratories around the world, but has become accessible to wider public with the recent launch of the DELopen platform. Here we report the results and follow-up of a DNA-encoded library screening by using the DELopen platform. This led to the discovery of two new hits with structural features not resembling UDP. Small focused libraries bearing those two scaffolds were made, leading to low micromolar inhibition of OGT and elucidation of their structure-activity relationship., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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11. Advances in the discovery of activin receptor-like kinase 5 (ALK5) inhibitors.
- Author
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Mansour MA, Hassan GS, Serya RAT, Jaballah MY, and Abouzid KAM
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Animals, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis, Receptor, Transforming Growth Factor-beta Type I antagonists & inhibitors, Receptor, Transforming Growth Factor-beta Type I metabolism, Drug Discovery
- Abstract
Activin receptor‑like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-β (TGF-β) family. (TGF-β) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation within the signaling pathway can cause variety of diseases, such as fibrosis, cardiovascular disease, and especially cancer, rendering ALK5 a potential drug target. Hence, various small molecules have been designed and synthesized as potent ALK5 inhibitors. In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure-activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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12. Recent developments on the synthesis of biologically active glycohybrids.
- Author
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Mishra VK, Khanna A, Tiwari G, Tyagi R, and Sagar R
- Subjects
- Drug Discovery methods, Carbohydrates
- Abstract
The exploration of hybridization emerges as a potent tool in advancing drug discovery research, with a significant emphasis on carbohydrate-containing hybrid scaffolds. Evidence indicates that linking carbohydrate molecules to privileged bioactive scaffolds enhances the bioactivity of drug molecules. This synergy results in a diverse range of activities, making carbohydrate scaffolds pivotal for synthesizing compound libraries with significant functional and structural diversity. Beyond their synthesis utility, these scaffolds offer applications in screening bioactive molecules, presenting alternative avenues for drug development. This comprehensive review spanning 2015 to 2023 focuses on synthesized glycohybrid molecules, revealing their bioactivity in areas such as anti-microbial, anti-cancer, anti-diabetic, anti-inflammatory activities, enzyme inhibition and pesticides. Numerous novel glycohybrids surpass positive control drugs in biological activity. This focused study not only highlights the diverse bioactivities of glycohybrids but also underscores their promising role in innovative drug development strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. Artificial intelligence in small molecule drug discovery from 2018 to 2023: Does it really work?
- Author
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Lv Q, Zhou F, Liu X, and Zhi L
- Subjects
- Drug Design, Drug Development, Artificial Intelligence, Drug Discovery methods
- Abstract
Utilizing artificial intelligence (AI) in drug design represents an advanced approach for identifying targets and developing new drugs. Integrating AI techniques significantly reduces the workload involved in drug development and enhances the efficiency of early-stage drug discovery. This review aims to present a comprehensive overview of the utilization of AI methods in the field of small drug design, with a specific focus on four key areas: protein structure prediction, molecular virtual screening, molecular design, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. Additionally, the role and limitations of AI in drug development are explored, and the impact of AI on decision-making processes is studied. It is important to note that while AI can bring numerous benefits to the early stage of drug development, the direction and quality of decision-making should still be emphasized, as AI should be considered as a tool rather than a decisive factor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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14. Native-compound-Coupled Affinity Matrix (NCAM) in target identification and validation of bioactive compounds: Application, mechanism and outlooks.
- Author
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Ma L, Li M, Gou S, Wang W, Liu K, and Zhang Y
- Subjects
- Proteolysis, Neural Cell Adhesion Molecules, Drug Discovery, Peptide Hydrolases
- Abstract
In drug discovery and development, the direct target identification of bioactive small molecules plays a significant role for understanding the mechanism of action, predicting the side effects, and rationally designing more potent compounds. However, due to the complicated regulatory processes in a cell together with thousands of biomacromolecules, target identification is always the major obstacle. New methods and technologies are continuously invented to tackle this problem. Nevertheless, the mainly used tools possess several disadvantages. High synthetic skills are typically required to laboriously synthesize a probe for protein enrichment. To detect the ligand-protein interaction by analyzing proteins' responses to proteolytic or thermal treatment, costly and precise instruments are always necessary. Therefore, convenient and practical techniques are urgently needed. Over the past decades, a strategy using native compounds without the requirement of chemical modification, also termed Native-compound-Coupled Affinity Matrix (NCAM), is developing continuously. Two practical tactics based on "label-free" compounds have been invented and used, that is Photo-cross-linked Small-molecule Affinity Matrix (PSAM) and Native-compound-Coupled CNBr-activated Beads (NCCB). Presently, we will elucidate the characteristics, coupling mechanism, advantages and disadvantages, and future prospect of NCAM in specific target identification and validation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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15. Chemical metabolite synthesis and profiling: Mimicking in vivo biotransformation reactions.
- Author
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Chhatrapati Bisen A, Nashik Sanap S, Agrawal S, Biswas A, and Sankar Bhatta R
- Subjects
- Biotransformation, Pharmaceutical Preparations, Drug Discovery methods, Drug Design
- Abstract
Biotransformation was previously viewed as merely the structural characterization of drug metabolites, and it was performed only when drug candidates entered clinical development. The synthesis of drug metabolites is crucial to the drug development process because it generates either pharmacologically active, inactive, or reactive molecules and hence their characterization and comprehensive pharmacological evaluation is necessary. The chemical metabolite synthesis is very challenging due to the complex structures of many drug molecules, presence of multiple stereocenters, poor reaction yields, and the formation of unwanted by-products. Drug metabolites and their chemical synthesis have immense significance in the drug discovery process. The chemical synthesis of metabolites facilitates on- or off-target pharmacological and toxicological evaluations at the easiest. In a broader view metabolite could be a target lead molecule for drug design, toxic reactive metabolites, pharmaceutical standards for bioanalytical methods, etc. Collectively these metabolite information dossiers will aid regulatory agencies such as the EMA and FDA in maintaining strict vigilance over drug manufacturers with regard to the safety of NCE's and their hidden metabolites. Herein, we are presenting a systematic compilation of chemical and biocatalytic strategies reported to date for pharmaceutical drug metabolite synthesis. This review report is very useful for the laboratory synthesis of new drug metabolites, and their preclinical biological evaluation could aid in the detection of early threats (alerts) in drug discovery, eliminate the toxicity profile, explore newer pharmacology, and delivering a promising and safe drug candidate to humankind., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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16. Monosaccharide acceptor substrate specificity of dextransucrase
- Author
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Robert M. Mayer and Mrinal K. Bhattacharjee
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Glycoside ,Biochemistry ,Acceptor ,Dextransucrase ,Paper chromatography ,Enzyme ,chemistry ,Polymerization ,Drug Discovery ,Monosaccharide ,Epimer ,Molecular Biology - Abstract
The acceptor substrate specificity of dextransucrase from Streptococcus sanguis 10558 was examined utilizing analogs of methyl-α- d -glucopyranoside. The analogs include a series of α-methyl glycosides of several epimers, derivatives blocked at position 6, 6 blocked epimers, several β-methyl derivatives, and L-sugars. The products formed during reactions between the analogs, the enzyme and radiolabeled sucrose were separated by paper chromatography. This analysis permitted the simultaneous evaluation of transfer as well as polymerization reaction. All analogs examined served as acceptors with varying degrees of effectiveness. From the data obtained, a rough model for interaction of the enzyme with acceptors is proposed. Structural modifications at C2 and C4 produced the most significant alteration in the ability to serve as acceptors, and also inhibited the total catalytic activity of the enzyme. The enzyme is capable of using sugars in either 4 C 1 or 1 C 4 conformations. In addition, sugars blocked at C6, the normal site of glucose addition, can serve as good acceptors and therefore probably bind to the enzyme in a different orientation. The broad spectrum of analogs that can serve as acceptor suggests that the acceptor site has some flexibility.
- Published
- 1991
17. Discovery of a novel and selective cathepsin L inhibitor with anti-metastatic ability in vitro and in vivo against breast cancer cells.
- Author
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Li Y, Ai X, Zou C, Liu Y, Ma L, Men J, Liu D, Sheng L, Ruan X, Liu H, Li W, Ma E, and Yuan L
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cathepsin L metabolism, Cell Line, Cell Proliferation drug effects, Cysteine Proteinase Inhibitors chemical synthesis, Cysteine Proteinase Inhibitors chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Cathepsin L antagonists & inhibitors, Cysteine Proteinase Inhibitors pharmacology, Drug Discovery
- Abstract
Asperphenamate is a natural product that has attracted considerable interest from researchers worldwide. In the last decade, aiming to increase the biological activity and improve druggability, modifications of the A-ring moiety in asperphenamate have been performed. Our laboratory has also recently reported functional derivatizations of the A ring and studied its effect on the inhibition of cysteine cathepsin L. However, the functional significance of the B-ring fragment toward cathepsin L has not been evaluated thus far. In this paper, forty-four derivatives of the B-ring substituted with different N-phenylsulfonyl groups were designed and synthesized. Among them, the paratrifluromethyl analog B-2a and the 2, 4-difluoro-5-chloro derivative B-11b showed more potent inhibitory activity against cathepsin L than the control compound, ABR, which displayed the strongest inhibitory effect on cathepsin L and S among all reported asperphenamate derivatives. In particular, compound B-2a showed more pronounced selectivity against cathepsin L than the other derivatives. Molecular docking revealed that the N-phenylsulfonylamide moiety was vital for the interactions between B-2a and cathepsin L. Moreover, B-2a displayed no toxicity against normal cells. Therefore, compound B-2a was selected for further studies. Wound-healing assays, Transwell chamber assays and breast cancer lung metastasis mouse models demonstrated that B-2a exhibited antimetastatic ability in vitro and in vivo., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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18. Discovery of novel indolin-2-one compounds as potent inhibitors of HsClpP for cancer treatment.
- Author
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Song R, Yang Y, Huang J, Qiao W, Luo B, Ju Y, Yang T, and Luo Y
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Movement drug effects, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Indoles chemical synthesis, Indoles chemistry, Molecular Docking Simulation, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Drug Discovery, Indoles pharmacology, Peptide Hydrolases metabolism, Protease Inhibitors pharmacology
- Abstract
Human caseinolytic protease proteolytic subunit (HsClpP) is a highly conserved serine protease that plays an essential role in cell homeostasis through removal of the damaged and/or misfolded proteins. Recently, due to its critical role in cancer proliferation and metastasis, HsClpP has been considered as a promising target for the cancer treatment. In this paper, through a random screening toward a library of 2086 bioactive chemicals, a novel compound I, 3-(3,5-dibromo-4-hydroxybenzylidene) -5-iodoindolin-2-one, was identified as a potent suppressor of HsClpP. Herein, a series of compound I derivatives were synthesized, and evaluated for their anti-cancer activities on a variety of cancers cells. Through the preliminary biological assay in vitro, including MTT assay and proteolytic activity assay, compound I was identified as the most potent inhibitor. Treatment with compound I impaired the migration of Hela cells. In addition, compound I disrupted the mitochondrial function, and reduced the level of the SDHB and induced the production of the ATF4. In general, compound I is a promising probe of HsClpP for cancer treatment, and is a good lead compound for the development of novel anti-cancer agent., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
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19. Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches.
- Author
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Farag AK, Hassan AHE, Chung KS, Lee JH, Gil HS, Lee KT, and Roh EJ
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Ligands, Molecular Structure, Pyrimidines chemistry, Structure-Activity Relationship, Urea analogs & derivatives, Urea chemistry, Antineoplastic Agents pharmacology, Drug Discovery, Pyrimidines pharmacology, Urea pharmacology
- Abstract
A series of diarylurea derivatives comprising 2,4-diarylpyrimidines were synthesized based on a combination of postulated molecular hybridization design and failed-ligands repurposing approaches, which enabled the discovery of novel potential antiproliferative agents. Towards credible biological evaluation, an in vitro anticancer activity assay was conducted employing a library of 60 cancer cell lines constituting nine panels representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. The results revealed high effectiveness and broad-spectrum anticancer activity of compounds 4m and 4g. Five-dose assay of compounds 4m and 4g proved their high potency that surpassed that of four standard kinase inhibitors FDA-approved anticancer drugs against many cancer cells. Towards the identification of their molecular target, screening of kinase inhibitory profile employing a panel of 51 kinases involved in cancer revealed inhibition of several kinases from the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) kinase family, which might mediate, at least in part, the antiproliferative activity. Molecular docking of 4g into the crystal structure of the Feline McDonough Sarcoma (FMS) kinase predicted that it binds to a pocket formed by the juxtamembrane domain, the catalytic loop, and the αE helix, thus stabilizing the inhibited conformation of the kinase. Flow cytometric study of the cytotoxic effects of compound 4g in A549 cells showed it induces dose- and time-dependent apoptotic events leading to cell death. Collectively, this work presents compound 4g as a potential broad-spectrum anticancer agent against multiple cancer types., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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20. Discovery of new benzhydrol biscarbonate esters as potent and selective apoptosis inducers of human melanomas bearing the activated ERK pathway: SAR studies on an ERK MAPK signaling modulator, ACA-28.
- Author
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Satoh R, Hamada N, Yamada A, Kanda Y, Ishikawa F, Takasaki T, Tanabe G, and Sugiura R
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Benzhydryl Compounds chemical synthesis, Benzhydryl Compounds chemistry, Carbonates chemical synthesis, Carbonates chemistry, Dose-Response Relationship, Drug, Esters chemical synthesis, Esters chemistry, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, MAP Kinase Signaling System drug effects, Melanoma metabolism, Melanoma pathology, Molecular Structure, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Benzhydryl Compounds pharmacology, Carbonates pharmacology, Drug Discovery, Esters pharmacology, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Melanoma drug therapy
- Abstract
The recent discovery that an ERK signaling modulator [ACA-28 (2a)] preferentially kills human melanoma cell lines by inducing ERK-dependent apoptosis has generated significant interest in the field of anti-cancer therapy. In the first SAR study on 2a, here, we successfully developed candidates (2b, 2c) both of which induce more potent and selective apoptosis towards ERK-active melanoma cells than 2a, thus revealing the structural basis for inducing the ERK-dependent apoptosis and proposing the therapeutic prospect of these candidates against ERK-dependent cancers represented by melanoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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21. Discovery of novel aminophosphonate derivatives containing pyrazole moiety as potential selective COX-2 inhibitors.
- Author
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Zhang B, Hu XT, Zhou KM, Yang YS, and Zhu HL
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Cycle drug effects, Cell Proliferation drug effects, Cells, Cultured, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors chemical synthesis, Cyclooxygenase 2 Inhibitors chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Organophosphonates chemical synthesis, Organophosphonates chemistry, Pyrazoles chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Drug Discovery, Organophosphonates pharmacology, Pyrazoles pharmacology
- Abstract
Cyclooxygenase is critical for maintaining physiological functions, whereas overexpression of COX-2 was closely implicated in various cancers. In this study, a series of novel aminophosphonate derivatives containing pyrazole moiety were synthesized with their anti-cancer activity evaluated. In vitro assays of the target compounds showed that Z21 displayed excellent COX-2 inhibitory activity against COX-2 (IC
50 = 0.22 ± 0.04 µM) and anti-proliferative activity against MCF-7 cell (IC50 = 4.37 ± 0.49 µM). The apoptosis induction of compound Z21 was confirmed by flow cytometry and polymerase chain reaction. Further investigation demonstrated that compound Z21 induced apoptosis of MCF-7 cells through a mitochondrion-dependent pathway and involved cell-cycle arrest in G2 phase. Overall, these results provided some new insights into the design of therapeutic drugs for COX-2 inhibitors and indicated the connection between selective COX-2 inhibition and the anti-tumor activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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22. Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study.
- Author
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Wang R, Zhao X, Yu S, Chen Y, Cui H, Wu T, Hao C, Zhao D, and Cheng M
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Focal Adhesion Protein-Tyrosine Kinases metabolism, Humans, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyridines chemical synthesis, Pyridines chemistry, Pyrroles chemical synthesis, Pyrroles chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Wound Healing drug effects, Antineoplastic Agents pharmacology, Drug Discovery, Focal Adhesion Protein-Tyrosine Kinases antagonists & inhibitors, Molecular Docking Simulation, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology, Pyrroles pharmacology
- Abstract
Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC
50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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23. Tubulin inhibitors: Discovery of a new scaffold targeting extra-binding residues within the colchicine site through anchoring substituents properly adapted to their pocket by a semi-flexible linker.
- Author
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Maklad RM, AbdelHafez EMN, Abdelhamid D, and Aly OM
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Colchicine chemical synthesis, Colchicine chemistry, Computer-Aided Design, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Hydrazines chemical synthesis, Hydrazines chemistry, Molecular Structure, Structure-Activity Relationship, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Colchicine pharmacology, Drug Discovery, Hydrazines pharmacology, Tubulin metabolism, Tubulin Modulators pharmacology
- Abstract
Bis-hydrazides 13a-h were designed and synthesized as potential tubulin inhibitors selectively targeting the colchicine site between α- and β-tubulin subunits. The newly designed ring-B substituents were assisted at their ends by 'anchor groups' which are expected to exert binding interaction(s) with new additional amino acid residues in the colchicine site (beyond those amino acids previously reported to interact with reference inhibitors as CA-4 and colchicine). Conformational flexibility of bis-hydrazide linker assisted these 'extra-binding' properties through reliving ligands' strains in the final ligand-receptor complexes. Compound 13f displayed the most promising computational and biological study results in the series: MM/GBSA binding energy of -62.362 kcal/mol (extra-binding to Arg α:221, Thr β:353 & Lys β:254); 34% NCI-H522 cells' death (at 10 µM), IC
50 = 0.073 µM (MTT assay); significant cell cycle arrest at G2/M phase; 11.6% preG1 apoptosis induction and 83.1% in vitro tubulin inhibition (at concentration = IC50 ). Future researchers in bis-hydrazide tubulin inhibitors are advised to consider the 2-chloro-N-(4-substituted-phenyl)acetamide derivatives as compound 13f due to extra-binding properties of their ring B., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Author contributions R.M. Maklad designed target compounds, carried out the molecular modeling studies, performed the chemical synthesis, literature survey, statistical analysis, data collection, analyzed the results wrote the manuscript. ES.M.N. AbdelHafez discussed the synthetic methodology, contacted NCI for cytotoxicity study, discussed biological results & revised the manuscript. D. Abdelhamid discussed the synthetic methodology, discussed the biological results, the conclusion & revised the manuscript. O.M. Aly put the research point (tubulin inhibitors), designed the biological evaluation tests, discussed the synthetic methodology & revised the manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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24. Discovery of novel multi-substituted benzo-indole pyrazole schiff base derivatives with antibacterial activity targeting DNA gyrase.
- Author
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Liu H, Chu ZW, Xia DG, Cao HQ, and Lv XH
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Dose-Response Relationship, Drug, Escherichia coli drug effects, Escherichia coli enzymology, Indoles chemical synthesis, Indoles chemistry, Listeria monocytogenes drug effects, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Pyrazoles chemical synthesis, Pyrazoles chemistry, Salmonella drug effects, Schiff Bases chemical synthesis, Schiff Bases chemistry, Schiff Bases pharmacology, Staphylococcus aureus drug effects, Structure-Activity Relationship, Topoisomerase II Inhibitors chemical synthesis, Topoisomerase II Inhibitors chemistry, Anti-Bacterial Agents pharmacology, DNA Gyrase metabolism, Drug Discovery, Indoles pharmacology, Pyrazoles pharmacology, Topoisomerase II Inhibitors pharmacology
- Abstract
The design and synthesis of novel multi-substituted benzo-indole pyrazole Schiff base derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activities against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella. In addition, we selected 20 compounds for the in vitro antibacterial activities assay of 6 drug-resistant bacteria strains. The result revealed compound 8I-w exhibited excellent antibacterial activity against 4 drug-resistant E. coli bacteria strains with IC
50 values of 7.0, 17.0, 13.5, and 1.0 μM, respectively. In vitro enzyme inhibitory assay showed that compound 8I-w displayed potent inhibition against DNA gyrase with IC50 values of 0.10 μM. The molecular docking model indicated that compounds 8I-w can bind well to the DNA gyrase by interacting with various amino acid residues. This study demonstrated that the compound 8I-w can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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25. Discovery and optimization of novel phenyldiazepine and pyridodiazepine based Aurora kinase inhibitors.
- Author
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Tamizharasan N, Gajendran C, Kristam R, Sulochana SP, Sivanandhan D, Mullangi R, Mathivathanan L, Hallur G, and Suresh P
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Aurora Kinase B metabolism, Azepines chemical synthesis, Azepines chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Mice, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Aurora Kinase B antagonists & inhibitors, Azepines pharmacology, Drug Discovery, Protein Kinase Inhibitors pharmacology
- Abstract
Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora B inhibitors, herein, we described the design, synthesis and evaluation of phenyl/pyridine diazepine analogs. The diazepane aniline pyrimidine (4a) was identified as an initial hit (Aurora B IC
50 6.9 µM). Molecular modeling guided SAR optimization lead to the identification of 8-fluorobenzodiazepine (6c) with single digit nM potency (Aurora B IC50 8 nM). In the antiproliferation assay 6c showed activity across the cell lines with IC50 of 0.57, 0.42, and 0.69 µM for MCF-7, MDA-MB 231, and SkoV3 respectively. In the in vivo PK profile. 6c has shown higher bioavailability (73%) along with good exposure (AUC of 1360 ng.h/mL)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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26. Discovery of novel pyrazoline derivatives containing methyl-1H-indole moiety as potential inhibitors for blocking APC-Asef interactions.
- Author
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Qi PF, Fang L, Li H, Li SK, Yang YS, Qi JL, Xu C, and Zhu HL
- Subjects
- Adenomatous Polyposis Coli Protein chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Indoles chemistry, Mitochondria drug effects, Mitochondria metabolism, Molecular Structure, Protein Binding drug effects, Pyrazoles chemical synthesis, Pyrazoles chemistry, Rho Guanine Nucleotide Exchange Factors antagonists & inhibitors, Rho Guanine Nucleotide Exchange Factors chemistry, Structure-Activity Relationship, Adenomatous Polyposis Coli Protein antagonists & inhibitors, Antineoplastic Agents pharmacology, Drug Discovery, Indoles pharmacology, Pyrazoles pharmacology
- Abstract
A series of novel pyrazoline derivatives containing methyl-1H-indole moiety were discovered as potential inhibitors for blocking APC-Asef interactions. The top hit Q19 suggested potency of inhibiting APC-Asef interactions and attractive preference for human-sourced colorectal cells. It was already comparable with the previous representative and the positive control Regorafenib before further pharmacokinetic optimization. The introduction of methyl-1H-indole moiety realized the Mitochondrial affection thus might connect the impact on the protein-interaction level with the apoptosis events. The molecular docking simulation inferred that bringing trifluoromethyl groups seemed a promising approach for causing more key interactions such as H-bonds. This work raised referable information for further discovery of inhibitors for blocking APC-Asef interactions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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27. Discovery of thiazole-based-chalcones and 4-hetarylthiazoles as potent anticancer agents: Synthesis, docking study and anticancer activity.
- Author
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Farghaly TA, Masaret GS, Muhammad ZA, and Harras MF
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Cycle drug effects, Cell Proliferation drug effects, Cells, Cultured, Chalcones chemical synthesis, Chalcones chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Thiazoles chemical synthesis, Thiazoles chemistry, Antineoplastic Agents pharmacology, Chalcones pharmacology, Drug Discovery, Thiazoles pharmacology
- Abstract
The crucial need for novel antitumor agents with high selectivity toward cancer cells has promoted us to synthesize new series of thiazole-based chalcones and 4-hetarylthiazoles (rigid chalcones). The synthesis of thiazolyl chalcones and 4-hetarylthiazoles and the assertion of their structure are described. Their anti-proliferative activity was estimated against three human cancer cell lines; HepG-2, A549 and MCF-7. 3-(4-Methoxyphenyl)-1-(5-methyl-2-(methylamino)thiazol-4-yl)prop-2-en-1-one (chalcone derivative 3a) showed significant and broad antitumor activity that was more potent than Doxorubicin. In addition, compounds 3d, 3e and 7a displayed potent activity compared to Doxorubicin. Additionally, these compounds were less toxic on normal lung cells WI-38 with high selectivity index. Further study on 3a regarding its effect on the normal cell cycle profile in A549 cells demonstrated cell cycle arrest at the G2/M phase together with rise in the percentage of the apoptotic pre-G1 cells. CDK1/CDK2/CDK4 inhibition assays were carried out on 3a, 3d, 3e and 7a and the results revealed non selective inhibition on the tested CDKs with IC
50 values of 0.78-1.97 µM. Moreover, docking study predicted that 3a, 3d, 3e and 7a can fit in the ATP binding site of CDK1 enzyme. The apoptosis induction potential of 3a, 3d, 3e and 7a was also estimated against some apoptosis markers. Interestingly, they elevated the level of Bax by 6.36-10.12 folds and reduced the expression of Bcl-2 by 1.94-4.12 folds compared to the control. Furthermore, they increased both active caspase-3 and p53 levels by 8.76-10.56 and 6.85-10.36 folds, respectively higher than the control which indicates their potential to induce apoptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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28. Discovery of benzo[cd]indol-2-one and benzylidene-thiazolidine-2,4-dione as new classes of NLRP3 inflammasome inhibitors via ER-β structure based virtual screening.
- Author
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Abdullaha M, Ali M, Kour D, Kumar A, and Bharate SB
- Subjects
- Animals, Benzylidene Compounds chemical synthesis, Benzylidene Compounds chemistry, Cell Line, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Estrogen Receptor beta metabolism, Inflammasomes metabolism, Mice, Molecular Structure, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Structure-Activity Relationship, Thiazolidinediones chemical synthesis, Thiazolidinediones chemistry, Benzylidene Compounds pharmacology, Drug Discovery, Estrogen Receptor beta antagonists & inhibitors, Inflammasomes drug effects, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Thiazolidinediones pharmacology
- Abstract
The structure-guided virtual screening (VS) has proved to be successful strategy in identification of new scaffolds for biological targets. The overactivity of NLRP3 inflammasome has been implicated in variety of inflammatory diseases including Alzheimer's disease. The up-regulation of estrogen-receptor β (ER-β) activity has been directly linked with inhibition of NLRP3 inflammasome activity. In the present study, we report discovery of new NLRP3 inflammasome inhibitors via ER-β crystal structure (PDB: 5TOA) guided virtual screening of 20,000 compound library. For experimental validation, top 10 ligands were selected based on structure novelty, docking score, prime MMGB/SA binding affinity and interaction pattern analysis. Amongst the tested compounds, three thiazolidin-4-ones IIIM-1268, IIIM-1269 and IIIM-1270 and benzo[cd]indol-2-one IIIM-1266 have shown 73, 69, 75 and 77% suppression of IL-1β release in mouse macrophages (J774A.1 cells) at 10 µM. Benzylidene-thiazolidine-2,4-diones IIIM-1268 and IIIM-1270 inhibited IL-1β release with IC
50 of 2.3 and 3.5 µM and also significantly decreased the protein expression level of mature form of IL-1β in western-blot analysis. IIIM-1266 and IIIM-1270 displayed bidentate H-bonding with Arg 346 and Glu 305 residues in the active site of ER-β; and they also strongly occupied the ADP-binding site of NLRP3 protein. The results presented herein, indicate that ER-β guided VS can be successfully used to identify new NLRP3 inflammasome inhibitors, which may have potential in the development of novel anti-Alzheimer agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2020
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29. Discovery of 5-naphthylidene-2,4-thiazolidinedione derivatives as selective HDAC8 inhibitors and evaluation of their cytotoxic effects in leukemic cell lines.
- Author
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Tilekar K, Upadhyay N, Jänsch N, Schweipert M, Mrowka P, Meyer-Almes FJ, and Ramaa CS
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemistry, Histone Deacetylases, Humans, Molecular Docking Simulation, Structure-Activity Relationship, Thiazolidinediones chemistry, Antineoplastic Agents pharmacology, Drug Discovery, Enzyme Inhibitors pharmacology, Repressor Proteins antagonists & inhibitors, Thiazolidinediones pharmacology
- Abstract
Histone deacetylases (HDACs) are being explored as a therapeutic target for interventions in different types of cancer. HDAC8 is a class I HDAC that is implicated as a therapeutic target in various indication areas, including different types of cancer and particularly childhood neuroblastoma. Most previously described HDAC8-selective inhibitors contain a hydroxamate function as zinc binding group (ZBG) to confer potency. However, hydroxamate class HDAC inhibitors have raised increasing concerns about their mutagenic character. Therefore, non-hydroxamate based inhibitors could prove to be safer than hydroxamates. In the present work, a series of novel 5-naphthylidene-2,4-thiazolidinedione was designed and evaluated as potential antiproliferative agents targeting selectively HDAC8 enzyme. Eleven novel derivatives were synthesized, purified and characterized by spectroscopic techniques. Compounds 3k and 3h was found to be most potent selective inhibitors of HDAC8 with IC
50 values of 2.7 μM and 6.3 μM respectively. 3a to 3i was found to be most cytotoxic in leukemic cell lines. 3a and 3 h both were found to induce apoptosis and cause cell cycle arrest in G2/M phase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2020
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30. Synthesis of the vasoactive intestinal peptide (VIP)
- Author
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Viktor Mutt, Cynthia Yang Lin, Yakir S. Klausner, and Miklos Bodanszky
- Subjects
chemistry.chemical_classification ,Chymotrypsin ,biology ,Arginine ,Tetrapeptide ,Chemistry ,Stereochemistry ,Organic Chemistry ,Vasoactive intestinal peptide ,Peptide ,Trypsin ,Biochemistry ,Paper chromatography ,Drug Discovery ,Aspartic acid ,biology.protein ,medicine ,Molecular Biology ,medicine.drug - Abstract
The protected heptapeptide derivative t -butyloxycarbonyl- l -threonyl-β-benzyl- l -aspartyl- l -asparaginyl- O -benzyl- l -tyrosyl- l -threonyl-nitro- l -arginyl- l - leucine methyl ester was prepared by stepwise chain lengthening. The protecting groups on the side chains of arginine, tyrosine, and aspartic acid residues were removed by hydrogenolysis and the partially deprotected heptapeptide ester converted to the hydrazide, an intermediate in the synthesis of the (porcine) vasoactive intestinal peptide (VIP). After the removal of the tert -butyloxycarbonyl group, the heptapeptide ester was exposed to the action of trypsin which split off its C-terminal residue, l -leucine methyl ester. The hexapeptide was then exposed to chymotrypsin, which cleaved it into an acidic, and a basic fragment. The former was, under the conditions used, indistinguishable on paper chromatography and paper electrophoresis from the tetrapeptide threonyl-aspartyl-asparaginyl-tyrosine which had previously been isolated from natural VIP, of which it comprises the sequence 7–10. Similarly, the basic fragment was indistinguishable from threonyl-arginine, the sequence 11–12 of VIP. This intestinal peptide increases visceral blood flow and reduces blood pressure in the dog, and also causes relaxation of different smooth muscle preparations, e.g., the trachea of guinea pigs. The principal aim of the present synthesis is to provide independent evidence for the sequence of (porcine) VIP.
- Published
- 1973
31. Phytochemical composition, bioactive properties, and toxicological profile of Tetrapleura tetraptera
- Author
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ThankGod Anyamele, Promise Nnaemeka Onwuegbuchu, Eziuche Amadike Ugbogu, and Chibuike Ibe
- Subjects
Organic Chemistry ,Drug Discovery ,Molecular Biology ,Biochemistry - Abstract
The use of medicinal plants has gained renewed wide popularity in Africa, Asia, and most parts of the world because of the decreasing efficacy of synthetic drugs. Thus, natural products serve as a potent source of alternative remedy. Tetrapleura tetraptera is a medicinal plant with cultural and traditional significance in West Africa. In addition to the plant being commonly used as a spice in the preparation of traditional spicy food for postpartum care it is also widely used to constitute herbal concoctions and decoctions for treatment of diseases. This review aimed to provide an up-to-date information on the ethnomedicinal uses, pharmacological activities and phytoconstituents of T. tetraptera. Preclinical studies regarding the plant's toxicity profile were also reviewed. For this updated review, literature search was done on PubMed, Science Direct, Wiley, and Google Scholar databases using the relevant keywords. The review used a total of 106 papers that met the inclusion criteria from January 1989 - February 2022 and summarised the bioactivities that have been reported for the rich phytoconstituents of T. tetraptera studied using various chemical methods. Considering the huge report, the review focused on the antimicrobial and antiinflammatory activities of the plant extracts and isolated compounds. Aridan, aridanin and several bioactive compounds of T. tetraptera have shown pharmacological activities though their mechanisms of action are yet to be fully understood. This study also highlighted the influence of plant parts and extraction solvents on its biological activities. It also presented data on the toxicological profile of the plant extracts using different models. From cultural uses to modern pharmacological research the bioactive compounds of T. tetraptera have proved effective in infectious disease management. We hope that this paper provided a robust summary of the biological activities and toxicological profile of T. tetraptera, thus calling for more research into the pharmacological and pharmacokinetic activities of natural products to help combat the growing threat of drug resistance and provide guidelines for their ethnomedicinal uses.
- Published
- 2022
32. Research progress on the structure and biological diversities of 2-phenylindole derivatives in recent 20 years.
- Author
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Wu, Pan, Zhao, Junxi, Shen, Xuelian, Liang, Xiaoxia, He, Changliang, Yin, Lizi, Xu, Funeng, Li, Haohuan, and Tang, Huaqiao
- Subjects
- *
MORPHOLOGY , *BIODIVERSITY , *DRUG discovery , *ANTIPARASITIC agents , *ANTIVIRAL agents , *CENTRAL nervous system , *STRUCTURE-activity relationships , *INDOLE compounds - Abstract
[Display omitted] The privileged structure binds to multiple receptors with high affinity, which is helpful to the development of new bioactive compounds. Indole is classified as a privileged structure, which may be one of the most important structural categories in drug discovery. As a special subset of indole compounds, 2-phenylindole seems to be one of most promising forerunners of drug development. In this paper, 106 articles were referenced to review the structural changes, biological activities and structure–activity relationship of compounds in recent 20 years, and classified them according to their pharmacological activities, from several aspects, including anticancer, antibacterial, anti-inflammatory, analgesic, antiviral, anti-parasite, the biological activities target to central nervous system, et al. It also points out the importance of artificial intelligence (AI) technology in discovery of new 2-phenylindole compounds in a broader prospect. This review will provide some ideas for researchers to develop new indole drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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33. Synthesis and antioxidant ability of 6,6′-diamino-6,6′-dideoxytrehalose
- Author
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Qing Li, Gang Wang, Zhou Tingting, Qiuhong Chen, Fang Dong, Wenqiang Tan, and Zhanyong Guo
- Subjects
Antioxidant ,DPPH ,medicine.medical_treatment ,Disaccharide ,02 engineering and technology ,01 natural sciences ,Biochemistry ,Antioxidants ,chemistry.chemical_compound ,Picrates ,Superoxides ,Drug Discovery ,medicine ,Organic chemistry ,Hydrogen peroxide ,Molecular Biology ,Amination ,Hydroxyl Radical ,010405 organic chemistry ,Biphenyl Compounds ,Organic Chemistry ,Trehalose ,Hydrogen Peroxide ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Biphenyl compound ,chemistry ,Hydroxyl radical ,0210 nano-technology - Abstract
In order to study the influence of amino group on antioxidant activity of oligosaccharides, an amino disaccharide, 6,6'-diamino-6,6'-dideoxytrehalose (DAMDT) was successfully prepared in this paper, and its antioxidant activities against DPPH, superoxide, hydrogen peroxide, and hydroxyl radicals, and reducing power were evaluated, respectively. The results indicated that DAMDT had better antioxidant activity than trehalose at any tested concentration. The influence of amino group on antioxidant activity of disaccharides is positive based on the results in this paper, and amination should be an effective method to improve the bioactivity of saccharides.
- Published
- 2017
34. Natural neuroprotective alkaloids from Stephania japonica (Thunb.) Miers
- Author
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Jingyu Liu, Bin Lin, Wei Li, Ning Li, Gang Chen, Tingyu Hao, Jiao Xiao, Yue Hou, Junyu Song, and Jikai Xu
- Subjects
Male ,Traditional Chinese medicine ,01 natural sciences ,Biochemistry ,Neuroprotection ,Japonica ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Alkaloids ,Stephania japonica ,Drug Discovery ,medicine ,Hasubanan ,Animals ,Molecular Biology ,Stroke ,Neuroinflammation ,Stephania ,Biological Products ,biology ,Traditional medicine ,010405 organic chemistry ,Chemistry ,Alkaloid ,Organic Chemistry ,Infarction, Middle Cerebral Artery ,Cerebral Infarction ,biology.organism_classification ,medicine.disease ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,Brain Injuries ,Nervous System Diseases - Abstract
Modulating inflammatory responses after stroke can prevent brain injury and, therefore, improve neurological outcome. Stephania japonica (Thunb.) Miers is a Chinese folk medicine with the function of dispelling the "wind and blockage" in the human body according to the Chinese medicine theory, in which the symptoms of stroke are caused by the "wind and blockage" in the body. In this paper, we for the first time linked S. japonica to stroke by clarifying fifteen alkaloidal constituents including five undescribed (1-5) ones and screening out six hasubanan type alkaloids (1-4, 7, 15) that elicited stronger anti-neuroinflammatory activities than the positive drug. Moreover, the total alkaloid fraction (ASJ) with previously undescribed 3 as the main component was subject to the in vivo evaluation of the protective effect in the MCAO-induced brain injury. The results showed that ASJ exhibited potent protective effect against brain injury in the MCAO rat model. The results reported in this paper suggested that the hasubanan alkaloids from S. japonica would be an important molecular source for discovering novel therapeutic agents for neuroinflammation-related diseases, such as stroke diseases.
- Published
- 2019
35. Synthesis of some novel 8-(4-Alkylpiperazinyl) caffeine derivatives as potent anti-Leishmania agents
- Author
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Mohammad Navid Soltani Rad, Somayeh Behrouz, Kamran Zokaei, Marzieh Behrouz, Ali Ghanbariasad, and Elham Zarenezhad
- Subjects
Molecular Docking Simulation ,Structure-Activity Relationship ,Molecular Structure ,Purines ,Caffeine ,Organic Chemistry ,Drug Discovery ,Molecular Biology ,Biochemistry ,Piperazine ,Leishmania major - Abstract
In this paper, the synthesis, characterization and the leishmanicidal assessments of novel 8-(4-alkylpiperazinyl) caffeine derivatives have been described. These compounds are new caffeine hybrid molecules that are structurally composed of three compartments comprising caffeinyl, piperazinyl and N-alkyl/aryl residues. The synthesis was carried out through the bromination of caffeine via NBS to attain the 8-bromocaffeine (8-BC) followed by the S
- Published
- 2022
36. Highly selective fluorescent probe based on AIE for identifying cysteine/homocysteine
- Author
-
Wei Wang, Zihao Peng, Min Ji, Junqing Chen, and Peng Wang
- Subjects
Organic Chemistry ,Drug Discovery ,Humans ,Cysteine ,Molecular Biology ,Biochemistry ,Glutathione ,Homocysteine ,Fluorescent Dyes ,HeLa Cells - Abstract
Cysteine (Cys) and homocysteine (Hcy) are involved in maintaining homeostasis in the body and are relevant to various diseases. While the level of Cys and Hcy is much lower than GSH in the living system, which leads to a major challenge to selectively identify Cys/Hcy in the presence of large amounts of GSH. In this paper, an AIE fluorescent probe SQM-NBD was obtained by connecting NBD to the hydroxyl group of the fluorophore SQM-OH for selective detection of Cys/Hcy. Probe SQM-NBD had no fluorescence itself. But, under the disturbance of GSH, the fluorescence signal of probe SQM-NBD could be turned on by Cys/Hcy. The study of the response mechanism showed that probe SQM-NBD could release both SQM-OH and Cys/Hcy-NBD after reacting with Cys/Hcy. While Cys/Hcy continued to quench the fluorescence of SQM-OH through the combination of Michael addition and the ion rich environment, resulting in only the fluorescence signal of Cys/Hcy-NBD being observed. SQM-NBD appeared superior sensitivity to Cys/Hcy, with LOD of 54 nM and 72 nM, respectively. Significantly, probe SQM-NBD realized the application of fluorescence imaging of Cys/Hcy in HeLa cells, indicating that probe SQM-NBD has the potential for Cys/Hcy identification under physiological and pathological conditions.
- Published
- 2022
37. Research progress on the structure and biological diversities of 2-phenylindole derivatives in recent 20 years
- Author
-
Pan, Wu, Junxi, Zhao, Xuelian, Shen, Xiaoxia, Liang, Changliang, He, Lizi, Yin, Funeng, Xu, Haohuan, Li, and Huaqiao, Tang
- Subjects
Organic Chemistry ,Drug Discovery ,Molecular Biology ,Biochemistry - Abstract
The privileged structure binds to multiple receptors with high affinity, which is helpful to the development of new bioactive compounds. Indole is classified as a privileged structure, which may be one of the most important structural categories in drug discovery. As a special subset of indole compounds, 2-phenylindole seems to be one of most promising forerunners of drug development. In this paper, 106 articles were referenced to review the structural changes, biological activities and structure-activity relationship of compounds in recent 20 years, and classified them according to their pharmacological activities, from several aspects, including anticancer, antibacterial, anti-inflammatory, analgesic, antiviral, anti-parasite, the biological activities target to central nervous system, et al. It also points out the importance of artificial intelligence (AI) technology in discovery of new 2-phenylindole compounds in a broader prospect. This review will provide some ideas for researchers to develop new indole drugs.
- Published
- 2023
38. Design, synthesis and biological activity evaluation of a series of bardoxolone methyl prodrugs
- Author
-
Lianqi Liu, Xingquan Pan, Fei Xie, Xin Xu, Dian Xiao, Junhai Xiao, and Xinbo Zhou
- Subjects
Kelch-Like ECH-Associated Protein 1 ,NF-E2-Related Factor 2 ,Organic Chemistry ,Drug Discovery ,Humans ,Prodrugs ,Oleanolic Acid ,Molecular Biology ,Biochemistry ,Signal Transduction - Abstract
Bardoxolone methyl (CDDO-Me) has exhibited positive therapeutic effects in clinical trials for diabetic nephropathy (DN), but serious safety risks in the heart exist because of the potential off-target response resulting from the highly active part of CDDO-Me. Herein, we reported a novel strategy to prepare Cathepsin B (CTSB) cleavable and improved water-soluble prodrugs of CDDO-Me. CTSB linkers connection to the highly active α-cyano-α, β-unsaturated ketone (CUK) part of CDDO-Me with the incorporation of polyethylene glycol (PEG) moieties, provided a series of prodrugs of CDDO-Me without CUK part exposure. Theoretically, these prodrugs shielding CUK part can be stably circulated and finally cleaved by CTSB in lysosomes to release CDDO-Me. In this paper, preliminary curative effects and safety of all prodrugs were determined. Wherein, prodrug 20 displayed relatively better activities than other prodrugs in inhibiting the release of NO from RAW264.7 cells, activating Keap1-Nrf2-ARE signaling pathway and inhibiting NF-κB signaling pathway, which were comparable to CDDO-Me. More importantly, prodrug 20 showed relatively lower human ether-a-go-go-related gene (hERG) inhibitory activity compared with CDDO-Me, which demonstrated prodrug 20 might be safer than CDDO-Me. In conclusion, the novel strategy of shielding CUK part with CTSB linkers provided a new idea for solving the limitations of CDDO-Me in clinical application.
- Published
- 2022
39. Development of a nitroreductase-dependent theranostic payload for antibody-drug conjugate
- Author
-
Zheng Su, Fei Xie, Xin Xu, Lianqi Liu, Dian Xiao, Xinbo Zhou, and Song Li
- Subjects
Immunoconjugates ,Cell Line, Tumor ,Molecular Probes ,Organic Chemistry ,Drug Discovery ,Humans ,Antineoplastic Agents ,Nitroreductases ,Precision Medicine ,Molecular Biology ,Biochemistry - Abstract
Antibody-drug conjugates are gradually revolutionizing anticancer therapy. Payload is one of the most crucial components of ADC for high antitumor activity. However, there is no direct and real-time monitoring method for the intracellular release mechanism of the payload. Herein, we developed a theranostic payload that possessed dual functions of therapy and imaging. This payload consisted of the classic payload MMAE and the novel nitro-coumarin probe reported for the first time, which has the dual characteristics of electron transfer ability and the on-off fluorescence property. In this paper, the theranostic property of the novel payload has been preliminarily demonstrated. The fluorescence intensity of the payload in target cells greatly increased approximately 9 times in 120 min through the high content analysis, and the intracellular distribution of the payload could be directly monitored by a confocal microscope. In in vitro cytotoxicity assays, the payload showed broad-spectrum and high antitumor activity (0.09 nM to 1.2 nM), which was equivalent to the MMAE (0.06 nM to 1.1 nM). Moreover, the ADC loaded with L-233 maintained the theranositc property. In conclusion, our work developed a theranostic payload for the first time and provides a new direct and real-time monitoring method for intracellular studies of ADC payloads.
- Published
- 2022
40. Water-soluble dual lysosome/mitochondria-targeted fluorescent probe for detection of SO2 in water, food, herb, and live cells
- Author
-
Zhenming, Dong, Wenfang, Liang, Yuxin, Dong, Hong, Ren, and Yu, Wang
- Subjects
Plants, Medicinal ,Organic Chemistry ,Drug Discovery ,Water ,Sulfur Dioxide ,Colorimetry ,Lysosomes ,Molecular Biology ,Biochemistry ,Food Analysis ,Fluorescent Dyes ,Mitochondria ,HeLa Cells - Abstract
In this paper, we present a new donor-π bridge-acceptor type fluorescent probe, MIB, which bears two organelle-targeted groups, namely positively charged benzothiazole group for mitochondria and morpholine moiety for lysosomes. In aqueous solution, the nucleophilic addition of HSOsub3/subsup-/sup(as SOsub2/subdonor) to MIB blocked its long-range π-conjugation and ICT process and resulted in significant optical signal changes (blue-shifted UV absorbance and fluorescence), which enabled colorimetric and ratiometric fluorescent detection of HSOsub3/subsup-/supwith high selectivity and sensitivity (detection limit of 63.15 nM). MIB offers obvious advantages of good water-solubility, fast response time (within 1 min), unique dual lysosome/mitochondria targeting capability and has been applied to the sensing of endogenous and exogenous SOsub2/subin live cells through fluorescent imagingsub./subIn addition, the proposed probe has been utilized for the determination of bisulfite in real water, food and herbal medicine samples, showing good recovery (91.45 % - 109.3 %) and precision.
- Published
- 2022
41. The Oxyanion Hole in Serine beta-Lactamase Catalysis: Interactions of Thiono Substrates with the Active Site
- Author
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Kieran Curley and R. F. Pratt
- Subjects
Chymotrypsin ,biology ,Chemistry ,Stereochemistry ,Organic Chemistry ,Active site ,Substrate (chemistry) ,Serine hydrolase ,Biochemistry ,Serine ,Acylation ,Tetrahedral carbonyl addition compound ,Drug Discovery ,biology.protein ,Oxyanion hole ,Molecular Biology - Abstract
Both functional and structural studies of serine beta-lactamases indicate the existence of an oxyanion hole at the active site with an important role in catalysis. The functional presence of the oxyanion hole is demonstrated by the previous observation that thiono-beta-lactams are very poor substrates of beta-lactamases (B. P. Murphy, and R. F. Pratt, 1988, Biochem. J. 256, 669-672) and in the present paper by the inability of these enzymes to catalyze hydrolysis of a thiono analog of a depsipeptide substrate. This thiono effect was first noted and interpreted in regard to classical serine hydrolases although the chemical basis for it has not been firmly established either in those enzymes or in beta-lactamases. In this paper a computational approach to a further understanding of the effect has been taken. The results for a class C beta-lactamase show that the deacylation tetrahedral intermediate interacted more strongly with the enzyme with an O(-) placed in the oxyanion hole than an S(-). On the other hand, the converse was true for acylation tetrahedral intermediate species, a result distinctly not in accord with experiment. These results indicate that the thiono effect does not arise from unfavorable interactions between enzyme and thiono substrate at the tetrahedral intermediate stage but must be purely kinetic in nature, i.e., arise in a transitional species at an early stage of the acylation reaction. The same conclusion as to the origin of the thiono effect was also indicated by a less extensive series of calculations on a class A beta-lactamase and on chymotrypsin.
- Published
- 2001
42. Discovery of a novel and selective cathepsin L inhibitor with anti-metastatic ability in vitro and in vivo against breast cancer cells
- Author
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Yanchun Li, Jinyu Men, Xinhui Ruan, Dongyue Liu, Chunyang Zou, Xinyu Ai, Lei Sheng, Lei Yuan, Lili Ma, Yutong Liu, Enlong Ma, Weixia Li, and Haihan Liu
- Subjects
Cathepsin L ,Druggability ,Antineoplastic Agents ,Cysteine Proteinase Inhibitors ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Humans ,Molecular Biology ,Cell Proliferation ,Cathepsin ,Natural product ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Biological activity ,In vitro ,biology.protein ,Female ,Drug Screening Assays, Antitumor ,Cysteine - Abstract
Asperphenamate is a natural product that has attracted considerable interest from researchers worldwide. In the last decade, aiming to increase the biological activity and improve druggability, modifications of the A-ring moiety in asperphenamate have been performed. Our laboratory has also recently reported functional derivatizations of the A ring and studied its effect on the inhibition of cysteine cathepsin L. However, the functional significance of the B-ring fragment toward cathepsin L has not been evaluated thus far. In this paper, forty-four derivatives of the B-ring substituted with different N-phenylsulfonyl groups were designed and synthesized. Among them, the paratrifluromethyl analog B-2a and the 2, 4-difluoro-5-chloro derivative B-11b showed more potent inhibitory activity against cathepsin L than the control compound, ABR, which displayed the strongest inhibitory effect on cathepsin L and S among all reported asperphenamate derivatives. In particular, compound B-2a showed more pronounced selectivity against cathepsin L than the other derivatives. Molecular docking revealed that the N-phenylsulfonylamide moiety was vital for the interactions between B-2a and cathepsin L. Moreover, B-2a displayed no toxicity against normal cells. Therefore, compound B-2a was selected for further studies. Wound-healing assays, Transwell chamber assays and breast cancer lung metastasis mouse models demonstrated that B-2a exhibited antimetastatic ability in vitro and in vivo.
- Published
- 2021
43. Design, synthesis, biological screening and molecular docking studies of novel multifunctional 1,4-di (aryl/heteroaryl) substituted piperazine derivatives as potential antitubercular and antimicrobial agents
- Author
-
Bruktawit Mekonnen Sanka, Dereje Mamo Tadesse, Endale Teju Bedada, Ephriem T. Mengesha, and Neelaiah Babu G.
- Subjects
Staphylococcus aureus ,Antifungal Agents ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Drug Evaluation, Preclinical ,Microbial Sensitivity Tests ,Mycobacterium tuberculosis ,Biochemistry ,Piperazines ,Anti-Bacterial Agents ,Molecular Docking Simulation ,Structure-Activity Relationship ,Fusarium ,Drug Design ,Drug Discovery ,Escherichia coli ,Aspergillus niger ,Molecular Biology - Abstract
In this paper, two series of novel multifunctional 1, 4-di (aryl/heteroaryl) substituted piperazine derivatives (6a-d7a-d) were synthesized, characterized, and evaluated for their antitubercular, antibacterial, and antifungal activities. A step-wise reduction, bromination and substitution reactions on various aldehydes resulted in alcohols (2a-d), bromides (3a-d), and titled novel compounds (6a-d7a-d) in moderate to good yields (48-85%). The novel compounds were evaluated for their antitubercular and antimicrobial activities. Compound 7a exhibited promising antitubercular activity (MIC: 0.65 µg/mL) almost equal to the Rifampicin, while the rest of the compounds were moderately active against MTB H37Rv except 6b. Compounds 7a and 6b showed good activity against tested fungal pathogens. Compounds 7a and 7b were proven as the best bacterial agents. Molecular docking studies were in agreement with the in-vitro results. Docking analyses show that all the synthesized molecules bind to the target protein Mtb RNAP (PDB ID: 5UHC) fairly strongly. All the compounds were evaluated for their in vitro cytotoxicity effect using the MTT assay method against human cancer cell line MCF-7. The compounds demonstrated growth inhibitory effect on the cell line with significant IC
- Published
- 2021
44. Characterization, quantitation, similarity evaluation and combination with Na+,K+-ATPase of cardiac glycosides from Streblus asper
- Author
-
Jiradej Manosroi, Feng Feng, Yun-Hui Xu, Jie Zhang, Haopeng Sun, Yidan Bai, Zijian Xie, Toshihiro Akihisa, Wenyuan Liu, and Wanfang Zhu
- Subjects
chemistry.chemical_classification ,biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Glycoside ,Streblus asper ,Biological activity ,Moraceae ,biology.organism_classification ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Similarity (network science) ,Drug Discovery ,Enzyme kinetics ,Na+/K+-ATPase ,Molecular Biology ,IC50 - Abstract
Streblus asper Lour. (Moraceae) is a medicinal plant in Asian countries including India and Thailand, possessing activities of anti-tumor, anti-allergy, anti-parasitic and anti-bacterial. In this paper, characterization, quantitation and similarity evaluation of cardiac glycosides in different parts of S. asper were investigated by HPLC-Q-TOF-MS and chemometric methods. Then, the inhibition of Na+,K+-ATPase activity by the compounds isolated from S. asper was measured. Meanwhile, enzyme kinetics and molecular docking were determined to exhibit the combination modes between cardiac glycosides and Na+,K+-ATPase. As a result, twenty peaks of cardiac glycosides were assigned. Strophanthidin-3-O-α- l -rhamnopyranosyl-(1 → 4)-6-deoxy-β- d -allopyranoside (1), glucostrebloside (2), strebloside (4) and mansonin (8) with a significant activity of inhibiting Na+,K+-ATPase (IC50 7.55–13.60 μM) were chosen for the determination of enzyme kinetics, exhibiting anticompetitive inhibitory characteristics towards Na+,K+-ATPase. Compound 4 could reasonably bind to the active sites of Na+,K+-ATPase, proved by molecular docking. Furthermore, the contents of the major compounds in four different parts of S. asper were extremely different, analyzed by chemometric methods, similarity analysis and principle compounds analysis. All these findings indicated that the contents of major compounds in different parts of S. asper were extremely different with a significant activity of inhibiting Na+,K+-ATPase, providing a reference for determination of effective part and administered dosage. The combination modes between cardiac glycosides and Na+,K+-ATPase were also revealed by enzyme kinetics and molecular docking, which provided a basis for further study of pharmacological activity.
- Published
- 2019
45. New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study
- Author
-
Joachim Kusz, Ewa Chodurek, Krzysztof Marciniec, Janusz Kasperczyk, Monika Kadela-Tomanek, Justyna Trynda, Bartosz Pawełczak, Elwira Chrobak, Stanisław Boryczka, Joanna Wietrzyk, Ewa Bębenek, and Piotr Paduszyński
- Subjects
Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Phosphates ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Tumor Cells, Cultured ,Humans ,Epidermal growth factor receptor ,Binding site ,Molecular Biology ,Transcription factor ,Density Functional Theory ,Cell Proliferation ,Betulin ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Topoisomerase ,Organic Chemistry ,Triterpenes ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,Docking (molecular) ,Cell culture ,biology.protein ,Drug Screening Assays, Antitumor - Abstract
Betulin derivatives exhibit an antiproliferative activity and have been tested for many cancer cell lines. This paper describes a new series of 3-phosphate derivatives of betulin bearing different substituents at C28 position. The synthesized compounds were tested in vitro for their antiproliferative effect against human leukemia (MV-4-11 and CCRF/CEM), lung carcinoma (A549), prostate cancer (DU 145), melanoma (Hs 294T) cell lines, and murine leukemia P388. To explore the possible mechanism of anticancer activity for the most in vitro active compounds (4, 5, 7 and 8) and betulin, molecular docking was performed to the binding sites of potential anticancer targets, described for the various triterpene derivatives, including topoisomerase I and II, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR), transcription factor NF-κB, anti-apoptotic protein Bcl-2 and peroxisome proliferator-activated receptor (PPARγ). According to the results of the docking, the best fit to the binding pocket of PPARγ was shown by compound 4.
- Published
- 2019
46. Synthesis, molecular modeling and BACE-1 inhibitory study of tetrahydrobenzo[b] pyran derivatives
- Author
-
Reshma Chowdary, Sheshagiri R. Dixit, Vijaya K. Bhaskar, and Shrinivas D. Joshi
- Subjects
Molecular model ,Ionic Liquids ,Alcohol ,01 natural sciences ,Biochemistry ,Aldehyde ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Catalytic Domain ,Drug Discovery ,Humans ,Protease Inhibitors ,Molecular Biology ,Pyrans ,Malononitrile ,chemistry.chemical_classification ,Aldehydes ,Binding Sites ,biology ,010405 organic chemistry ,Organic Chemistry ,Active site ,Combinatorial chemistry ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Pyran ,Ionic liquid ,biology.protein ,Amyloid Precursor Protein Secretases - Abstract
β-Secretase (BACE1) has been broadly documented as one of the possible therapeutic targets for the treatment of Alzheimer's disease. In this paper, we report the synthesis and the for β-secretase (BACE-1) inhibitory activity of new series of tetrahydrobenzo [b] pyran derivatives. One-pot synthesis of tetrahydrobenzo [b] pyrans was carried out by condensing aromatic aldehyde, malononitrile and 1,3-cyclohexanedione using ionic liquid 1-butyl-3-methyl imidazolium chloride ([bmIm]Cl-) in aqueous alcohol media. The addition of alcohol and water in the ratio of 1:2 keeps all the reactants in solution which facilitates the reaction and makes the product formation very easy. The synthesized compounds were subjected to BACE1 inhibition assay and six compounds, 4d, 4e, 4f, 4h, 4i, and 4p have shown significant IC50 values at micromolar level. Among these six active compounds, 4e was a potential inhibitor with its IC50 value in nanomolar range. All the synthesized compounds were docked onto the active site of β-Secretase enzyme.
- Published
- 2019
47. Identification and Structure–Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)
- Author
-
Dali Yin, Jing Jin, Xiaoguang Chen, Jinping Hu, Xiaojian Wang, Yonghui Chen, Qiumu Xi, Yan Li, Tianqi Liu, and Wenqiang Jia
- Subjects
010405 organic chemistry ,Chemistry ,Sphingosine-1-phosphate receptor ,Lymphocyte ,Organic Chemistry ,Oxadiazole ,Pharmacology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,medicine.anatomical_structure ,Pharmacokinetics ,Drug Discovery ,medicine ,Potency ,Structure–activity relationship ,Selectivity ,Receptor ,Molecular Biology - Abstract
Agonism of S1P1 receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P1 modulators. In this paper we described a series of oxadiazole-based S1P1 direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P1 receptor and favorable selectivity against S1P3 receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16-3b and the activated S1P1 model was also studied.
- Published
- 2019
48. Iridoids and sesquiterpenoids from Valeriana jatamansi and their anti-influenza virus activities
- Author
-
Li-Qiu, Quan, Yan, Zhou, Dan, Liu, Chin-Ho, Chen, Hong-Mei, Li, and Rong-Tao, Li
- Subjects
Influenza A Virus, H1N1 Subtype ,Molecular Structure ,Valerian ,Influenza A Virus, H3N2 Subtype ,Organic Chemistry ,Drug Discovery ,Iridoids ,Plant Roots ,Sesquiterpenes ,Molecular Biology ,Biochemistry ,Nardostachys - Abstract
Twenty-one new iridoids, jatamansidoids A-U (1-12, 21-26, 32, 35 and 36), two new natural ones, jatamansidoids V (37) and W (38), eighteen known ones (13-20, 27-31, 33 and 34), together with three patchoulol-type sesquiterpenoids (39-41), were isolated from the roots and rhizomes of Valeriana jatamansi. Structurally, compounds 1-7 were the first examples of iridoids from V. jatamansi with unique α, β, γ, δ-unsaturated aldehyde fragment between C-11, C-4, C-5, C-9 and C-8; compound 8 was an unprecedented iridoid derivative with a methyl group (Me-10) at C-1, rather than C-8, and its plausible biogenetic pathway was proposed in this paper; compounds 22 and 23 were the first examples of Δ
- Published
- 2022
49. Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and evaluation of selective non-pteridine analogues as antitubercular agents
- Author
-
Mymoona Akhter, Omprakash Tanwar, Kalicharan Sharma, M. S. Zaman, Shakir Ali, Shweta Sharma, and Mohammad Mumtaz Alam
- Subjects
0301 basic medicine ,medicine.drug_class ,Population ,Antitubercular Agents ,Microbial Sensitivity Tests ,Antimycobacterial ,01 natural sciences ,Biochemistry ,Molecular Docking Simulation ,Structure-Activity Relationship ,03 medical and health sciences ,Bacterial Proteins ,Catalytic Domain ,parasitic diseases ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,heterocyclic compounds ,Enzyme Inhibitors ,education ,Molecular Biology ,education.field_of_study ,Virtual screening ,Binding Sites ,010405 organic chemistry ,Chemistry ,Pteridines ,Organic Chemistry ,Hydrogen Bonding ,Mycobacterium tuberculosis ,respiratory system ,bacterial infections and mycoses ,Protein Structure, Tertiary ,0104 chemical sciences ,Tetrahydrofolate Dehydrogenase ,030104 developmental biology ,Docking (molecular) ,Drug Design ,Nucleic acid ,Pteridine ,medicine.drug - Abstract
Tuberculosis is an infectious disease that affects millions of population every year. Mtb-DHFR is a validated target that is vital for nucleic acids biosynthesis and therefore DNA formation and cell replication. This paper report identification and synthesis of novel compounds for selective inhibition of Mtb-DHFR and unleash the selective structural features necessary to inhibit the same. Virtual screening of databases was carried out to identify novel compounds on the basis of difference between the binding pockets of the two proteins. Consensus docking was performed to improve upon the results and best ten hits were selected. Hit 1 was subjected to analogues design and the analogues were docked against Mtb-DHFR. From the docking results 11 compounds were selected for synthesis and biological assay against H37Rv. Most potent compound (IND-07) was tested for selectivity using enzymatic assay against Mtb-DHFR and h-DHFR. The compounds were found to have good inhibitory activity (25-200 µM) against H37Rv and in enzyme assay against Mtb-DHFR and h-DHFR the compound was found selective towards Mtb-DHFR with selectivity index of 6.53. This work helped to identify indole moiety as novel scaffold for development of novel selective Mtb-DHFR inhibitors as antimycobacterial agents.
- Published
- 2018
50. Lipid reducing activity of novel cholic acid (CA) analogs: Design, synthesis and preliminary mechanism study
- Author
-
Qian Zhouyang, Hua Xiang, Qidong You, Qiu Rongmao, and Guoshun Luo
- Subjects
0301 basic medicine ,Cholic Acid ,Biochemistry ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Animals ,Liver X receptor ,Molecular Biology ,Liver X Receptors ,biology ,Chemistry ,Cholesterol ,Anticholesteremic Agents ,Macrophages ,Organic Chemistry ,Cholic acid ,Lipid Metabolism ,Molecular Docking Simulation ,RAW 264.7 Cells ,030104 developmental biology ,Nuclear receptor ,Drug Design ,030220 oncology & carcinogenesis ,ABCA1 ,Lipogenesis ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Farnesoid X receptor ,Efflux ,Signal Transduction - Abstract
Bile acids, initially discovered as endogenous ligands of farnesoid X receptor (FXR), play a central role in the regulation of triglyceride and cholesterol metabolism and have recently emerged as a privileged structure for interacting with nuclear receptors relevant to a large array of metabolic processes. In this paper, phenoxy containing cholic acid derivatives with excellent drug-likeness have been designed, synthesized, and assayed as agents against cholesterol accumulation in Raw264.7 macrophages. The most active compound 14b reduced total cholesterol accumulation in Raw264.7 cells up to 30.5% at non-toxic 10 μM and dosage-dependently attenuated oxLDL-induced foam cell formation. Western blotting and qPCR results demonstrate that 14b reduced both cholesterol and lipid in Raw264.7 cells through (1) increasing the expression of cholesterol transporters ABCA1 and ABCG1, (2) accelerating ApoA1-mediated cholesterol efflux. Through a cell-based luciferase reporter assay and molecular docking analysis, LXR was identified as the potential target for 14b. Interestingly, unlike conventional LXR agonist, 14b did not increase lipogenesis gene SREBP-1c expression. Overall, these diverse properties disclosed herein highlight the potential of 14b as a promising lead for further development of multifunctional agents in the therapy of cardiovascular disease.
- Published
- 2018
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