112 results
Search Results
2. 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
3. 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
4. Synthesis of the vasoactive intestinal peptide (VIP)
- Author
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Viktor Mutt, Cynthia Yang Lin, Yakir S. Klausner, and Miklos Bodanszky
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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
5. 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
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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
6. 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
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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
7. 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
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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
8. Highly selective fluorescent probe based on AIE for identifying cysteine/homocysteine
- Author
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Wei Wang, Zihao Peng, Min Ji, Junqing Chen, and Peng Wang
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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
9. Research progress on the structure and biological diversities of 2-phenylindole derivatives in recent 20 years
- Author
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Pan, Wu, Junxi, Zhao, Xuelian, Shen, Xiaoxia, Liang, Changliang, He, Lizi, Yin, Funeng, Xu, Haohuan, Li, and Huaqiao, Tang
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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
10. Design, synthesis and biological activity evaluation of a series of bardoxolone methyl prodrugs
- Author
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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
11. Development of a nitroreductase-dependent theranostic payload for antibody-drug conjugate
- Author
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Zheng Su, Fei Xie, Xin Xu, Lianqi Liu, Dian Xiao, Xinbo Zhou, and Song Li
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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
12. Water-soluble dual lysosome/mitochondria-targeted fluorescent probe for detection of SO2 in water, food, herb, and live cells
- Author
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Zhenming, Dong, Wenfang, Liang, Yuxin, Dong, Hong, Ren, and Yu, Wang
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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
13. 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
14. 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
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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
15. Characterization, quantitation, similarity evaluation and combination with Na+,K+-ATPase of cardiac glycosides from Streblus asper
- Author
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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
16. New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study
- Author
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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
17. Synthesis, molecular modeling and BACE-1 inhibitory study of tetrahydrobenzo[b] pyran derivatives
- Author
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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
18. Identification and Structure–Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)
- Author
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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
19. Iridoids and sesquiterpenoids from Valeriana jatamansi and their anti-influenza virus activities
- Author
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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
20. Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and evaluation of selective non-pteridine analogues as antitubercular agents
- Author
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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
21. Lipid reducing activity of novel cholic acid (CA) analogs: Design, synthesis and preliminary mechanism study
- Author
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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
22. Isolation and characterization of neolignan derivatives with hepatoprotective and neuroprotective activities from the fruits of Citrus medica L. var. Sarcodactylis Swingle
- Author
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Zhipei Sang, Qinge Ma, Fang Wang, Rongrui Wei, Jiang-Hong Dong, Ming Yang, and Huang Xiaoying
- Subjects
Citrus ,Magnetic Resonance Spectroscopy ,Cell Survival ,Molecular Conformation ,Protective Agents ,01 natural sciences ,Biochemistry ,PC12 Cells ,Lignans ,Structure-Activity Relationship ,food ,Functional food ,Drug Discovery ,Animals ,Humans ,Spectral data ,Molecular Biology ,chemistry.chemical_classification ,Traditional medicine ,010405 organic chemistry ,Organic Chemistry ,Glycoside ,Hep G2 Cells ,food.food ,0104 chemical sciences ,Citrus medica ,Rats ,010404 medicinal & biomolecular chemistry ,chemistry ,Hepg2 cells ,Fruit - Abstract
The fruit of Citrus medica L. var. sarcodactylis Swingle is a functional food with rich nutrients and medicinal values because of its content of bioactive compounds. A bioactivity-guided chemical investigation from the fruits of C. medica L. var. sarcodactylis Swingle afforded three new benzodioxane neolignans (1–3), three new phenanthrofuran neolignan glycosides (4–6), two new biphenyl-ketone neolignans (7–8), two new 1′,7′-bilignan neolignans (9–10), as well as fourteen known neolignan derivatives (11–24), which were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. These neolignan derivatives were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, IR spectral data and compared with the data described in the literature. Among them, compounds 1–3 and 12–13 exhibited moderate hepatoprotective activities to improve the survival rates of HepG2 cells from 46.26 ± 1.90% (APAP, 10 mM) to 67.23 ± 4.25%, 62.87 ± 4.43%, 60.06 ± 6.34%, 56.75 ± 2.30%, 58.35 ± 6.14%, respectively. Additionally, compounds 7–8 and 21–22 displayed moderate neuroprotective activities to raise the survival rates of PC12 cells from 55.30 ± 2.25% to 66.94 ± 3.37%, 70.98 ± 5.05%, 64.64 ± 1.93%, and 62.81 ± 4.11% at 10 μM, respectively. The plausible biogenetic pathway and preliminary structure–activity relationship of the selected compounds were scientifically summarized and discussed in this paper.
- Published
- 2020
23. Design and synthesis of 4-anilinoquinazolines as Raf kinase inhibitors. Part 1. Selective B-Raf/B-Raf
- Author
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Cheng-I, Lee, Chu-Bin, Liao, Chih-Shang, Chen, Fen-Ying, Cheng, Yu-Hsuan, Chung, Yu-Chuan, Wang, Sian-Yi, Ciou, Wen-Yun, Hsueh, Tzu-Hao, Lo, Guan-Ru, Huang, Hsin-Yi, Huang, Chia-Shen, Tsai, Yu-Jung, Lu, Shih-Hsien, Chuang, and Jiann-Jyh, Huang
- Subjects
ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,Proto-Oncogene Proteins B-raf ,Cell Line, Tumor ,Quinazolines ,Humans ,raf Kinases ,Vascular Endothelial Growth Factor Receptor-2 - Abstract
This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-Raf
- Published
- 2020
24. Bioactive imidamide-based compounds targeted against nitric oxide synthase
- Author
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Fabio Arias, Francisco Franco-Montalban, Miguel Romero, Juan Duarte, M. Dora Carrión, and M. Encarnación Camacho
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Imidamide ,Organic Chemistry ,Nitric Oxide Synthase Type II ,Nitric Oxide ,Biochemistry ,Rats ,Synthesis ,Inducible Nitric Oxide Synthase ,Nitric Oxide Synthase Inhibitors ,Septic shock ,Drug Discovery ,Animals ,Enzyme Inhibitors ,Nitric Oxide Synthase ,Molecular Biology ,Neuronal nitric oxide synthase - Abstract
The selective inhibition of inducible nitric oxide synthase (iNOS) has become an interesting goal for the treatment of diseases where the immune and inflammatory response of the organism is involved. Septic shock is one prominent example of this type of affections. In this paper, the design and synthesis of twelve substituted pyridinyl- imidamide derivatives is described, together with their biological evaluation as NOS inhibitors. The most potent and selective compound was N-(3-hydroxy-3-(pyridin-3-yl)propyl)acetimidamide 9a (IC50 = 4.6 µM, against iNOS). Pharmacological assays in aortic rat tissue, have confirmed its inhibitory activity on iNOS and the absence of undesired cardicovascular effects. In silico analysis of the most promising compounds (9a, 9b, 9e and 9g) have predicted good drug-likeness properties. Furthermore, they have shown an adequate cell viability. Docking studies carried out on 9a suggest a particular binding mode that involves the essential residue Glu377, and might explain its iNOS selectivity. From a chemical point of view, the article describes an unusual cyclization to obtain pyridinyl-pyrimidine derivatives with high yield., Centro de Supercomputación de la Universidad de Granada (CSIRC), Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV) y Ministerio de Economía y competitividad (MINECO) (SAF2017-84894-R y PID2020-116347RB-100), Biblioteca de la Universidad de Granada
- Published
- 2022
25. Identification of a potent heme oxygenase-2 (HO-2) inhibitor by targeting the secondary hydrophobic pocket of the HO-2 western region
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Valeria Sorrenti, Loredana Salerno, Antonio Rescifina, Valeria Pittalà, Giuseppe Floresta, Antonino N. Fallica, and Giuseppe Romeo
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Gene isoform ,Stereochemistry ,Substituent ,Structure-activity relationships ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Nitriles ,Animals ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Rational design ,Brain ,Heme breakdown ,0104 chemical sciences ,Rats ,Heme oxygenase ,Imidazole derivatives ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Docking (molecular) ,Heme oxygenase-1 ,Azalanstat ,Heme Oxygenase (Decyclizing) ,Heme oxygenase-2 ,Hydrophobic and Hydrophilic Interactions ,Western region ,Algorithms ,Spleen - Abstract
The enzymatic family of heme oxygenase (HO) is accountable for heme breakdown. Among the two isoforms characterized to date, HO-2 is poorly investigated due to the lack of potent HO-2 chemical modulators and the greater attentiveness towards HO-1 isoform. In the present paper, we report the rational design and synthesis of HO-2 inhibitors achieved by modulating the volume of known HO-1 inhibitors. The inhibition preference has been moved from HO-1 to HO-2 by merely increasing the volume of the substituent in the western region of the inhibitors. Docking studies demonstrated that new derivatives soak differently in the two binding pockets, probably due to the presence of a Tyr187 residue in HO-2. These findings could be useful for the design of new selective HO-2 compounds.
- Published
- 2020
26. History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action
- Author
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Mohammad Shafiei, Mehrnoosh Hashemzadeh, Lee Peyton, and Alireza Foroumadi
- Subjects
Drug ,Antifungal ,Azoles ,medicine.medical_specialty ,Antifungal Agents ,medicine.drug_class ,media_common.quotation_subject ,Antifungal drugs ,Microbial Sensitivity Tests ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Intensive care medicine ,Molecular Biology ,media_common ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Fungi ,Antimicrobial ,0104 chemical sciences ,Clinical trial ,010404 medicinal & biomolecular chemistry ,Drug development ,Azole ,Fluconazole ,medicine.drug - Abstract
With the increasing risk of invasive and life threating fungal infections, there is now a great concern regarding the lower discovery rate of antifungal drugs in comparison to antimicrobial agents. Drugs conventionally used in clinics are not adequate enough to combat the increasing fungal infections, especially fungal forms resistant to fluconazole. Among the limited antifungal agents in clinics, azoles have the largest number of drug candidates in clinical trials and are partly marketed due to the particular focus of pharmaceutical companies and medicinal scientific centers. With the rise in the number of papers on azole antifungal design and discovery, a more in-depth understanding the most recent and authentic information about this class of drugs might be beneficial. To this end, we for the first time summarized the state-of-the-art information about azole drugs, with a specific focus on those in the pipelines of pharmaceutical companies, into four generations with regard to their structural similarity. More importantly, this review highlights information on the structure activity relationship (SAR), target description, hybrid antifungal agents as possible future generation, and other useful issues to streamline research towards designing new efficient azole antifungal structures in future.
- Published
- 2020
27. Synthesis and biological evaluation of β-ionone oriented proapoptosis agents by enhancing the ROS generation
- Author
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Guo-Yun Liu, Jie Yang, Yu-Xin Cao, and Wen-Wen Mu
- Subjects
Caspase 3 ,Antineoplastic Agents ,Apoptosis ,Ionone ,01 natural sciences ,Biochemistry ,Lipid peroxidation ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Humans ,MTT assay ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Curcumin ,Drug Screening Assays, Antitumor ,Norisoprenoids ,Reactive Oxygen Species - Abstract
β-ionone, a cyclic terpenoid compound present in many fruits, has been showed a broad spectrum of biological activities. In this paper, we synthesized a panel of β-ionone derivatives and tested their anti-proliferation activity on cancer cell by the MTT assay. The results showed that most of the β-ionone derivatives were more active than β-ionone and curcumin. Particularly, the β-ionone derivatives (1a, 1d and 1g) with ortho-substituents on the aromatic ring exhibited much stronger cytotoxicity than their corresponding meta- and para-substituted compounds. Importantly, the cytotoxicity of the β-ionone derivatives (1a, 1d and 1g) were relationship with their reactive oxygen species (ROS)-generation abilities, which could lead to the redox imbalance, lipid peroxidation, the loss of mitochondrial membrane potential (MMP), the activation of Bax and Caspase 3, followed by cell apoptosis. This work suggest that the “ortho effect”, the ROS-generation ability and drawing fluorine atom into drugs may play a potent role in enhancing the anticancer activity of β-ionone derivatives.
- Published
- 2020
28. Synthesis, characterization, in vitro tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP) inhibition studies and computational evaluation of novel thiazole derivatives
- Author
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Julie Pelletier, Hamid Aziz, Aamer Saeed, Zahid Shafiq, Jean Sévigny, Abid Mahmood, Sumera Zaib, and Jamshed Iqbal
- Subjects
Models, Molecular ,Phosphatase ,Context (language use) ,01 natural sciences ,Biochemistry ,Dephosphorylation ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Chlorocebus aethiops ,Structure–activity relationship ,Animals ,Humans ,Enzyme Inhibitors ,Thiazole ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Alkaline Phosphatase ,In vitro ,0104 chemical sciences ,Intestines ,010404 medicinal & biomolecular chemistry ,Thiazoles ,Enzyme ,chemistry ,COS Cells ,Alkaline phosphatase - Abstract
Alkaline phosphatases (APs) are a class of homodimeric enzymes which physiologically possess the dephosphorylation ability. APs catalyzes the hydrolysis of monoesters into phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are nitrogen and sulfur containing aromatic heterocycles considered as effective APs inhibitors. In this context, the current research paper presents the successful synthesis, spectroscopic characterization and in vitro alkaline phosphatase inhibitory potential of new thiazole derivatives. The structure activity relationship and molecular docking studies were performed to find out the binding modes of the screened compounds with the target site of tissue non-specific alkaline phosphatase (h-TNAP) as well as intestinal alkaline phosphatase (h-IAP). Compound 5e was found to be potent inhibitor of h-TNAP with IC50 value of 0.17 ± 0.01 µM. Additionally, compounds 5a and 5i were found to be highly selective toward h-TNAP with IC50 values of 0.25 ± 0.01 µM and 0.21 ± 0.02 µM, respectively. In case of h-IAP compound 5f was the most potent inhibitor with IC50 value of 1.33 ± 0.10 µM. The most active compounds were resort to molecular docking studies on h-TNAP and h-IAP to explore the possible binding interactions of enzyme-ligand complexes. Molecular dynamic simulations were carried out to investigate the overall stability of protein in apo and holo state.
- Published
- 2020
29. P2X7 receptor inhibition by 2-amino-3-aryl-1,4-naphthoquinones
- Author
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Nubia Boechat, Lucas Villas Bôas Hoelz, Daniela de Luna Martins, Adriel Alves Borges, Robson Xavier Faria, Murilo Lamim Bello, Vitor F. Ferreira, Hellen Valério Chaves Moura de Souza, Nayane Abreu do Amaral e Silva, and Juliana Vieira Faria
- Subjects
Male ,Purinergic P2X Receptor Antagonists ,Carrageenan ,Biochemistry ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Adenosine Triphosphate ,In vivo ,Drug Discovery ,Extracellular ,Potency ,Animals ,Edema ,Humans ,Binding site ,Receptor ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Aryl ,Organic Chemistry ,Purinergic receptor ,In vitro ,HEK293 Cells ,Receptors, Purinergic P2X7 ,Caco-2 Cells ,Naphthoquinones - Abstract
Extracellular ATP activates purinergic receptors such as P2X7, cationic channels for Ca2+, K+, and Na+. There is robust evidence of the involvement of these receptors in the immune response, so P2X7 receptors (P2X7R) are considered a potential therapeutic target for the development of anti-inflammatory drugs. Although there are many studies of the anti-inflammatory properties of naphthoquinones, these molecules have not yet been explored as P2X7 antagonists. In previous work, our group prepared 3-substituted (halogen or aryl) 2-hydroxy-1,4-naphthoquinones and studied their action on P2X7R. In this paper, eight 2-amino-3-aryl-1,4-naphthoquinones were evaluated to identify the inhibitory activity on P2X7R and the toxicological profile. Three analogues (AD-4CN, AD-4Me, and AD-4F) exhibited reduced toxicity for mammalian cells with CC50 values higher than 500 µM. These three 3-substituted 2-amino-1,4-naphthoquinones inhibited murine P2X7R (mP2X7R) in vitro. However, the analogues AD-4CN and AD-4Me showed low selectivity index values. AD-4F inhibited both mP2X7R and human P2X7R (hP2X7R) with IC50 values of 0.123 and 0.93 µM, respectively. Additionally, this analogue exhibited higher potency than BBG at inhibiting the ATP-induced release of IL-1β in vitro. Carrageenan-induced paw edema in vivo was reversed for AD-4F with an ID50 value of 11.51 ng/kg. Although AD-4F was less potent than previous 3-substituted (halogen or aryl) 2-hydroxy-1,4-naphthoquinones such as AN-04 in vitro, this 3-substituted 2-amino-1,4-naphthoquinone revealed higher potency in vivo to reduce the edematogenic response. In silico analysis suggests that the binding site of the novel 2-amino-3-aryl-1,4-naphthoquinone derivatives, including all the tautomeric forms, is located in the pore area of the hP2X7R model. Based on these results, we considered AD-4F to be a satisfactory P2X7R inhibitor. AD-4F might be used as a scaffold structure to design a novel series of inhibitors with potential inhibitory activity on murine (mP2X7R) and human (hP2X7R) P2X7 receptors.
- Published
- 2020
30. Structure-activity relationships of rationally designed AMACR 1A inhibitors
- Author
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Guat Ling Lee, Maksims Yevglevskis, Tony D. James, Amit Nathubhai, Michael D. Threadgill, Timothy J. Woodman, Matthew D. Lloyd, and Yoana D. Petrova
- Subjects
0301 basic medicine ,Drug target ,Racemases and Epimerases ,Drug design ,Structure-activity relationships ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Drug Discovery ,Humans ,Potency ,Rational drug design ,Enzyme Inhibitors ,Molecular Biology ,Enzyme Assays ,Molecular Structure ,Chemistry ,Organic Chemistry ,Drug lipophilicity ,Enzyme inhibitors ,Stereoisomerism ,Isoenzymes ,030104 developmental biology ,α-Methylacyl-CoA racemase (AMACR, P504S) ,Drug Design ,030220 oncology & carcinogenesis ,Lipophilicity ,Acyl Coenzyme A ,Hydrophobic and Hydrophilic Interactions - Abstract
α-Methylacyl-CoA racemase (AMACR; P504S) is a promising novel drug target for prostate and other cancers. Assaying enzyme activity is difficult due to the reversibility of the ‘racemisation’ reaction and the difficulties in the separation of epimeric products; consequently few inhibitors have been described and no structure–activity relationship study has been performed. This paper describes the first structure–activity relationship study, in which a series of 23 known and potential rational AMACR inhibitors were evaluated. AMACR was potently inhibited (IC 50 = 400–750 nM) by ibuprofenoyl-CoA and derivatives. Potency was positively correlated with inhibitor lipophilicity. AMACR was also inhibited by straight-chain and branched-chain acyl-CoA esters, with potency positively correlating with inhibitor lipophilicity. 2-Methyldecanoyl-CoAs were ca. 3-fold more potent inhibitors than decanoyl-CoA, demonstrating the importance of the 2-methyl group for effective inhibition. Elimination substrates and compounds with modified acyl-CoA cores were also investigated, and shown to be potent inhibitors. These results are the first to demonstrate structure–activity relationships of rational AMACR inhibitors and that potency can be predicted by acyl-CoA lipophilicity. The study also demonstrates the utility of the colorimetric assay for thorough inhibitor characterisation.
- Published
- 2018
31. Synthesis, molecular modelling and biological evaluation of tetrasubstituted thiazoles towards cholinesterase enzymes and cytotoxicity studies
- Author
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Sumera Zaib, Amara Mumtaz, Aamer Saeed, Muhammad Shakil Shah, Izhar Hussain, Jamshed Iqbal, Huma Aslam Bhatti, and Muhammad Shoaib
- Subjects
Cell Survival ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Biochemistry ,HeLa ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Horses ,Cytotoxicity ,Thiazole ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,biology ,010405 organic chemistry ,Organic Chemistry ,Carbon-13 NMR ,biology.organism_classification ,Combinatorial chemistry ,0104 chemical sciences ,Molecular Docking Simulation ,Kinetics ,Thiazoles ,Enzyme ,chemistry ,Thiourea ,Butyrylcholinesterase ,Electrophorus ,Acetylcholinesterase ,Proton NMR ,Cholinesterase Inhibitors ,Drug Screening Assays, Antitumor ,HeLa Cells ,Acetophenone - Abstract
Alzheimer is a neurodegenerative disease and requires the development of new scaffold to treat it. In this regard, thiazoles derivative are playing their significant role. In the current research paper we have focused our attention for the development of tetrasubstituted thiazole (3a-h) derivatives using domino synthesis by mixing the thiourea as a precursor, with acetophenone in the presence of iodine and tosic acid in DMSO and refluxed for 12–22 h. The structures of the newly synthesized compounds were confirmed by FTIR, 1H NMR, 13C NMR and EIMS analysis. Thiazole derivatives were analyzed for their biological significances against acetyl and butylcholinesterase enzymes and compound 3b and 3d were found more active against these enzyme, respectively. The mode of inhibition was determined for the potent compounds against both the enzymes. Moreover, the molecular docking studies were carried out to explore the interactive behavior of the compounds within the active pocket of enzymes. Furthermore, the derivatives (3a-h) were evaluated for their anticancer potential against HeLa cancer cell lines. Most potent inhibition was observed by compound 3b.
- Published
- 2018
32. Design, synthesis and evaluation of novel nonquaternary and 3 non-oxime reactivators for acetylcholinesterase inhibited by organophosphates
- Author
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Zhao Wei, Zhibing Zheng, Qin Ouyang, and Huanglei Bi
- Subjects
Obidoxime ,Sarin ,Cholinesterase Reactivators ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Oximes ,medicine ,Humans ,Pesticides ,Molecular Biology ,Piperazine ,Nerve agent ,010405 organic chemistry ,Organic Chemistry ,Oxime ,Acetylcholinesterase ,Salicylaldoxime ,Organophosphates ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Kinetics ,chemistry ,Drug Design ,Cholinesterase Inhibitors ,Nerve Agents ,medicine.drug - Abstract
A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. Conjugates with piperazine linked to the substituted salicylaldoxime emerged as efficient reactivators for VX inhibited hAChE. The in vitro reactivation experiment showed that some of them were equal or more efficient reactivators for pesticides inhibited hAChE than obidoxime. It was also found that some non-oxime derivatives of Mannich phenols displayed obvious reactivation potency for VX, sarin and pesticides inhibited hAChE even in very low concentration. It has been proved that introduction of peripheral site ligands with widespread aromatic system and amide substitutions could increase binding affinity for inhibited hAChE in most cases, which contribute to the reactivation efficiency.
- Published
- 2019
33. New cassane-type diterpenoids from kernels of Caesalpinia bonduc (Linn.) Roxb. and their inhibitory activities on phosphodiesterase (PDE) and nuclear factor-kappa B (NF-κB) expression
- Author
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Yiren Yang, Huiyuan Gao, Shizhou Qi, Shen Xueying, Ting Liu, Miao Wang, Ying Wang, Wenhua Jing, and X. Li
- Subjects
Circular dichroism ,Stereochemistry ,Phosphodiesterase Inhibitors ,Anti-Inflammatory Agents ,01 natural sciences ,Biochemistry ,Drug Discovery ,Molecular Biology ,Caesalpinia ,biology ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Spectrum Analysis ,Organic Chemistry ,NF-kappa B ,Phosphodiesterase ,Carbon-13 NMR ,biology.organism_classification ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Caesalpinia bonduc ,Docking (molecular) ,Proton NMR ,Target protein ,Diterpenes ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
In this paper, chemical investigation on the chloroform soluble fraction of seed kernels of Caesalpinia bonduc resulted in the isolation of five new cassane diterpenoids: norcaesalpinin O (1), norcaesalpinin P (2), caesalpinin MQ (3), caesall O/P (4/5) and seven known compounds (6–12). Compounds structures were elucidated by 1H NMR, 13C NMR, 2D NMR, HR-MS and ECD (electronic circular dichroism) spectral analysis. The characters for new compounds with the presence of an aromatized C ring or demethyl group at C-17 position in the structures were found. By means of bioactive screenings, the inhibitory effect on type-4 phosphodiesterase (PDE4, the target protein of asthma disease) and nuclear factor-kappa B (NF-κB) expression were valued. Compound 1 was found to exhibit moderate inhibitory activity on PDE4 and much better binding affinity than other structures by docking studies for interaction analyzing. Compounds 6, 10 and 11 displayed considerable inhibitory strength against NF-κB expression with inhibitory ratio 48.6%, 42.9% and 37.1% at 10 µM, respectively. The isolation of cassane-type diterpenoids with anti-inflammation activity from C. bonduc implied that this plant might be a good source for anti-inflammation agents finding.
- Published
- 2019
34. Improving the carbonic anhydrase inhibition profile of the sulfamoylphenyl pharmacophore by attachment of carbohydrate moieties
- Author
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Silvia Bua, Claudiu T. Supuran, Leonardo E. Riafrecha, and Pedro A. Colinas
- Subjects
0301 basic medicine ,PHARMACOPHORE ,Stereochemistry ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Isozyme ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Glucosides ,Aldol reaction ,Topiramate ,CARBOHYDRATE ,Carbonic anhydrase ,Drug Discovery ,Humans ,Moiety ,Glycosyl ,Phenols ,Carbonic Anhydrase Inhibitors ,Molecular Biology ,Enzyme Assays ,Sulfonamides ,Molecular Structure ,biology ,010405 organic chemistry ,CARBONIC aNHYDRASES ,Organic Chemistry ,Ciencias Químicas ,Carbohydrate ,0104 chemical sciences ,Química Orgánica ,030104 developmental biology ,chemistry ,biology.protein ,C-GLYCOSYL SULFAMATES ,Pharmacophore ,CIENCIAS NATURALES Y EXACTAS - Abstract
One of the most successful approaches for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was denominated ‘the sugar approach’. The sugar approach consists in attaching different carbohydrates to CA inhibiting pharmacophores for modulating the physicochemical properties of these pharmacological agents. In line with this approach, in this paper, we present a new class of C-glycosides incorporating the sulfamoylphenyl moiety. These compounds have been prepared by sulfamoylation of C-glycosyl phenols, which have been synthetized by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. The inhibition profile of the new glycomimetics was determined against four human (h) CA isozymes, comprising hCAs I and II (cytosolic, ubiquitous isozymes), hCA IV and hCA IX (tumor associated isozyme). Peracetylated and deprotected C-glycosyl sulfamates showed better inhibition selectivity compared to structurally related phenylsulfamates. In this study, deprotected compound 12 was identified as selective inhibitor of hCA IX. These results confirm that attaching carbohydrate moieties to CA sulfamoylphenyl pharmacophore improves its inhibitory activity. Fil: Riafrecha, Leonardo Ezequiel. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bua, Silvia. Università degli Studi di Firenze; Italia Fil: Supuran, Claudiu T.. Università degli Studi di Firenze; Italia Fil: Colinas, Pedro Alfonso. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
- Published
- 2018
35. Nucleus-targeting imaging and enhanced cytotoxicity based on naphthalimide derivatives
- Author
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Ke-Rang Wang, Shao-Ying Du, Xu He, Yu-Ming Qi, Zhi-Ran Cao, Xiao-Liu Li, Shan-Shan Wang, and Rui-Xue Rong
- Subjects
Cell Nucleus ,Fluorescence-lifetime imaging microscopy ,Cell Cycle ,Optical Imaging ,Organic Chemistry ,Acylhydrazine ,Antineoplastic Agents ,Cell cycle ,Biochemistry ,Combinatorial chemistry ,Naphthalimides ,chemistry.chemical_compound ,chemistry ,Cell Line, Tumor ,Neoplasms ,Amide ,Drug Discovery ,Organelle ,Humans ,Cytotoxicity ,Molecular Biology ,DNA ,HeLa Cells ,Conjugate - Abstract
Organelles possess critical biological effects in cellular processes. However, the relationship between organelle targeting and antitumour activity is a challenging issue. In this paper, a number of amide/acylhydrazine modified naphthalimide derivatives were designed and synthesized. Interestingly, amide modified naphthalimide derivatives NI-A-NH and NI-C-NH with (R)-piperdine and (S)-pyrrolidine functionalization exhibited enhanced cytotoxicity compared with acylhydrazine modified derivatives NI-A-2NH and NI-C-2NH. However, acylhydrazine modified derivatives NI-B-2NH and NI-D-2NH with (S)-piperdine and achiral piperdine conjugates possessed better cytotoxicity than NI-B-NH and NI-D-NH with amide modifications. Fluorescence imaging, DNA binding interactions and cell cycle analyses were further completed to clarify that the nucleus-targeting effects showed enhanced cytotoxic activity, strong DNA binding and the blocking of cells in S phase. These results provide a preliminary theoretical basis for the further design of organelle-targeting antitumour drugs.
- Published
- 2021
36. Inactivation of bovine plasma amine oxidase by 1,1,1–trihalo–3–aminopropanes
- Author
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Jisook Kim and Irene N. Lee
- Subjects
Models, Molecular ,0301 basic medicine ,Amine oxidase ,Magnetic Resonance Spectroscopy ,chemistry.chemical_element ,Photochemistry ,Biochemistry ,Medicinal chemistry ,Inhibitory Concentration 50 ,Propane ,03 medical and health sciences ,Catalytic Domain ,Drug Discovery ,Animals ,Copper Amine Oxidase ,Enzyme Inhibitors ,Molecular Biology ,Enzyme Assays ,030102 biochemistry & molecular biology ,Chemistry ,Organic Chemistry ,Bovine plasma ,Copper ,Quinone ,Kinetics ,030104 developmental biology ,Halogen ,Cattle ,Amine Oxidase (Copper-Containing) - Abstract
In this paper, we report the inactivation of copper containing bovine plasma amine oxidase (BPAO) by a series of saturated alkylamines containing halogen atoms at γ-position, which are 1,1,1-trihalo-3-aminopropane, 1,1,1-trifluoro-2-hydroxy-3-aminopropane, 1,1,1-trichloro-2-hydroxy-3-aminopropane, and 1,1,1-trichloro-2-(2-phenethyloxy)-3-aminopropane. The trihalo-2-hydroxypropylamine analogs exhibited a time-dependent inactivation behavior of BPAO, with 1,1,1-trifluoro-2-hydroxy-3-aminopropane as the most efficient inactivator. The incorporation of a OH group at β-position increased inactivation efficiency by 10-fold within the trifluoro analogs, and the incorporation of a phenethyloxy group at β-position exhibited a higher efficiency by 3-fold within the trichloro analogs based on I75 values. All four compounds were found to be irreversible inactivators for BPAO.
- Published
- 2017
37. 1H-1,2,3-triazole grafted tacrine-chalcone conjugates as potential cholinesterase inhibitors with the evaluation of their behavioral tests and oxidative stress in mice brain cells
- Author
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Rajbir Bhatti, Prishani Kisten, Sumanjit, Njabulo J. Gumede, Vipan Kumar, Jashanpreet Kaur, Anu Rani, Amandeep Singh, Parvesh Singh, and Gurjit Singh
- Subjects
Chalcone ,Anxiety ,Pharmacology ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Lipid peroxidation ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Chalcones ,Drug Discovery ,medicine ,TBARS ,Animals ,Molecular Biology ,Butyrylcholinesterase ,Cholinesterase ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Depression ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Brain ,Glutathione ,Triazoles ,Rats ,0104 chemical sciences ,Molecular Docking Simulation ,Oxidative Stress ,010404 medicinal & biomolecular chemistry ,Tacrine ,Acetylcholinesterase ,biology.protein ,Cholinesterase Inhibitors ,Oxidative stress ,medicine.drug - Abstract
The present paper explicates the synthesis of 1H-1,2,3-triazole tethered tacrine-chalcone conjugates and evaluation of their AChE and BuChE inhibitory activity. In-vitroAChE inhibition assay revealed three compounds, 9h, 9i, and 11f, being more potent than the standard drug tacrine and further evaluated against butyrylcholinesterase. The present study was extended to investigate the anti-amnestic effect of promising compoundson scopolamine-induced behavioral and neurochemical changes in mice. Inclined plane model and Elevated plus-maze model were performed to assess general limb motor activity and anxiety-like behavior, respectively, in mice pre-treated with scopolamine. Oxidative stress parameters reduced glutathione contents (GSH) and lipid peroxidation products (TBARS) in the brain homogenates as estimated using ex-vivo studies. Furthermore, molecular docking studies were performed for the potent compounds to decipher the mechanism of observed activities.
- Published
- 2021
38. Design, green synthesis, antioxidant activity screening, and evaluation of protective effect on cerebral ischemia reperfusion injury of novel monoenone monocarbonyl curcumin analogs
- Author
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Yugang Liu, Lu Zhu, Jingsong Wang, Shengwei Huang, Jiafeng Zhang, Qiling Jin, Hua Wang, Mengya Shen, Jianzhang Wu, Lili Huang, Wulan Li, Zewu Jin, Linya Hu, Wenfei He, and Qichuan Zhuge
- Subjects
Male ,Quantitative structure–activity relationship ,Curcumin ,Antioxidant ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Ischemia ,Pharmacology ,Protective Agents ,medicine.disease_cause ,PC12 Cells ,01 natural sciences ,Biochemistry ,Antioxidants ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Molecular Biology ,Cells, Cultured ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Cell growth ,Chemistry ,Organic Chemistry ,Green Chemistry Technology ,Infarction, Middle Cerebral Artery ,medicine.disease ,Rats ,0104 chemical sciences ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,010404 medicinal & biomolecular chemistry ,Drug Design ,Reperfusion Injury ,Toxicity ,Reperfusion injury ,Oxidative stress - Abstract
Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H2O2-induced oxidative stress damage model, and quantitative evaluation of structure–activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.
- Published
- 2021
39. Rational design of phenyl thiophene (pyridine) derivatives that overcome P-glycoprotein mediated MDR in MCF-7/ADR cell
- Author
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Bin Wei, Xinyi Ye, Can-Can Wang, Jianwei Chen, Dong-Sheng Zhao, Zi-Ning Cui, Xiaoze Bao, Ya-Sheng Li, Hong Wang, Gui-Jun Liu, Si-Jia Wang, Xi Yang, Shen Mao, Dan Zu, and Bo Zhang
- Subjects
Pyridines ,Daunorubicin ,Chemosensitizer ,Thiophenes ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Doxorubicin ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Molecular Biology ,Cell Proliferation ,P-glycoprotein ,Antibiotics, Antineoplastic ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,Multiple drug resistance ,Paclitaxel ,chemistry ,Drug Resistance, Neoplasm ,Drug Design ,biology.protein ,Efflux ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
P- glycoprotein (P-gp)-mediated multidrug resistance (MDR) has become an important hindrance in the clinical treatment of malignant tumors. In this paper, based on our lead compound 5m and strategies of bioisosteric replacement and alkoxy effect, phenylthiophene and phenylpyridine derivatives were designed as chemosensitizers for front-line antineoplastic agents and overcomes P-gp mediated MDR in MCF-7/ADR cell. Generally, 4-phenylthiophene-2-carboxamide derivative 60 has been screened and obtained with optimal activity against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 1.02 μM, RF = 49.9 with 5 μM 60 treated). The results of western blot and Rh123 accumulation assays showed that 60 effectively inhibited P-gp efflux function but not its expression. It is noted that compound 60 is a potentially broad-spectrum chemosensitizer in combination with commonly used anti-tumor drugs, such as doxorubicin, paclitaxel, daunorubicin and vincristine with RF value of 20–80.
- Published
- 2021
40. Optimization of pyrazole-based compounds with 1,2,4-triazole-3-thiol moiety as selective COX-2 inhibitors cardioprotective drug candidates: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory, ulcerogenicity, cardiovascular evaluation, and molecular modeling studies
- Author
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Eman K. A. Abdelall, John N. Philoppes, Emad H.M. Hassanein, Khaled R.A. Abdellatif, Heba A.H. Elshemy, and Nesma M. Kahk
- Subjects
Male ,Models, Molecular ,Cardiotonic Agents ,medicine.drug_class ,Triazole ,ADME Study ,Pharmacology ,Pyrazole ,Carrageenan ,01 natural sciences ,Biochemistry ,Anti-inflammatory ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Edema ,Moiety ,Stomach Ulcer ,Rats, Wistar ,Molecular Biology ,Inflammation ,Cyclooxygenase 2 Inhibitors ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,Triazoles ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Cyclooxygenase 2 ,Docking (molecular) ,Drug Design ,Celecoxib ,biology.protein ,Pyrazoles ,Cyclooxygenase ,medicine.drug - Abstract
The cardiovascular side effects associated with COX-2 selective drugs were the worst for coxibs leading to their withdrawal from the market a few years after their discovery. Therefore, the design of new series of pyrazole (4a,b 5a,b, 7a,b, 9a,b, 10a-h, and 11a-f) substituted with a triazole moiety as selective COX-2 inhibitors with cardioprotective effect was aimed in this paper. The target compounds were prepared and evaluated in-vitro against COX-1 and COX-2 enzymes. Compound 5-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole-3-thiol (7a) showed the highest selectivity towards COX-2 enzyme (S.I. = 27.56) and was the most active anti-inflammatory agent. Interestingly, its cardiovascular profile showed the cardiac biomarkers (ALP, AST, CK-MB, and LDH), as well as inflammatory cytokines named (TNF-α and IL-6) nearly similar to the control. Besides, a histopathological study of the heart muscle and the stomach was also included. The results confirmed that compound 7a has a more favorable cardio profile than celecoxib. Moreover, docking simulation for the most selective compounds 4b, 7a, 10e, 11c, and 11e inside COX-2 active site was performed to explain their binding mode. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti-inflammatory agent. In conclusion, the newly developed compound 7a represents a potential selective COX-2 NSAID candidate with minimum cardiovascular risks.
- Published
- 2021
41. 8-Hydroxyquinoline derived p-halo N4-phenyl substituted thiosemicarbazones: Crystal structures, spectral characterization and in vitro cytotoxic studies of their Co(III), Ni(II) and Cu(II) complexes
- Author
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Avinash Kotian, Karthik Kumara, Vinayak Kamat, Kishore Bhat, Dhoolesh Gangaram Kokare, Krishna Naik, Krishnappagowda Lokanath Neratur, Vidyanand K. Revankar, and Vijay Kumbar
- Subjects
Models, Molecular ,Thiosemicarbazones ,Cell Survival ,Antineoplastic Agents ,Crystal structure ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Coordination Complexes ,Bromide ,Metals, Heavy ,Drug Discovery ,Octahedral molecular geometry ,Humans ,Methylene ,Molecular Biology ,Thioamide ,Cell Proliferation ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Ligand ,Organic Chemistry ,Oxyquinoline ,Tautomer ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Crystallography ,Microscopy, Fluorescence ,Acridine ,MCF-7 Cells ,Drug Screening Assays, Antitumor - Abstract
The current paper deals with 8-hydroxyquinoline derived p-halo N4-phenyl substituted thiosemicarbazones, their crystal structures, spectral characterization and in vitro cytotoxic studies of Co(III), Ni(II) and Cu(II) complexes. The molecular structures of the ligands, (E)-4-(4-halophenyl)-1-((8-hydroxyquinoline-2-yl)methylene)thiosemicarbazones (halo = fluoro/chloro/bromo) are determined by single crystal X-ray diffraction method. The crystal structures reveal that the ligands are non-planar and exist in their thioamide tautomeric forms. The various physicochemical investigations of the synthesized complexes reveal metal to ligand stoichiometry to be 1:2 in Co(III) complexes whereas 1:1 in Ni(II) and Cu(II) complexes. The ligands coordinate in a tridentate NNS fashion around Co(III) centers to form an octahedral geometry and square planar geometry around Ni(II) and Cu(II) metal centers. The oxidation of Co(II) to Co(III) is observed on complexation. The synthesized compounds are subjected to in vitro cytotoxicity studies. When compared to bare ligands, the complexes show enhancement of the antiproliferative activity against MCF-7, breast cancer cell lines. The Co(III) complexes of fluoro and bromo derivatives of ligands have displayed remarkable results with roughly two fold increase in their activity in correlation to the standard drug, Paclitaxel. Moreover, the fluorescence microscopy images of cells stained with acridine orange-ethidium bromide suggest an apoptotic mode of cell death.
- Published
- 2021
42. Discovery of novel indolin-2-one compounds as potent inhibitors of HsClpP for cancer treatment
- Author
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Tao Yang, Yang Yang, Baozhu Luo, Wenliang Qiao, Yuan Ju, Rao Song, Youfu Luo, and Jiasheng Huang
- Subjects
Indoles ,medicine.medical_treatment ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Metastasis ,HeLa ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Movement ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Protease Inhibitors ,MTT assay ,Molecular Biology ,Cell Proliferation ,Serine protease ,Protease ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Cancer ,medicine.disease ,biology.organism_classification ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,biology.protein ,Drug Screening Assays, Antitumor ,Lead compound ,Peptide Hydrolases - 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.
- Published
- 2021
43. Design and synthesis of 4-anilinoquinazolines as Raf kinase inhibitors. Part 1. Selective B-Raf/B-RafV600E and potent EGFR/VEGFR2 inhibitory 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines
- Author
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Tzu-Hao Lo, Yu-Hsuan Chung, Shih-Hsien Chuang, Cheng-I Lee, Jiann-Jyh Huang, Guan-Ru Huang, Chu-Bin Liao, Chia-Shen Tsai, Wen-Yun Hsueh, Hsin-Yi Huang, Fen-Ying Cheng, Yu-Chuan Wang, Sian-Yi Ciou, Chih-Shang Chen, and Yu-Jung Lu
- Subjects
Sorafenib ,010405 organic chemistry ,Chemistry ,Kinase ,Stereochemistry ,Melanoma ,Organic Chemistry ,medicine.disease ,Inhibitory postsynaptic potential ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Docking (molecular) ,Drug Discovery ,medicine ,Side chain ,Potency ,Molecular Biology ,IC50 ,medicine.drug - Abstract
This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-RafV600E and potent EGFR/VEGFR2 kinase inhibitors. Total 14 compounds of scaffold 9 having different side chains at the triazolyl group with/without fluoro substituents at the anilino group were synthesized and investigated. Among them, 9m with a 2-carbamoylethyl side chain and C-4′/C-6′ difluoro substituents was the most potent, which selectively inhibited B-Raf (IC50: 57 nM) and B-RafV600E (IC50: 51 nM) over C-Raf (IC50: 1.0 μM). Compound 9m also actively inhibited EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM) but not EGFRT790M and PDGFR-β (IC50: >10 μM). Despite having good potency for B-Raf and B-RafV600E in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf600E. The inferior activity of 9m for A375 was similar to that of sorafenib (6), suggesting that 9m might bind to the inactive conformations of B-Raf and B-RafV600E. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-RafV600E, and VEGFR2 kinases.
- Published
- 2021
44. Renoprotective chemical constituents from an edible mushroom, Pleurotus cornucopiae in cisplatin-induced nephrotoxicity
- Author
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Hyung Jun Noh, Dahae Lee, Seoung Rak Lee, Ki Sung Kang, Hae-Jeung Lee, Kiwon Jung, and Ki-Hyun Kim
- Subjects
Swine ,Antineoplastic Agents ,Apoptosis ,Kidney ,Pleurotus ,Protective Agents ,01 natural sciences ,Biochemistry ,Cell Line ,Nephrotoxicity ,chemistry.chemical_compound ,Drug Discovery ,Pleurotus cornucopiae ,Animals ,Pleurotaceae ,Fruiting Bodies, Fungal ,Molecular Biology ,Biological Products ,Mushroom ,Nicotinamide ,biology ,010405 organic chemistry ,Organic Chemistry ,Uracil ,biology.organism_classification ,Uridine ,0104 chemical sciences ,Edible mushroom ,010404 medicinal & biomolecular chemistry ,chemistry ,Cisplatin - Abstract
Pleurotus cornucopiae (Pleurotaceae) is an edible and medicinal mushroom widely distributed in Korea, China, and Japan. The MeOH extract of the fruiting bodies of P. cornucopiae showed renoprotective effects against cisplatin-induced kidney cell damage. Chemical investigation of the MeOH extract led to the isolation and identification of 12 compounds including noransine (1), uridine (2), uracil (3), (3β, 5α, 6β, 22E, 24S) -ergosta-7, 22-diene-3, 5, 6, 9-tetrol (4), (22E,24S)-ergosta-7,22-diene-3β,5α,6β-triol (5), (22E,24R)-ergosta-8(14),22-diene-3β,5α,6β,7α-tetrol (6), cerebroside B (7), (2R) -N- [(1S, 2R, 3E, 7E) -1- [(β-d-glucopyranosyloxy) methyl] -2-hydroxy-8-methyl-3, 7-heptadecadien-1-yl] -2-hydroxy-heptadecanamide (8), cerebroside D (9), nicotinamide (10), 1,2-bis(hydroxymethyl)-4,5-dimethoxybenzene (11), and benzoic acid (12). Among them, compounds 1 and 11 were isolated as naturally occurring products for the first time, though they were reported as synthetic products in previous papers. All of the compounds (except 8 and 11) abrogated cisplatin-induced LLC-PK1 cell damage in a dose-dependent manner. Of special note, compounds 2, 5, 6, and 12 ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 10μM. The protective effects of compounds 2, 5, 6, and 12 were mediated via the deactivation of JNK-caspase 3 apoptotic cascade. This study is the first to demonstrate that the chemical constituents of P. cornucopiae display renoprotective effects against anticancer drug-induced damage in kidney cells.
- Published
- 2017
45. Synthesis of dual-action parthenolide prodrugs as potent anticancer agents
- Author
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Mehrdad Iranshahi, Mohammad Ali Nasseri, and Akram Taleghani
- Subjects
Drug ,media_common.quotation_subject ,Antineoplastic Agents ,Apoptosis ,Chemistry Techniques, Synthetic ,Pharmacology ,Sesquiterpene lactone ,01 natural sciences ,Biochemistry ,Catalysis ,Lactones ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cancer stem cell ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,LNCaP ,medicine ,Humans ,Prodrugs ,Parthenolide ,Melphalan ,Molecular Biology ,media_common ,chemistry.chemical_classification ,010405 organic chemistry ,Organic Chemistry ,Cytarabine ,Prodrug ,0104 chemical sciences ,Hep G2 ,chemistry ,030220 oncology & carcinogenesis ,Sesquiterpenes ,medicine.drug - Abstract
Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency. We prepared novel parthenolide derivatives through the aza-Michael addition of nitrogen-containing anticancer drug molecules (cytarabine and melphalan) to the α-methylene-γ-lactone group of parthenolide. Different types of catalysts were used to catalyze the aza-Michael addition. Among all the used catalysts, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was found to have the highest catalytic activity. In addition, we examined the effects of parthenolide-anticancer drug hybrids on the growth and proliferation of three cancer cell lines (MCF-7, LNcaP, Hep G2) and CHO. The parthenolide prodrugs showed potent cytotoxic property with IC50 values ranging from 0.2 to 5.2μM, higher than those of parthenolide and anticancer drugs (cytarabine and melphalan).
- Published
- 2017
46. Experimental, computational and chemometrics studies of BSA-vitamin B6 interaction by UV–Vis, FT-IR, fluorescence spectroscopy, molecular dynamics simulation and hard-soft modeling methods
- Author
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Firouzeh Manouchehri, Elham Aghaee, Yahya Izadmanesh, and Jahan B. Ghasemi
- Subjects
Analytical chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Molecular Docking Simulation ,Fluorescence spectroscopy ,Molecular dynamics ,Spectroscopy, Fourier Transform Infrared ,Drug Discovery ,Animals ,Molecular Biology ,Quenching (fluorescence) ,010405 organic chemistry ,Chemistry ,Hydrogen bond ,Organic Chemistry ,Serum Albumin, Bovine ,Ligand (biochemistry) ,Binding constant ,Vitamin B 6 ,0104 chemical sciences ,Spectrometry, Fluorescence ,Docking (molecular) ,Cattle ,Spectrophotometry, Ultraviolet - Abstract
The interaction of pyridoxine (Vitamin B6) with bovine serum albumin (BSA) is investigated under pseudo-physiological conditions by UV-Vis, fluorescence and FTIR spectroscopy. The intrinsic fluorescence of BSA was quenched by VB6, which was rationalized in terms of the static quenching mechanism. According to fluorescence quenching calculations, the bimolecular quenching constant (kq), dynamic quenching (KSV) and static quenching (KLB) at 310K were obtained. The efficiency of energy transfer and the distance between the donor (BSA) and the acceptor (VB6) were calculated by Foster's non-radiative energy transfer theory and were equal to 41.1% and 2.11nm. The collected UV-Vis and fluorescence spectra were combined into a row-and column-wise augmented matrix and resolved by multivariate curve resolution-alternating least squares (MCR-ALS). MCR-ALS helped to estimate the stoichiometry of interactions, concentration profiles and pure spectra for three species (BSA, VB6 and VB6-BSA complex) existed in the interaction procedure. Based on the MCR-ALS results, using mass balance equations, a model was developed and binding constant of complex was calculated using non-linear least squares curve fitting. FT-IR spectra showed that the conformation of proteins was altered in presence of VB6. Finally, the combined docking and molecular dynamics (MD) simulations were used to estimate the binding affinity of VB6 to BSA. Five-nanosecond MD simulations were performed on bovine serum albumin (BSA) to study the conformational features of its ligand binding site. From MD results, eleven BSA snapshots were extracted, at every 0.5ns, to explore the binding affinity (GOLD score) of VB6 using a docking procedure. MD simulations indicated that there is a considerable flexibility in the structure of protein that affected ligand recognition. Structural analyses and docking simulations indicated that VB6 binds to site I and GOLD score values depend on the conformations of both BSA and ligand. Molecular modeling results showed that VB6-BSA complex formed not only on the basis of electrostatic forces, but also on the basis of π-π staking and hydrogen bond. There was an excellent agreement between the experimental and computational results. The results presented in this paper, will offer a reference for detailed and systematic studies on the biological effects and action mechanism of small molecules with proteins.
- Published
- 2016
47. Thermostability detection and optimization of glycoengineered antibodies and antibody-drug conjugates based on differential scanning flouremitry analysis
- Author
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Ken Qin, Mingjie Li, Feng Tang, Lei Zhao, Wei Shi, Faridoon, Yubo Tang, Wei Huang, and Bofeng Jiang
- Subjects
Glycan ,Glycosylation ,Immunoconjugates ,medicine.drug_class ,Drug Evaluation, Preclinical ,Monoclonal antibody ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Fluorometry ,Cytotoxicity ,Molecular Biology ,Thermostability ,Antibody-dependent cell-mediated cytotoxicity ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Temperature ,Antibodies, Monoclonal ,0104 chemical sciences ,body regions ,010404 medicinal & biomolecular chemistry ,chemistry ,biology.protein ,Antibody ,Conjugate - Abstract
Thermostability of monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), as a critical property of biotherapeutics, is important for their physicochemical processes, pharmacodynamics, and pharmacokinetics. Fc glycosylation of mAbs plays a crucial role in antibody functions including thermostability, however, due to the lack of homogeneous glycosylation for comparison, the precise impact of glycoforms on thermostability of mAbs and ADCs remains challenging to elucidate. In this paper, we employed the technique of differential scanning fluorimetry (DSF) to investigate the thermostability of Fc domains, glycoengineered mAbs, and ADCs, carrying well-defined N-glycan structures for comparison. The results revealed that high-mannose-type N-glycans dramatically reduce the Tm value of Fc, compared to complex-type N-glycans. We also found that core-fucose contributes to the thermostability of mAbs, and the unnatural modification on non-reducing end of biantennary N-glycan can compensate the reduced stability of afucosylated mAbs and maintain the advantage of enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). DSF analysis of lysine-linked and glycosite-specific ADCs indicated that thermostability of glycan-linked ADCs is reduced, but it could be improved by using an optimized linkage. This work provides an in-depth analysis on thermostability of mAbs and ADCs with homogeneous glycoforms, and also proposes new strategies for optimizing glycoengineered mAbs and glycosite-specific ADCs using unnatural glycan and stabilized linkage.
- Published
- 2019
48. Design, synthesis and antifungal activity evaluation of isocryptolepine derivatives
- Author
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Wang Renxuan, Zhong-Min Zhao, Yin-Fang Yan, Peng Jingwen, Xiao-Fei Shang, Jun-Cai Li, Guan-fang Hu, Rui Zhou, Yu Sun, Ying-Qian Liu, Jia-Kai Zhu, and Yu-Ling Wang
- Subjects
Antifungal Agents ,Microbial Sensitivity Tests ,01 natural sciences ,Biochemistry ,Indole Alkaloids ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Quinazoline ,Structure–activity relationship ,Mode of action ,Molecular Biology ,Mycelium ,EC50 ,chemistry.chemical_classification ,Reactive oxygen species ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Fungi ,Plants ,In vitro ,0104 chemical sciences ,Fungicides, Industrial ,Fungicide ,010404 medicinal & biomolecular chemistry ,chemistry ,Drug Design ,Quinolines ,Nuclear chemistry - Abstract
In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the “Aza”-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of “Aza”-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC50 values of 2.72 μg/mL, 5.90 μg/mL and 4.00 μg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC50 values of 8.81 μg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC50, 6.27 μg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 μg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides.
- Published
- 2019
49. Design, synthesis, DNA binding studies and evaluation of anticancer potential of novel substituted biscarbazole derivatives against human glioma U87 MG cell line
- Author
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Nitin Kumar, Neetika Lal, Pratibha Mehta Luthra, and Vishal Nemaysh
- Subjects
Circular dichroism ,Cell Survival ,Carbazoles ,Antineoplastic Agents ,Biochemistry ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,MTT assay ,Molecular Biology ,Carmustine ,biology ,Chemistry ,Brain Neoplasms ,Topoisomerase ,Organic Chemistry ,DNA ,Glioma ,Carbon-13 NMR ,Combinatorial chemistry ,Fluorescence ,Molecular Docking Simulation ,Cell culture ,Drug Design ,biology.protein ,medicine.drug - Abstract
In this research paper, we report the design and synthesis of novel substituted biscarbazole derivatives which were characterized by 1H and 13C NMR, high resolution mass spectroscopy (HRMS). The SAR study of the compounds is reported based on different substituents and their positions in the biscarbazole scaffold. In vitro cytotoxicity of the compounds was evaluated against human glioma U87 MG cell line by MTT assay for 24 h. The IC50 values of the compounds (30-35, 48-53 and 54-62) were calculated at the concentration range from 1.00 µM to 500 µM. The compound 34 showed the most significant in vitro cytotoxicity (IC50 = 3.9 µM) against human glioma U87 MG cell line and was found to be better than standard drugs used for the treatment of brain tumors such as temozolomide (IC50 = 100 µM) and carmustine (IC50 = 18.2 µM) respectively. To determine the mode of binding of compound 34 with CT-DNA, various biophysical techniques like UV-spectrophotometer, fluorescence, circular dichroism, viscosity, topoisomerase assay and molecular docking analysis, were used. Our results demonstrated groove binding mode of interaction of the compound 34 with CT-DNA with a plausible static bio-molecular quenching rate constant (Kq) 1.7 × 1012 M−1 s−1. The studies of biscarbazole derivatives are anticipated to develop potential novel anticancer agents against brain tumors.
- Published
- 2019
50. A mass spectrometric stochastic dynamic diffusion approach to selective quantitative and 3D structural analyses of native cyclodextrins by electrospray ionization and atmospheric pressure chemical ionization methods
- Author
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Bojidarka Ivanova and Michael Spiteller
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Electrospray ionization ,Analytical chemistry ,Molecular Conformation ,Atmospheric-pressure chemical ionization ,Molecular Dynamics Simulation ,Mass spectrometry ,01 natural sciences ,Biochemistry ,Quantum chemistry ,Spectral line ,Ion ,symbols.namesake ,Drug Discovery ,Diffusion (business) ,Molecular Biology ,Arrhenius equation ,Cyclodextrins ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Reproducibility of Results ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Atmospheric Pressure ,symbols ,Quantum Theory - Abstract
The paper addressed shortcoming with highly precise and selective 3D structural analysis of native cyclodextrins in mixture using ions observable at low m/z–region by ESI– and APCI–mass spectrometry. Because of, the quantitative and structural analyses of CDs, in general, are vexed by a set of complications. The study outlines our own stochastic dynamic approaches to the latter issues based on new model relations, quantifing the measurable MS outcome intensity. They introduce the so–called stochastic dynamic mass spectrometric diffusion “DSD” parameter, exhibiting high accuracy, precision, sensitivity and selectivity, respectively. It is linearly connected with the so–called quantum chemical diffusion parameter “DQC” according to Arrhenius’s theory. The most important upshot is that statistical parameters r = 0.99639–0.99981 has been obtained correlating between DSD and DQC parameters. Therefore, we determine high accurately 3D molecular and electronic structures of analytes by mass spectrometry. Fragment peaks at m/z 313, 279, 272, 252, 231, 214, 198, 171, 158 and 141 are examined. Mixtures of CDs and monomeric and acyclic oligomer carbohydrates glucose (1), sucrose (2), raffinose (3), melezitose (4) and cellotriose (5) are also studied. Our method is able to account precisely for the effect of the temperature under ESI– and APCI–MS conditions, as well. Correlative analysess between DSD parameters of ESI– and APCI–MS measurements under different temperatures is also shown. Chemometric tests are used. Another important results and conclusions, among others, to draw from this research are: (i) excellent linear correlation between DSD and DQC parameters of r = 0.99636 is found looking at common ions at m/z 141, 158 and 171, belonging to 2-formyl-3,4-dihydroxy-pyranylium, 4,5,6-trihydroxy-6H-pyran-2-carbaldehyde and 3,4,5-trihydroxy-6-oxo-6H-pyran-2-ylmethylidyne-oxonium ions. Thus, we distinguish precisely between the last structure and 3-formyl-4,5-dihydroxy-2,7-dioxa-8-oxonia-bicyclo[4.2.0]octa-1(8),3,5-triene cation. In the case of ion at m/z 141 subtle electronic effects are distinguished between the mentioned structure and the charged 3,4-dihydroxy-6H-pyran-2-carbaldehyde one. The method determines precisely very similar structurally poly–OH–substituted derivatives. Because of, (ii) absolute reproducibility (r = 1) of DSD parameters of ESI–MS spectra is obtained studying the shown in point (i) MS peaks of β-CD between jth and jth numbers of experiments. The statistical equation is DiSD = (0.51 ± 3.1.10−5) × DjSD; (iii) the APCI– and ESI–MS provide identical results studying common MS ions of CDs and the correlation between DAPCISD and DESISD parameters excludes from error, due to, experiment; and (iv) The correlation between theory and experiment accounting for the factor temperature within our model equations shows r = 0.9828 looking at the MS peaks at m/z 313 280, 279, 274 and 252, respectively. The effect of the temperature under both ESI– and APCI–MS conditions on the 3D molecular and electronic structures of CDs is precisely studied, respectively.
- Published
- 2019
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