School Of Basic And Applied Sciences
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Item Design, one-pot synthesis, computational and biological evaluation of diaryl benzimidazole derivatives as MEK inhibitors(Taylor and Francis Ltd., 2023-10-09T00:00:00) Ram, Teja; Singh, Ankit Kumar; Pathak, Prateek; Kumar, Adarsh; Singh, Harshwardhan; Grishina, Maria; Novak, Jurica; Kumar, PradeepMEK mutations are more common in various human malignancies, such as pancreatic cancer (70�90%), mock melanoma (50%), liver cancer (20�40%), colorectal cancer (25�35%), melanoma (15�20%), non-small cell lung cancer (10�20%) and basal breast cancer (1�5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1�S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT ?29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1�15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item The medicinal perspective of 2,4-thiazolidinediones based ligands as antimicrobial, antitumor and antidiabetic agents: A review(John Wiley and Sons Inc, 2022-06-18T00:00:00) Kajal, Kumari; Singh, Gurpreet; Pradhan, Tathagata; Bhurta, Deendyal; Monga, Vikramdeep2,4-Thiazolidinedione (2,4-TZD), commonly known as glitazone, is a ubiquitous heterocyclic pharmacophore possessing a plethora of pharmacological activities and offering a vast opportunity for structural modification. The diverse range of biological activities endowed with a novel mode of action, low cost, and easy synthesis has attracted the attention of medicinal chemists. Several researchers have integrated the TZD core with different structural fragments to develop a wide range of lead molecules against various clinical disorders. The most common sites for structural modifications at the 2,4-TZD nucleus are the N-3 and the active methylene at C-5. The review covers the recent development of TZD derivatives such as antimicrobial, anticancer, and antidiabetic agents. Various 2,4-TZD based agents or drugs, which are either under clinical development or in the market, are discussed in the study. Different synthetic methodologies for synthesizing the 2,4-TZD core are also included in the manuscript. The importance of various substitutions at N-3 and C-5 and the mechanisms of action and structure�activity relationships are also discussed. We hope this study will serve as a valuable tool for the scientific community engaged in the structural exploitation of the 2,4-TZD core for developing novel drug m\olecules for life-threatening ailments. � 2022 Deutsche Pharmazeutische Gesellschaft.Item Recent Advancement of Polymersomes as Drug Delivery Carrier(Bentham Science Publishers, 2022-04-14T00:00:00) Singh, Kuldeep; Biharee, Avadh; Vyas, Amber; Thareja, Suresh; Jain, Akhlesh KumarBackground: Biomedical applications of polymersomes have been explored, including drug and gene delivery, insulin delivery, hemoglobin delivery, the delivery of anticancer agents, and various diagnostic purposes. Objectives: Polymersomes, which are self-assembled amphiphilic block copolymers, have received a lot of at-tention in drug delivery approaches. This review represents the methods of preparation of polymersomes, including thin-film rehydration, electroformation, double emulsion, gel-assisted rehydration, PAPYRUS method, and solvent injection methods, including various therapeutic applications of polymersomes. Methods: Data was searched from PubMed, Google Scholar, and Science Direct through searching of the following keywords: Polymersomes, methods of preparation, amphiphilic block copolymers, anticancer drug delivery Results: Polymersomes provide both hydrophilic and hydrophobic drug delivery to a targeted site, increasing the formulation's stability and reducing the cytotoxic side effects of drugs. Conclusion: Polymersomes have the potential to be used in a variety of biological applications, including drug and gene delivery, insulin delivery, hemoglobin delivery, delivery of anticancer agents, as well as in various diagnostic purposes. Recently, polymersomes have been used more frequently because of their stability, reducing the encapsulated drug's leakage, site-specific drug delivery, and increasing the bioavailability of the drugs and different diagnostic purposes. The liposomes encapsulate only hydrophilic drugs, but polymersomes encapsulate both hydrophilic and hydrophobic drugs in their cores. � 2022 Bentham Science Publishers.Item Isolation, Characterization, and Quantification of a New Anticancer Constituent from Leaves of Nyctanthes arbor-tristis(Springer, 2022-05-03T00:00:00) Grover, P.; Kaur, J.; Suri, K.A.; Kumar, R.; Bansal, G.A new compound, 1,1,2-tris(2?,4?-di-tert-butylphenyl)-4,4-dimethylpent-1-ene, was isolated and characterized from the leaves of Nyctanthes arbor-tristis L. The plant was subjected to bioactivity-guided fractionation, and a compound was isolated from chloroform extract that was found to have potent anticancer activity. The chloroform extract was further fractionated, and a pure compound was isolated that was found to be active against three cancer cell lines (HL-60, HCT-116, and A-549). An RP-HPLC method was developed for quantification of the isolated compound. The content of the isolated compound was 0.88% in the chloroform extract and 0.08% in N. arbor-tristis leaves. � 2022, Springer Science+Business Media, LLC, part of Springer Nature.Item Recent Developments in Oxazole Derivatives as Anticancer Agents: Review on Synthetic Strategies, Mechanism of Action and SAR Studies(Bentham Science Publishers, 2021-09-16T00:00:00) Kulkarni, Swanand; Kaur, Kamalpreet; Jaitak, VikasBackground: Cancer is the world�s third deadliest disease. Despite the availability of numerous treatments, researchers are focusing on the development of new drugs with no resistance and toxicity issues. Many newly synthesized drugs fail to reach clinical trials due to poor pharmacokinetic properties. Therefore, there is an imperative requi-site to expand novel anticancer agents with in vivo efficacy. Objective: This review emphasizes synthetic methods, contemporary strategies used for the inclusion of oxazole moie-ty, mechanistic targets, along with comprehensive structure-activity relationship studies to provide perspective into the rational design of highly efficient oxazole-based anticancer drugs. Methods: Literature related to oxazole derivatives engaged in cancer research is reviewed. This article gives a detailed account of synthetic strategies, targets of oxazole in cancer, including STAT3, Microtubules, G-quadruplex, DNA topoisomerases, DNA damage, protein kinases, miscellaneous targets, in vitro studies, and some SAR studies. Results: Oxazole derivatives possess potent anticancer activity by inhibiting novel targets such as STAT3 and G-quadruplex. Oxazoles also inhibit tubulin protein to induce apoptosis in cancer cells. Some other targets such as DNA topoisomerase enzyme, protein kinases, and miscellaneous targets including Cdc25, mitochondrial enzymes, HDAC, LSD1, HPV E2 TAD, NQO1, Aromatase, BCl-6, Estrogen receptor, GRP-78, and Keap-Nrf2 pathway are inhibited by oxazole derivatives. Many derivatives showed excellent potencies on various cancer cell lines with IC50 values in na-nomolar concentrations. Conclusion: Oxazole is a five-membered heterocycle, with oxygen and nitrogen at 1 and 3 positions, respectively. It is often combined with other pharmacophores in the expansion of novel anticancer drugs. In summary, oxazole is a promising entity to develop new anticancer drugs. � 2022 Bentham Science Publishers.Item Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity(Bentham Science Publishers, 2022-10-28T00:00:00) Dwivedi, Ashish Ranjan; Rawat, Suraj Singh; Kumar, Vijay; Kumar, Naveen; Kumar, Vinay; Yadav, Ravi Prakash; Baranwal, Somesh; Prasad, Amit; Kumar, VinodAims: Development of anticancer agents targeting tubulin protein. Background: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Objective: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. Methods: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. Results: ARV-2 with IC50 values of 3.16 �M, 5.31 �M, 10.6 �M against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. Conclusion: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents. � 2023 Bentham Science Publishers.Item Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity(Bentham Science Publishers, 2022-10-28T00:00:00) Dwivedi, Ashish Ranjan; Rawat, Suraj Singh; Kumar, Vijay; Kumar, Naveen; Kumar, Vinay; Yadav, Ravi Prakash; Baranwal, Somesh; Prasad, Amit; Kumar, VinodAims: Development of anticancer agents targeting tubulin protein. Background: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Objective: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. Methods: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. Results: ARV-2 with IC50 values of 3.16 �M, 5.31 �M, 10.6 �M against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. Conclusion: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents. � 2023 Bentham Science Publishers.Item Flavonoids as emerging notch signaling pathway modulators in cancer(Taylor and Francis Ltd., 2023-04-21T00:00:00) Singh, Atul Kumar; Kumar, ShashankNotch signaling is an evolutionary conserved pathway important for the developmental processes and implicated in the tumor formation. Notch signaling pathway (NSP) inhibitors have been tested in clinical trials alone or in combination with the chemotherapy but none got clinical approval due to severe toxicity in patients. Flavonoids inhibit NSP by inhibiting notch receptor cleavage and/or inhibiting transcriptional regulation by Notch intracellular domain (NICD). Interestingly, some flavonoids are reported to inhibit NSP by mediating the microRNA expression. NSP inhibitory flavonoid(s) in combination with standard therapy is might be an effective strategy in cancer treatment. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Natural Steroidal Lactone Induces G1/S Phase Cell Cycle Arrest and Intrinsic Apoptotic Pathway by Up-Regulating Tumor Suppressive miRNA in Triple-Negative Breast Cancer Cells(MDPI, 2022-12-27T00:00:00) Shuaib, Mohd; Prajapati, Kumari Sunita; Gupta, Sanjay; Kumar, ShashankTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with minimal treatment options. In the present work, Withaferin A (WA), a natural steroidal lactone found in Withania somnifera (Solanaceae), was studied to deduce the miRNA expression modulation mediated anticancer mode of action in TNBC cells. Small RNA next generation sequencing (NGS) of WA (2 �M) and vehicle (0.1% DMSO)-treated MDA-MB-231 cells revealed a total of 413 differentially expressed miRNAs (DEMs) and demonstrated that WA potentially up-regulates the miR-181c-5p, miR-15a-5p, miR-500b-5p, miR-191-3p, and miR-34a-5p and down-regulates miR-1275, miR-326, miR-1908-5p, and miR-3940-3p among total DEMs. The NGS and qRT-PCR expression analysis revealed a significantly higher expression of miR-181c-5p among the top 10 DEMs. Predicted target genes of the DEMs showed enrichment in cancer-associated gene ontology terms and KEGG signaling pathways. Transient up-expression of mir-181c-5p showed a time-dependent decrease in MDA-MB-231 and MDA-MB-453 cell viability. Co-treatment of miR-181c-5p mimic and WA (at varying concentration) down-regulated cell cycle progression markers (CDK4 and Cyclin D1) at mRNA and protein levels. The treatment induced apoptosis in MDA-MB-231 cells by modulating the expression/activity of Bax, Bcl2, Caspase 3, Caspase 8, Caspase 3/7, and PARP at mRNA and protein levels. Confocal microscopy and Annexin PI assays revealed apoptotic induction in miRNA- and steroidal-lactone-treated MDA-MB-231 cells. Results indicate that the Withaferin A and miRNA mimic co-treatment strategy may be utilized as a newer therapeutic strategy to treat triple-negative breast cancer. � 2022 by the authors.Item Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone(Frontiers Media S.A., 2021-09-27T00:00:00) Kumar, Shashank; Prajapati, Kumari Sunita; Shuaib, Mohd; Kushwaha, Prem Prakash; Tuli, Hardeep Singh; Singh, Atul KumarIn the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2�62��M while in vivo efficacy was studied in the range of 20�500�mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-?B, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models. � Copyright � 2021 Kumar, Prajapati, Shuaib, Kushwaha, Tuli and Singh.