Department Of Pharmaceutical Sciences and Natural Products
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Item In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice(MDPI, 2022-08-30T00:00:00) Bhat, Zahid Rafiq; Kumar, Manvendra; Sharma, Nisha; Yadav, Umesh Prasad; Singh, Tashvinder; Joshi, Gaurav; Pujala, Brahmam; Raja, Mohd; Chatterjee, Joydeep; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, RajTyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes. � 2022 by the authors.Item Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines(Academic Press Inc., 2021-11-01T00:00:00) Yadav, Umesh Prasad; Ansari, Arshad J.; Arora, Sahil; Joshi, Gaurav; Singh, Tashvinder; Kaur, Harsimrat; Dogra, Nilambra; Kumar, Raj; Kumar, Santosh; Sawant, Devesh M.; Singh, SandeepA series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC50 values ranging from 1 to 5.5 ?M. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase II? inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression. � 2021 Elsevier Inc.Item Synthesis of 1,4-dihydropyrazolo[4,3-b]indoles via intramolecular C(sp2)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment(Academic Press Inc., 2021-06-29T00:00:00) Kaur, Manpreet; Mehta, Vikrant; Abdullah Wani, Aabid; Arora, Sahil; Bharatam, Prasad V.; Sharon, Ashoke; Singh, Sandeep; Kumar, RajWe herein report a new synthetic route for a series of unreported 1,4-dihydropyrazolo[4,3-b]indoles (6�8) via deoxygenation of o-nitrophenyl-substituted N-aryl pyrazoles and subsequent intramolecular (sp2)-N bond formation under microwave irradiation expedite modified Cadogan condition. This method allows access to NH-free as well as N-substituted fused indoles. DFT study and controlled experiments highlighted the role of nitrene insertion as one of the plausible reaction mechanisms. Furthermore, the target compounds exhibited cytotoxicity at low micromolar concentration against lung (A549), colon (HCT-116), and breast (MDA-MB-231, and MCF-7) cancer cell lines, induced the ROS generation and altered the mitochondrial membrane potential of highly aggressive MDA-MB-231 cells. Further investigations revealed that these compounds were selective Topo I (6h) or Topo II (7a, 7b) inhibitors. � 2021 Elsevier Inc.Item Design and synthesis of non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of EGFR and their anti-cancer assessment(MDPI AG, 2021-03-09T00:00:00) Kumar, Manvendra; Joshi, Gaurav; Arora, Sahil; Singh, Tashvinder; Biswas, Sajal; Sharma, Nisha; Bhat, Zahid Rafiq; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, RajA series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 �M) as compared to gefitinib (IC50 > 20 �M). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported. Copyright: � 2021 by the authors. Licensee MDPI, Basel, Switzerland.Item Design, synthesis, biological evaluation of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehydes as non-purine xanthine oxidase inhibitors: Tracing the anticancer mechanism via xanthine oxidase inhibition(Academic Press Inc., 2021-01-07T00:00:00) Joshi, Gaurav; Sharma, Manisha; Kalra, Sourav; Gavande, Navnath S.; Singh, Sandeep; Kumar, RajXanthine oxidase (XO) has been primarily targeted for the development of anti-hyperuriciemic /anti-gout agents as it catalyzes the conversion of xanthine and hypoxanthine into uric acid. XO overexpression in various cancer is very well correlated due to reactive oxygen species (ROS) production and metabolic activation of carcinogenic substances during the catalysis. Herein, we report the design and synthesis of a series of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehyde derivatives (2a-2x) as xanthine oxidase inhibitors (XOIs). A docking model was developed for the prediction of XO inhibitory activity of our novel compounds. Furthermore, our compounds anticancer activity results in low XO expression and XO-harboring cancer cells both in 2D and 3D-culture models are presented and discussed. Among the array of synthesized compounds, 2b and 2m emerged as potent XO inhibitors having IC50 values of 9.32 � 0.45 �M and 10.03 � 0.43 �M, respectively. Both compounds induced apoptosis, halted the cell cycle progression at the G1 phase, elevated ROS levels, altered mitochondrial membrane potential, and inhibited antioxidant enzymes. The levels of miRNA and expression of redox sensors in cells were also altered due to increase oxidative stress induced by our compounds. Compounds 2b and 2m hold a great promise for further development of XOIs for the treatment of XO-harboring tumors. � 2021 Elsevier Inc.Item Synthesis, in vitro, and docking analysis of c-3 substituted coumarin analogues as anticancer agents(Bentham Science Publishers, 2020-01-28T00:00:00) Thakur, Anuradha; Kaur, Kamalpreet; Sharma, Praveen; Singla, Ramit; Singh, Sandeep; Jaitak, VikasBackground: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effects along with multidrug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-? target protein by molecular docking. Methods: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. Results: Among the synthesized analogues, 12 and 13 show good antiproliferative activity with IC50 values 1 and 1.3 ?M, respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit a docking score of -4.10 kcal/mol and -4.38 kcal/mol, respectively. Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future. � 2021 Bentham Science Publishers.Item Synthetic versus enzymatic pictet-spengler reaction: An overview(Bentham Science Publishers B.V., 2018) Sharma, Sachin; Joshi, Gaurav; Kalra, Sourav; Singh, Sandeep; Kumar, RajBackground: Pictet-Spengler reactions is an irreplaceable part of cyclization reaction leading to the formation of indispensable heterocyclic moieties including imidazole, benzoxazole, pyrrole, indole and others having immense biological and chemical significance. Researchers have explored this reaction using different types of catalysts and reactions conditions (including solvents, acids, etc.) to ensure the better selectivity, less reaction time and high product yields. A total of five Pictet-Spenglerases have been discovered from various sources including plants, animals, fungi, and microbes, and are responsible for the synthesis of various important alkaloids of biological medicinal importance. Objective: The present review is a strenuous effort to assemble information mainly focusing on synthetic as well as biological Pictet-Spengler reactions catalysed by enzymes called Pictet-Spenglerase. Conclusion: In the present review, the recent advances in the PS-mediated synthesis of diverse heterocycles such as tetrahydroisoquinoline, tetrahydro-?-carbolines, tetrahydroimidazopyridines and other fused heterocycles via chemical as well as enzymatic pathways have been covered. The compounds find their scope as medicinal agents for the treatment of cancer, tuberculosis, bacterial infection, leishmanial, etc. The compilation is expected to provide a mechanistic insight to chemists to enhance the reaction condition, yields and another parameter to ensure the safe and inexpensive reaction conditions considering the "Green-Concept" of chemistry.Item Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies(Academic Press Inc., 2018) Kumar, Bhupinder; Sharma, Praveen; Gupta, Vivek Prakash; Khullar, Madhu; Singh, Sandeep; Dogra, Nilambra; Kumar, VinodA number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC50 values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC50 values of 4.67 ?M & 3.38 ?M and 4.63 ?M & 3.71 ?M against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket. ? 2018 Elsevier Inc.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 Synthesis and xanthine oxidase inhibitory activity of 5,6 dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives(Elsevier, 2014) Kumar, Deependra; Kaur, Gagandeep; Negi, Arvind; Kumar, Sanjeev; Singh, Sandeep; Kumar, RajSome 5,6-dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives were rationally designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Some notions about structure activity relationships are presented. The compounds 6g, 6h and 6e were found to be significantly active against XO. The compound 6g emerged as the most potent XO inhibitor as compared to allopurinol and free radical scavenger. The molecular docking of 6g into the XO active site highlighted its mode of binding and important interactions such as hydrogen bonding, π–π stacking with amino acid residues like Ser876, Thr1010, Phen914, Phe1009 and Phe649 and its close proximity to dioxothiomolybdenum (MOS).