Department Of Pharmaceutical Sciences and Natural Products
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Item Unanticipated Cleavage of 2-Nitrophenyl-Substituted N-Formyl Pyrazolines under Bechamp Conditions: Unveiling the Synthesis of 2-Aryl Quinolines and Their Mechanistic Exploration via DFT Studies(American Chemical Society, 2018) Joshi, Gaurav; Wani, Aabid Abdullah; Sharma, Sahil; Bhutani, Priyadeep; Bharatam, Prasad V.; Paul, Atish T.; Kumar, RajWe herein report for the first time an unusual decomposition of 2-nitrophenyl-substituted N-formyl pyrazolines under Bechamp reduction condition employed to yield 2-aryl quinolines exclusively instead of pyrazolo[1,5-c]quinazolines. The reaction investigation suggests acid-mediated cleavage of 1 followed by a retro-Michael addition, and a subsequent in situ intramolecular reductive cyclization through a modified Friedlander mechanism afforded 2-aryl quinolines (2) in good yields. The proposed mechanistic pathways were supported via experimental evidence and density functional theory studies. B3LYP/6-31+G(d) analysis indicated the involvement of trans-2-hydroxyaminochalcone as a key intermediate and its isomerization and cyclization, leading to unusual product formation.Item Dual inhibitors of epidermal growth factor receptor and topoisomerase IIa derived from a quinoline scaffold(Royal Society of Chemistry, 2016) Chauhan, Monika; Joshi, Gaurav; Kler, Harveen; Kashyap, Archana; Amrutkar, Suyog M.; Sharma, Praveen; Bhilare, Kiran D.; Banerjee, Uttam C.; Singh, Sandeep; Kumar, RajBased on the quinazoline bearing EGFR inhibitors, a series of thirty four compounds having a quinoline scaffold were synthesised and evaluated in vitro for EGFR kinase inhibitory activity. A structure-activity relationship study revealed that 2,4-bis(arylamino) substituted quinolines possessed better anti-EGFR kinase activity. Compounds 3f and 3m emerged as potent EGFR kinase inhibitors (200 and 210 nM, respectively) and showed excellent anticancer activity at the micromolar level against a panel of cancer cell lines comparable to erlotinib. Furthermore, representative compounds inhibited the human topoisomerase II? selectively and catalytically, did not intercalate with DNA, increased intracellular ROS concentration (except 3m) and altered the mitochondrial membrane potential of the cancer cells. Cell cycle analysis and annexin-V staining in a lung cancer cell line showed that the compounds delayed cell cycle progression by inducing cell cycle arrest and subsequent apoptosis at the G1 phase. The facts were further corroborated through molecular modeling studies. ? 2018 The Royal Society of Chemistry.Item Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases(John Wiley and Sons Inc., 2018) Kumar, Raj; Joshi, Gaurav; Kler, Harveen; Kalra, Sourav; Kaur, Manpreet; Arya, RamandeepAlmost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases? binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes. ? 2017 Wiley Periodicals, Inc.Item Synthesis and biological evaluation of new 2, 5- dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors(Royal Society of Chemistry, 2016) Darpan; Joshi, Gaurav; Amrutkar, Suyog M.; Baviskar, Ashish T.; Kler, Harveen; Singh, Sandeep; Banerjee, Uttam C.; Kumar, RajBased on the reported pharmacophores as topoiomerase inhibitors, 2,5 dimethylthiophen/furan based N-acetyl pyrazolines were designed and envisaged as topoisomerase inhibitors. The target compounds were synthesized and tested in vitro against human topoisomerases in decatenation, relaxation, cleavage complex and DNA intercalation assay. Out of 29 compounds, three (10, 11 and 29) showed potent and selective toposiomerse II inhibitory activity with no intercalation with DNA. Further, molecular docking studies also endorsed them as ATP dependent topoisomerase II catalytic inhibitors. These compounds exerted potential anticancer effects on breast, colon, lung and prostate cancer cell lines at low micromolar level as compared to etoposide and low toxicity to normal cells. Apart from the topoisomerase II inhibition, these compounds also induced the reactive oxygen species (ROS) level in cancer cells. The cell cycle analyses showed their apoptotic effect at G1 phase.Item Natural products based ayurvedic formulations: Chemical constituents and treatment in neurodegenerative disorders(Bentham Science Publishers B.V., 2017) Muraleedharan, Ammu; Joshi, Gaurav; Kumar, RajNeurodegenerative diseases are linked with high morbidity and mortality rates. Medical science has made considerable progress in understanding the mechanisms associated with the development of the neurodegenerative diseases. Each neurodegenerative disease is associated with precise pathways of cell death with its own mechanisms that lead to the development of novel therapeutic strategies for each case. In spite of various western medicines available, there still remains too many complications to manage the progressive and severe symptoms of these diseases. Ayurveda is not the mainstream treatment system, but it can provide better results than mainstream medications, with less severe side effects. A detailed study, scientific validation and standardization of the active biomolecules of herbal-mineral formulations are required for the evolution of ayurvedic medicines. This review is a concerted effort to identify the major ayurvedic formulations and treatment strategies based on Ayurvedic literature for the treatment of neurodegenerative disorders. ? 2017 Bentham Science Publishers.Item Pyrimidine containing epidermal growth factor receptor kinase inhibitors: Synthesis and biological evaluation(Blackwell Publishing Ltd, 2017) Joshi, Gaurav; Nayyar, Himanshu; Kalra, Sourav; Sharma, Praveen; Munshi, Anjana; Singh, Sandeep; Kumar, RajStructure-based design and synthesis of pyrimidine containing reversible epidermal growth factor receptor (EGFR) inhibitors 1a?d are reported. The compounds (1a?d) inhibited the EGFR kinase activity in vitro with IC50 range 740?nm to 3??m. mRNA expression of EGFR downstream target genes, that is twist, c-fos and aurora were found to be altered upon treatment with compounds 1a?d. The compounds 1a?d exhibited excellent anticancer activity at low micromolar level (3.2?9??m) in lung, colon and breast cancer cell lines. Furthermore, compounds induced the alteration in mitochondrial membrane potential and reactive oxygen species level and. Selected compound 1b was found to increase sub-G1 population indicative of cell death, the mode of cell death was apoptotic as evident from Annexin V verses propidium iodide assay. Molecular modelling further helped to investigate the binding recognition pattern of the compounds in ATP binding EGFR domain similar to erlotinib and dissimilar to WZ4002. ? 2017 John Wiley & Sons A/S.Item Epidermal Growth Factor Receptor (EGFR) and its Cross-Talks with Topoisomerases: Challenges and Opportunities for Multi-Target Anticancer Drugs(Bentham Science Publishers B.V., 2016) Chauhan, Monika; Sharma, Gourav; Joshi, Gaurav; Kumar, RajBackground: The interactions of Epidermal Growth Factor Receptor (EGFR) and topoisomerases have been seen in various cancer including brain, breast, ovarian, colorectal, gastric, etc. Methods: The studies in adenocarcinoma patients, chromogenic in situ hybridization, western blotting, receptor binding assay and electromobility shift assays, etc. threw light on the biophysical and biochemical features of EGFR and Topoisomerase cross-talks. Results: It has been revealed that both the isomers of topoisomerase (Topo I and Topo II) interact via different mechanisms with EGFR. Topo II and HER2 share the same location i.e. 17q12-21 regions which could be a possible cause of predominant interactions seen between them. Topo I and EGFR interactions are mechanically related to the nucleolar translocation of heparenase by EGF and c-Jun. Conclusion: We compiled literature findings including the mechanistic interventions, signaling pathways, patents, in vitro and in vivo data of tested inhibitors and combinations in clinical trials, which provide convincing confirmations for the interactions of EGFR and topoisomerases. These interactions may be used for deriving a consistent route of mechanism, design and development of standard drug combinations and dual or multi inhibitors. ? 2016 Bentham Science Publishers.Item Pyrimidine-fused derivatives: Synthetic strategies and medicinal attributes(Bentham Science Publishers B.V., 2016) Joshi, Gaurav; Nayyar, Himanshu; Alex, Jimi Marin; Vishwakarma, Gajendra S.; Mittal, Sunil; Kumar, RajPyrimidine-fused derivatives traits the inextricable part of DNA and RNA, exhibit indispensable role in numerous biological processes, possessing momentous chemical and biological importance. Pyrimidine-condensed derivatives as the pharmacophore exhibit broad spectrum of biological activities encompassing antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, anticancer and anti-HIV. Several retrosynthetic approaches, are available for the synthesis of pyrimidine-fused analogues which offers enormous scope in the field of medicinal chemistry. Ring fused pyrimidine and their innumerable derivatives continue to hold the attention of chemists since their presence in the biologically active resources have been known to elicit additive effects on the bio-efficacy of the molecules. The present review is a concerted effort to congregate information mainly focusing on the comprehensive categorization of pyrimidine ring based on their fusion with five, six, seven and eight-membered ring(s). Moreover, it also puts forward their systematic nomenclature, synthetic strategies, and bioactivities including SAR studies. This review is being put forwarded with an incentive to provide researchers with a comprehensive and updated literature. In addition, the manuscript also brings to light the various pharmacophore designs based on fusedpyrimidine ring system, delving deeper into synthesis and the subsequent generation of new libraries of pyrimidine-fused derivatives including their biological assessments. ? 2016 Bentham Science Publishers.