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Abstract Precise and effective initiation of the apoptotic mechanism in tumor cells is one of the most promising approaches for the treatment of solid tumors. However, current techniques such as high-temperature ablation or gene editing suffer from the risk of damage to adjacent normal tissues. This study proposes a magnetothermal-induced CRISPR-Cas9 gene editing system for the targeted knockout of HSP70 and BCL2 genes, thereby enhancing tumor cell apoptosis. The magnetothermal nanoparticulate platform is composed of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles and the modified polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface, on which plasmid DNA can be effectively loaded. Under the induction of a controllable alternating magnetic field, the mild magnetothermal effect (42℃) not only triggers dual-genome editing to disrupt the apoptosis resistance mechanism of tumor cells but also sensitizes tumor cells to apoptosis through the heat effect itself, achieving a synergistic therapeutic effect. This strategy can precisely regulate the activation of the CRISPR-Cas9 system for tumor cell apoptosis without inducing significant damage to healthy tissues, thus providing a new avenue for cancer treatment.

Precise and effective initiation of the apoptotic mechanism in tumor cells is one of the most promising approaches for the treatment of solid tumors. However, current techniques such as high-temperature ablation or gene editing suffer from the risk of damage to adjacent normal tissues. This study proposes a magnetothermal-induced CRISPR-Cas9 gene editing system for the targeted knockout of HSP70 and BCL2 genes, thereby enhancing tumor cell apoptosis. The magnetothermal nanoparticulate platform is composed of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles and the modified polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface, on which plasmid DNA can be effectively loaded. Under the induction of a controllable alternating magnetic field, the mild magnetothermal effect (42℃) not only triggers dual-genome editing to disrupt the apoptosis resistance mechanism of tumor cells but also sensitizes tumor cells to apoptosis through the heat effect itself, achieving a synergistic therapeutic effect. This strategy can precisely regulate the activation of the CRISPR-Cas9 system for tumor cell apoptosis without inducing significant damage to healthy tissues, thus providing a new avenue for cancer treatment. [ABSTRACT FROM AUTHOR]

In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart. [ABSTRACT FROM AUTHOR]

New phenylacetic acid derivatives with potentially valuable biological activities and the ability to act as starting materials for various functionalizations have been prepared by a multi-step synthesis. Starting from 2,6-dibromo-4-methylaniline, the synthetic route involves the construction of the basic aromatic structure (3,4,5-triphenyltoluene) (two steps), followed by its conversion into 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives (up to five steps). Based on this multi-step synthesis, five compounds not previously reported in the literature were synthesized; the literature-known 3,4,5-triphenyltoluene was synthesized for the first time in the manner described. This synthesis is applicable for the preparation of numerous new representatives of this class of compounds. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib's cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations. [ABSTRACT FROM AUTHOR]

New phenylacetic acid derivatives with potentially valuable biological activities and the ability to act as starting materials for various functionalizations have been prepared by a multi-step synthesis. Starting from 2,6-dibromo-4-methylaniline, the synthetic route involves the construction of the basic aromatic structure (3,4,5-triphenyltoluene) (two steps), followed by its conversion into 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives (up to five steps). Based on this multi-step synthesis, five compounds not previously reported in the literature were synthesized; the literature-known 3,4,5-triphenyltoluene was synthesized for the first time in the manner described. This synthesis is applicable for the preparation of numerous new representatives of this class of compounds.

Abstract In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart.

Simple Summary: This work describes the synthesis and characterization of four small-molecule derivatives based on the 1,10-phenanthroline heterocyclic system as potential telomeric quadruplex DNA ligands with antitumor properties. DNA-ligand interaction studies were carried out to determine thermal stabilization, structural effects and binding affinity towards the human telomeric DNA sequence Tel22. Cytotoxicity in tumor and normal cells was preliminarily tested, along with alterations in cell cycle and the ability to induce apoptosis. Three of the studied compounds can bind and stabilize the telomeric quadruplex sequence and exhibit moderate cytotoxicity in tumor cells. In addition, they were shown to induce apoptosis in HeLa cells, which highlights their potential applications as chemical tools for the development of novel antitumor agents. Four 1,10-phenanthroline derivatives (1–4) were synthesized as potential telomeric DNA binders, three substituted in their chains with thiosemicarbazones (TSCs) and one 4-phenylthiazole derivative. The compounds were characterized using NMR, HRMS, FTIR-spectroscopy and combustion elemental analysis. Quadruplex and dsDNA interactions were preliminarily studied, especially for neutral derivative 1, using FRET-based DNA melting assays, equilibrium dialysis (both competitive and non-competitive), circular dichroism and viscosity titrations. The TSC derivatives bind and stabilize the telomeric Tel22 quadruplex more efficiently than dsDNA, with an estimated 24-fold selectivity determined through equilibrium dialysis for compound 1. In addition, cytotoxic activity against various tumor cells (PC-3, DU145, HeLa, MCF-7 and HT29) and two normal cell lines (HFF-1 and RWPE-1) was evaluated. Except for the 4-phenylthiazole derivative, which was inactive, the compounds showed moderate cytotoxic properties, with the salts displaying lower IC50 values (30–80 μM), compared to the neutral TSC, except in PC-3 cells (IC50 (1) = 18 μM). However, the neutral derivative was the only compound that exhibited a modest selectivity in the case of prostate cells (tumor PC-3 versus healthy RWPE-1). Cell cycle analysis and Annexin V/PI assays revealed that the compounds can produce cell death by apoptosis, an effect that has proven to be similar to that demonstrated by other known 1,10-phenanthroline G4 ligands endowed with antitumor properties, such as PhenDC3 and PhenQE8. [ABSTRACT FROM AUTHOR]

Simple Summary: Soft tissue sarcomas represent a large heterogeneous group of malignant neoplasms that are characterized by a poor disease outcome and being poorly studied. Recently, more and more studies have been directed to the role of tumor microenvironment components in establishing the aggressive potential of the tumor. Many antitumor drugs, in addition to their direct effect on tumor cells, modify the tumor microenvironment; in particular, they act on the immune component, which may be the reason for their effectiveness in soft tissue sarcoma. Immune cells themselves are now considered as promising antitumor strategies for the treatment of soft tissue sarcomas. Understanding the mechanisms of interaction between tumor cells and immune cells in different types of soft tissue sarcomas will allow us to divide patients into those for whom immunotherapy will be highly effective and those for whom this type of treatment will be ineffective. Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent. [ABSTRACT FROM AUTHOR]

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins. [ABSTRACT FROM AUTHOR]

Twenty-five azole compounds (P1–P25) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities in silico and in vitro. P25 exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, P14 was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC50 15.9 μM), with activity greater than arbutin and kojic acid. Also, P6 exhibited noteworthy free radical-scavenging activity. Furthermore, in silico docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified – some with multiple activities – warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents. [ABSTRACT FROM AUTHOR]

A library of 24 congeners of the natural product sulfuretin were evaluated against nine panels representing nine cancer diseases. While sulfuretin elicited very weak activities at 10 µM concentration, congener 1t was identified as a potential compound triggering growth inhibition of diverse cell lines. Mechanistic studies in HCT116 colon cancer cells revealed that congener 1t dose-dependently increased levels of cleaved-caspases 8 and 9 and cleaved-PARP, while it concentration-dependently decreased levels of CDK4, CDK6, Cdc25A, and Cyclin D and E resulting in induction of cell cycle arrest and apoptosis in colon cancer HCT116 cells. Mechanistic study also presented MET receptor tyrosine kinase as the molecular target mediating the anticancer activity of compound 1t in HCT116 cells. In silico study predicted folded p-loop conformation as the form of MET receptor tyrosine kinase responsible for binding of compound 1t. Together, the current study presents compound 1t as an interesting anticancer lead for further development. [ABSTRACT FROM AUTHOR]

Bacterial extracellular vesicles (BEVs), bacteria-derived extracellular vesicles, are key intermediates of bacteria-bacteria and bacteria-host interactions. They are a 'double-edged sword'. On one hand, they play a negative role in the onset and progression of various diseases, including intestinal inflammatory disease, neurological disease, liver disease, metabolic disease, autoimmune disease and cancer. On the other hand, they play a positive role as potential biomarkers, vaccines, antitumor agents. The application of BEVs may provide novel strategies for the diagnosis and treatment of diseases. However, research on BEVs is still in its infancy, and challenges remain in vesicle isolation techniques, disease diagnostic specificity, optimization of vesicle storage and transport. Thus rigorously designed clinical studies are required to verify their diagnostic and therapeutic value.

Background: Actinomycetes particularly the Streptomyces sp. derived from marine and coastal habitats are regarded as the main source of antibiotics. In the current study, to isolate the antibiotic-producing actinomycetes sediment samples were collected from Manakudy estuary, Kanyakumari District, Tamil Nadu. Results: The isolates were selected based on the antagonistic activity; the highly active isolate was identified as Streptomyces sp. CMSTAAHL-3. The culture media for the antibiotic production was optimized by one variable at a time and confirmed by the zone of inhibition against tested pathogens such as Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Then by altering the four factors starch, urea, MgSO4 and NaCl at five levels, statistical optimization of the media components was explored using Response Surface Methodology-Central Composite Design and found that the predicted antibiotic response was closely correlated with the experimentally one and was confirmed by the zone of inhibition. Conclusions: The Streptomyces sp. CMSTAAHL-3 and its antibiotics may be of great use in the treatment of a variety of pathogens, and the ideal culture medium discovered in this experiment will be helpful for further research involving large-scale fermentation for the effective production of antibiotics.How to cite: Selvaraj JN, Ganapathi U, Vincent SGP, et al. Statistical optimization of media components for antibiotic production in Streptomyces sp. CMSTAAHAL-3. Electron J Biotechnol 2023;64. https://doi.org/10.1016/j.ejbt.2023.03.005.

Twenty-five azole compounds (P1–P25) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities in silico and in vitro. P25 exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, P14 was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC50 15.9 μM), with activity greater than arbutin and kojic acid. Also, P6 exhibited noteworthy free radical-scavenging activity. Furthermore, in silico docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified – some with multiple activities – warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents.

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

Background: Actinomycetes particularly the Streptomyces sp. derived from marine and coastal habitats are regarded as the main source of antibiotics. In the current study, to isolate the antibiotic-producing actinomycetes sediment samples were collected from Manakudy estuary, Kanyakumari District, Tamil Nadu. Results: The isolates were selected based on the antagonistic activity; the highly active isolate was identified as Streptomyces sp. CMSTAAHL-3. The culture media for the antibiotic production was optimized by one variable at a time and confirmed by the zone of inhibition against tested pathogens such as Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Then by altering the four factors starch, urea, MgSO4 and NaCl at five levels, statistical optimization of the media components was explored using Response Surface Methodology-Central Composite Design and found that the predicted antibiotic response was closely correlated with the experimentally one and was confirmed by the zone of inhibition. Conclusions: The Streptomyces sp. CMSTAAHL-3 and its antibiotics may be of great use in the treatment of a variety of pathogens, and the ideal culture medium discovered in this experiment will be helpful for further research involving large-scale fermentation for the effective production of antibiotics. [ABSTRACT FROM AUTHOR]

Introduction: Heterocyclic compounds have diverse biological activities and potential in drug development. This study aims to synthesize novel compounds with two 1,2,4-triazole cores and evaluate their biological properties, particularly their inhibitory activity against thymidine phosphorylase (TP), an enzyme involved in various physiological processes.Methods: The compounds were synthesized by reacting 5,5'-butane-bis-1,2,4-triazole derivatives with prenyl bromide. Characterization involved various techniques, including spectroscopy and elemental analysis. Antimicrobial potential was evaluated against bacteria and fungi, with comparative antibiotics as references. Inhibitory activity against TP was assessed, and molecular docking studies were conducted.Results: Six compounds were successfully synthesized and their structures confirmed. The synthesized triazole derivatives exhibited high biological activity, with compounds 2 and 6 showing the most promising TP inhibition. Molecular docking studies revealed interactions between compound 2 and TP, involving nine amino acids.Discussion: The synthesis of novel compounds with two 1,2,4-triazole cores contributes significantly to bis-triazole research. These compounds have potential as anti-tumor agents due to their inhibitory activity against TP, a crucial enzyme in tumor growth and metastasis. Comparative evaluation against antibiotics highlights their potency. Docking results provide insights into their interactions with TP, supporting their potential as potent TP inhibitors. Further research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and optimizing their activities.Conclusion: The synthesized compounds with two 1,2,4-triazole cores exhibit significant biological activity, including strong TP inhibition and broad-spectrum antimicrobial effects. These findings emphasize their potential as anti-tumor agents and the need for further exploration and optimization. Future research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and developing more potent bis-triazole derivatives for drug discovery efforts. The combined results from assays and docking studies support the therapeutic potential of these compounds as anti-tumor agents. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib’s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

Background: The use of nanodiamonds (NDs) and fluorescent nanodiamonds (FNDs) as nonallergenic biocompatible additives in incomplete Freund's adjuvant (IFA) to elicit immune responses in vivo was investigated. Methods: C57BL/6 mice were immunized with chicken egg ovalbumin (OVA) in IFA and also OVA-conjugated NDs (or OVA-conjugated FNDs) in IFA to produce antibodies. OVA-expressing E.G7 lymphoma cells and OVA-negative EL4 cells were inoculated in mice to induce tumor formation. Results: The new formulation significantly enhanced immune responses and thus disease resistance. It exhibited specific therapeutic activities, effectively inhibiting the growth of E.G7 tumor cells in mice over 35 days. Conclusion: The high biocompatibility and multiple functionalities of NDs/FNDs render them applicable as active and trackable vaccine adjuvants and antitumor agents. [ABSTRACT FROM AUTHOR]

The search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents.

Cell division cycle 20 (CDC20), a critical partner of anaphase promoting complex (APC/C), is indispensably required for metaphase-to-anaphase transition. CDC20 overexpression in TNBC breast cancer patients has been found to be correlated with poor prognosis, hence, we aimed to target CDC20 for TNBC therapeutics. In silico molecular docking of large-scale chemical libraries (phytochemicals/synthetic drugs) against CDC20 protein structure identified five synthetic drugs and four phytochemicals as potential hits interacting with CDC20 active site. The molecular selection was done based on docking scores, binding interactions, binding energies and MM/GBSA scores. Further, we analysed ADME profiles for all the hits and identified lidocaine, an aminoamide anaesthetic group of synthetic drug, with high drug-likeness properties. We explored the anti-tumorigenic effects of lidocaine on MDA-MB-231 TNBC breast cancer cells, which resulted in increased growth inhibition in dose-dependent manner. The molecular mechanism behind the cell viability defect mediated by lidocaine was found to be induction of G2/M cell cycle arrest and cellular apoptosis. Notably, lidocaine treatment of TNBC cells also resulted in downregulation of CDC20 gene expression. Thus, this study identifies lidocaine as a potential anti-neoplastic agent for TNBC cells emphasizing CDC20 as a suitable therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas. [ABSTRACT FROM AUTHOR]

A series of new 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with different aryl substituents at the 5 position are synthesized and characterized by 1H/ 13C NMR and IR-spectroscopy and mass-spectrometry, as well as single crystal X-ray diffraction (SCXRD). It was demonstrated that the type of hydrogen bonding can play a key role in the chiral discrimination of these compounds in the crystalline phase. The hydrogen bond of the O–H...N type leads to 1D supramolecular heterochiral chains or conglomerate crystallization in the case of the formation of homochiral chains. The hydrogen bond of O–H...O type gave racemic dimers, which are packed into 2D supramolecular layers with a parallel or angular dimers arrangement. Halogen bonding of the N...Br or O...Br type brings a new motif into supramolecular self-assembly in the crystalline phase: the formation of 1D supramolecular homochiral chains instead 2D supramolecular layers. The study of cytotoxicity against various tumor cells in vitro was carried out. It was found that 2-hydroxy−3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with 3-nitrophenyl substituent at C5 carbon atom demonstrated a high efficiency against M-HeLa (cervical adenocarcinoma) and low cytotoxicity against normal liver cells. [ABSTRACT FROM AUTHOR]

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds. [ABSTRACT FROM AUTHOR]

Four 1,10-phenanthroline derivatives (1–4) were synthesized as potential telomeric DNA binders, three substituted in their chains with thiosemicarbazones (TSCs) and one 4-phenylthiazole derivative. The compounds were characterized using NMR, HRMS, FTIR-spectroscopy and combustion elemental analysis. Quadruplex and dsDNA interactions were preliminarily studied, especially for neutral derivative 1, using FRET-based DNA melting assays, equilibrium dialysis (both competitive and non-competitive), circular dichroism and viscosity titrations. The TSC derivatives bind and stabilize the telomeric Tel22 quadruplex more efficiently than dsDNA, with an estimated 24-fold selectivity determined through equilibrium dialysis for compound 1. In addition, cytotoxic activity against various tumor cells (PC-3, DU145, HeLa, MCF-7 and HT29) and two normal cell lines (HFF-1 and RWPE-1) was evaluated. Except for the 4-phenylthiazole derivative, which was inactive, the compounds showed moderate cytotoxic properties, with the salts displaying lower IC50 values (30–80 μM), compared to the neutral TSC, except in PC-3 cells (IC50 (1) = 18 μM). However, the neutral derivative was the only compound that exhibited a modest selectivity in the case of prostate cells (tumor PC-3 versus healthy RWPE-1). Cell cycle analysis and Annexin V/PI assays revealed that the compounds can produce cell death by apoptosis, an effect that has proven to be similar to that demonstrated by other known 1,10-phenanthroline G4 ligands endowed with antitumor properties, such as PhenDC3 and PhenQE8.

A library of 24 congeners of the natural product sulfuretin were evaluated against nine panels representing nine cancer diseases. While sulfuretin elicited very weak activities at 10 µM concentration, congener 1t was identified as a potential compound triggering growth inhibition of diverse cell lines. Mechanistic studies in HCT116 colon cancer cells revealed that congener 1t dose-dependently increased levels of cleaved-caspases 8 and 9 and cleaved-PARP, while it concentration-dependently decreased levels of CDK4, CDK6, Cdc25A, and Cyclin D and E resulting in induction of cell cycle arrest and apoptosis in colon cancer HCT116 cells. Mechanistic study also presented MET receptor tyrosine kinase as the molecular target mediating the anticancer activity of compound 1t in HCT116 cells. In silico study predicted folded p-loop conformation as the form of MET receptor tyrosine kinase responsible for binding of compound 1t. Together, the current study presents compound 1t as an interesting anticancer lead for further development.

Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R1 = CH3, showed the best capacity for inhibiting APN with an IC50 value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His297, Glu298 and His301. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S2′ and S1 pockets via hydrophobic effects, respectively. [ABSTRACT FROM AUTHOR]

A series of new thiazolo[3,2-a]pyrimidines different by aryl substituents in 2 and 5 positions are synthesized and characterized in solution as well as in the crystalline phase using 1H and 13C NMR-, IR-spectroscopies, mass-spectrometry methods, and single crystal X-ray diffraction (SCXRD). The SCXRD study revealed the role of intermolecular H-bonding in the formation of supramolecular architectures (racemic monomers, centrosymmetric racematic dimers, or homochiral 1D chains) of obtained thiazolo[3,2-a]pyrimidines derivatives depending on solvents (aprotic DMSO or protic EtOH) used upon the crystallization process. Moreover, the in vitro study of cytotoxicity toward different tumor cells showed their high or moderate efficiency with moderate cytotoxicity against normal liver cells which allows to consider the obtained thiazolo[3,2-a]pyrimidine derivatives as promising candidates for application as antitumor agents. [ABSTRACT FROM AUTHOR]

The search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents. [ABSTRACT FROM AUTHOR]

The aim of the work is to generalize the literature data on indolocarbazole derivatives with an antitumor activity.Materials and methods. The objects of the study were the preparations based on indolocarbazole derivatives with the antitumor activity. To search for materials on the problem under study, the following search and information as well as library databases were used: ebibrary, PubMed, CyberLeninka, ResearchGate, the State Register of Medicines, clinical trials registries clinline.ru and clinicaltrials.gov. The search for the following words / phrases was performed: indolocarbazoles, indolocarbazole derivatives, staurosporine, rebeccamycin, staurosporine derivatives. The search was conducted from January 11 until March 1, 2021. The compounds with a biological activity which were undergoing or had undergone preclinical and clinical trials, were taken into account. All the materials from 1977 to January 1, 2021, were taken into account.Results. The materials obtained indicate that indolocarbazole derivatives are promising compounds for the creation of anticancer medicinal preparations due to their properties and peculiarities of the action mechanism. These drugs have a selective action due to the targeted interaction with specific molecular targets: kinases (especially protein kinase C and its isozymes), DNA and DNA topoisomerase. To date, many compounds from the class of indolocarbazoles have been synthesized and investigated. They have shown a high antitumor activity in the treatment of systemic and solid tumors. However, despite this, only one MP based on a staurosporine derivative, registered by the TN of Rydapt® (in the USA and EU countries) and Miticaid® (in the Russian Federation), is approved for use in the clinical practice.Conclusion. Thus, the basic data from scientific publications on promising anticancer medicinal preparations based on compounds from the class of indolocarbazoles, have been summarized. The information is provided, in particular, on their molecular structure, the origin, classification, the main representatives of the class, which are at various stages of the research and are approved for use in the clinic.

Glucose, the central macronutrient, releases energy as ATP through carbon bond oxidation and supports various physiological functions of living organisms. Hepatocarcinogenesis relies on the bioenergetic advantage conferred by glucometabolic reprogramming. The exploitation of reformed metabolism induces a uniquely inert environment conducive to survival and renders the hepatocellular carcinoma (HCC) cells the extraordinary ability to thrive even in the nutrient-poor tumormicroenvironment. The rewiredmetabolism also confers a defensive barrier which protects the HCC cells from environmental stress and immune surveillance. Additionally, targeted interventions against key players of HCC metabolic and signaling pathways provide promising prospects for tumor therapy. The active search for novel drugs based on innovative mutation targets is warranted in the future for effectively treating advanced HCC and the preoperative downstage. This article aims to review the regulatorymechanisms and therapeutic value of glucometabolic reprogramming on the disease progression of HCC, to gain insights into basic and clinical research. [ABSTRACT FROM AUTHOR]

Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare subtype of cancer, with a poor prognosis in children and adults. Mitotane is the only approved adrenolytic drug for the treatment of ACC, which has controversies regarding its efficacy and side effects on patients. Onion (Allium cepa), a worldwide consumed food, is associated with many health benefits. Along with its glycosides, the flavonoid quercetin is abundant in onions. After evaluating the cytotoxicity of A. cepa extracts on adrenocortical carcinoma cell line (H295R), the rich quercetin fractions had better results. Then, we aimed to compare the quercetin vs. mitotane effectiveness, using adrenocortical carcinoma cell lines H295R and SW-13. Quercetin showed a higher cytotoxicity response on both cancerous cell lines after 10 µM concentration, while mitotane only after 30 µM. Cell cycle dynamics were altered upon quercetin treatments, with G2 phase increase with 30 µM of quercetin on H295R cell line and G1 arrest on SW-13 cell line with 15 µM. Early and late apoptosis, alongside intracellular calcium, were increased on SW-13 treated with 30 µM of quercetin, and ROS rates were reduced by quercetin on H295R. Therefore, quercetin-rich onions have the potential to be a natural source of anticancer agents for adrenocortical carcinoma. [ABSTRACT FROM AUTHOR]

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry. [ABSTRACT FROM AUTHOR]

The transcription factor, sterol regulatory element binding protein 1 (SREBP-1), plays important roles in modulating the proliferation, metastasis, or resistance to antitumor agents by promoting cellular lipid metabolism and related cellular glucose-uptake/Warburg Effect. However, the underlying mechanism of SREBP-1 regulating the proliferation or drug-resistance in lung squamous cell carcinoma (LUSC) and the therapeutic strategies targeted to SREBP-1 in LUSC remain unclear. In this study, SREBP-1 was highly expressed in LUSC tissues, compared with the paired non-tumor tissues (the para-tumor tissues). A novel small-molecule inhibitor of SREBP-1, MSI-1 (Ma's inhibitor of SREBP-1), based on natural product monomers, was identified by screening the database of natural products. Treatment with MSI-1 suppressed the activation of SREBP-1-related pathways and the Warburg effect of LUSC cells, as indicated by decreased glucose uptake or glycolysis. Moreover, treatment of MSI-1 enhanced the sensitivity of LUSC cells to antitumor agents. The specificity of MSI-1 on SREBP-1 was confirmed by molecular docking and point-mutation of SPEBP-1. Therefore, MSI-1 improved our understanding of SREBP-1 and provided additional options for the treatment of LUSC. [ABSTRACT FROM AUTHOR]

The transcription factor, sterol regulatory element binding protein 1 (SREBP-1), plays important roles in modulating the proliferation, metastasis, or resistance to antitumor agents by promoting cellular lipid metabolism and related cellular glucose-uptake/Warburg Effect. However, the underlying mechanism of SREBP-1 regulating the proliferation or drug-resistance in lung squamous cell carcinoma (LUSC) and the therapeutic strategies targeted to SREBP-1 in LUSC remain unclear. In this study, SREBP-1 was highly expressed in LUSC tissues, compared with the paired non-tumor tissues (the para-tumor tissues). A novel small-molecule inhibitor of SREBP-1, MSI-1 (Ma’s inhibitor of SREBP-1), based on natural product monomers, was identified by screening the database of natural products. Treatment with MSI-1 suppressed the activation of SREBP-1-related pathways and the Warburg effect of LUSC cells, as indicated by decreased glucose uptake or glycolysis. Moreover, treatment of MSI-1 enhanced the sensitivity of LUSC cells to antitumor agents. The specificity of MSI-1 on SREBP-1 was confirmed by molecular docking and point-mutation of SPEBP-1. Therefore, MSI-1 improved our understanding of SREBP-1 and provided additional options for the treatment of LUSC.

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas.

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds.

Abstract Rhamnolipids (RLs) are surface-active compounds and belong to the class of glycolipid biosurfactants, mainly produced from Pseudomonas aeruginosa. Due to their non-toxicity, high biodegradability, low surface tension and minimum inhibitory concentration values, they have gained attention in various sectors like food, healthcare, pharmaceutical and petrochemicals. The ecofriendly biological properties of rhamnolipids make them potent materials to be used in therapeutic applications. RLs are also known to induce apoptosis and thus, able to inhibit proliferation of cancer cells. RLs can also act as immunomodulators to regulate the humoral and cellular immune systems. Regarding their antimicrobial property, they lower the surface hydrophobicity, destruct the cytoplasmic membrane and lower the critical micelle concentration to kill the bacterial cells either alone or in combination with nisin possibly due to their role in modulating outer membrane protein. RLs are also involved in the synthesis of nanoparticles for in vivo drug delivery. In relation to economic benefits, the post-harvest decay of food can be decreased by RLs because they prevent the mycelium growth, spore germination of fungi and inhibit the emergence of biofilm formation on food. The present review focuses on the potential uses of RLs in cosmetic, pharmaceutical, food and health-care industries as the potent therapeutic agents.

Many transition metal complexes have unique physicochemical properties that can be efficiently exploited in medicinal chemistry for cancer treatment. Traditionally, double-stranded DNA has been assumed to be the main binding target; however, recent studies have shown that nucleosomal DNA as well as proteins can act as dominant molecular binding partners. This has raised new questions about the molecular determinants that govern DNA versus protein binding selectivity, and has offered new ways to rationalize their biological activity and possible side effects. To address these questions, molecular simulations at an atomistic level of detail have been used to complement, support, and rationalize experimental data. Herein we review some relevant studies-focused on platinum and ruthenium compounds-to illustrate the power of state-of-the-art molecular simulation techniques and to demonstrate how the interplay between molecular simulations and experiments can make important contributions to elucidating the target preferences of some promising transition metal anticancer agents. This contribution aims at providing relevant information that may help in the rational design of novel drug-discovery strategies.

Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells, Glc-Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro.

Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R1 = CH3, showed the best capacity for inhibiting APN with an IC50 value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His297, Glu298 and His301. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S2′ and S1 pockets via hydrophobic effects, respectively.

A series of new thiazolo[3,2-a]pyrimidines different by aryl substituents in 2 and 5 positions are synthesized and characterized in solution as well as in the crystalline phase using 1H and 13C NMR-, IR-spectroscopies, mass-spectrometry methods, and single crystal X-ray diffraction (SCXRD). The SCXRD study revealed the role of intermolecular H-bonding in the formation of supramolecular architectures (racemic monomers, centrosymmetric racematic dimers, or homochiral 1D chains) of obtained thiazolo[3,2-a]pyrimidines derivatives depending on solvents (aprotic DMSO or protic EtOH) used upon the crystallization process. Moreover, the in vitro study of cytotoxicity toward different tumor cells showed their high or moderate efficiency with moderate cytotoxicity against normal liver cells which allows to consider the obtained thiazolo[3,2-a]pyrimidine derivatives as promising candidates for application as antitumor agents.

We previously found that p97 ATPase inhibitors 2-(2-amino-1H-benzo[d]imidazol-1-yl)-N-benzyl-8-methoxyquinazolin-4-amine (ML240) and 2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine (ML241) specifically target the D2 domain of wild-type p97. In addition, one of the major p97 cofactors, p47, decreases their potencies by ∼50-fold. In contrast, N(2) ,N(4) -dibenzylquinazoline-2,4-diamine (DBeQ) targets both the D1 and D2 domains and shows only a four- to sixfold decrease in potency against the p97-p47 complex. To elucidate structure-activity relationships for the inhibitors, we screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of either or both of the D1 or D2 domains, as well for their effects on p47 potency. The selectivity of 29 of these compounds was further examined by eight-dose titrations. Four compounds showed modest selectivity for inhibiting the ATPase activity of D1. Eleven compounds inhibited D2 with greater potencies, and four showed similar potencies against D1 and D2. p47 decreased the potencies of the majority of the compounds and increased the potencies of five compounds. These results highlight the possibility of developing domain-selective and complex-specific p97 inhibitors in order to further elucidate the physiological roles of p97 and its cofactors.

The family of polyhalogenated monoterpenes from Plocamium counts over a hundred known members. Using glyceraldehyde acetonide as a chiral-pool precursor, an enantioselective and divergent strategy was developed that provides a blueprint for the synthesis of many of the small yet complex acyclic members of this family. The broad applicability of this approach is demonstrated with the short, eight-step synthesis of four natural products and three analogues. These syntheses are the first of any members of the acyclic polyhalogenated Plocamium monoterpenes and permitted the evaluation of their selectivity against a range of tumor cell lines.

Background: The chemistry and applications of 2-pyridone structures have recently attracted a lot of attention due to their uses as synthetic intermediates and their biological importance. Furthermore, 2-pyridones are a different category of pharmacophores that exhibit several biological activities. Results: The 2-pyridones substrates are synthetically multilateral, where they can be used to synthesize a wide range of heterocyclic compounds and as a drug synthesis raw material. Therefore, it was the purpose of this review to evaluate the pharmacological properties of various substituted 2-pyridone systematically and collates these findings to be used as a guide for future structure–activity relationship and mode of action studies. Conclusion: Taken together, we demonstrate that the fused 2-pyridone is a versatile scaffold for biological applications.

Metal complexes play an essential role in pharmaceutical sciences for their multiple and important activities. Schiff bases are versatile pharmacophores able to form chelating complexes with several metals in different oxidation states. Complexes with Schiff bases are widely described in the literature for their multiple actions and numerous advantages, such as low cost and easy synthesis. They show multiple biological activities, including antimicrobial, antioxidant, antimalarial, antinflammatory and antitumor. Schiff bases may also form complexes with lanthanides and actinides acting as catalysts (e.g., in various synthetic processes) and antitumor agents. This review intends to extend on our previous paper regarding Schiff bases as antitumorals, highlighting the importance, in the field of the anticancer agents, of these tools as ligands of metal complexes. [ABSTRACT FROM AUTHOR]

In the present study, synthesis of a simple series of nitrogen heterocycles containing N-(pbromophenyl) carboxamide moiety, such as benzimidazole, benzoxazine, oxadiazole and triazole compounds, by using 4-bromo aniline and diethyl oxalate as a key starting material has been described. Five nitrogen heterocycles compounds moiety were evaluated for their anticancer activity against MCF-7 cell line. The results revealed that compound 8 (N-(4-bromophenyl)-5-thioxo-1,3,4-oxadiazole-2-carboxamide) was the most potent cytotoxic activity. Cell cycle analysis demonstrated that compound 8 induce cell cycle arrest at G1 phase with apoptosis inducing activity marked by increase in G0 phase. [ABSTRACT FROM AUTHOR]

Herein we demonstrate a new strategy by introducing Se atom with strong polarization effects to obtain highly bioactive organoselenium with electrophilic center. Organoselenium interact with Cys16 and Thr18 of PDGFB in malignant osteosarcoma MG63 cells through non-covalent bond, which further block the activation of intracellular AKT/JNK and downstream signaling pathways to promote cancer cells apoptosis. [Display omitted] • Organic selenium with high bioactivity electrophilic center was synthesized. • Org-Se can target PDGFB protein in MG63 cells and promote apoptosis. • Org-Se combined with radiotherapy can promote apoptosis of MG63 cells. Growth factor-like proteins play an important role in promoting oncogenesis. Therefore, designing specific inhibitors of such targets would facilitate the development of targeted drugs with low toxicity. However, low affinity and poor specificity between drugs and target proteins always affect the selectivity and action efficacy. Herein we demonstrates a new strategy by introducing selenium (Se) atom with strong polarization effects to obtain highly bioactive organoselenium with electrophilic center. The results of target-capturing analysis reveals that organoselenium interact with Cys16 and Thr18 of the platelet-derived growth factor B (PDGFB) protein in malignant osteosarcoma MG63 cells through non-covalent bond, thus inhibiting the expression and activity of PDGFB, which further block the activation of intracellular protein kinase B/c-Jun N-terminal kinases (AKT/JNK) and downstream signaling pathways to promote cancer cells apoptosis. Taken together, we have developed a novel strategy by introducing Se-based electrophilic centers for the development of targeted therapeutic agents for malignant tumors. [ABSTRACT FROM AUTHOR]