School Of Basic And Applied Sciences
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Item Caulerpa taxifolia inhibits cell proliferation and induces oxidative stress in breast cancer cells(Springer, 2018) Mehra, Richa; Bhushan, Satej; Yadav, Umesh Prasad; Bast, Felix; Singh, SandeepCaulerpa taxifolia (M. Vahl) C. Agardh or killer alga is known to possess several bioactive secondary metabolites with unique structural modifications. We investigated anti-oxidant and anti-proliferative activity of C. taxifolia extract (CTE) on breast and lung cancer cells, along with possible effects on mitochondrial membrane potential (MMP) and cell cycle progression. The results revealed up to 6-folds increase in reactive oxygen species (ROS), 2-folds increase in glutathione reductase (GR) activity, 1.7-fold increase in superoxide dismutase (SOD) activity and 1.8-fold change in catalase activity w.r.t. untreated cells i.e. 10.72 to 21.44 nmol/min/mL, 2.0 to 3.49 U/mL and 37.51 to 69.26 U/min/g FW, respectively, in MDA-MB-cells. Likewise, selective anti-proliferative activity with IC50 0.19 + 0.1, 0.27 + 0.1, and 0.43 + 0.1 μg/μL, was recorded in MDA-MB-231, T-47D, and H1299 cells. In addition, dose-dependent increase in MMP of up to 40% and G1/S phase mitotic arrest was documented by CTE treatment in MDA-MB-231 cells. The results suggest an anti-proliferative and oxidative stress inducing activity of CTE. Changes in MMP and cell cycle arrest further support the anti-cancer effects of CTE. It is believed that C. taxifolia may be considered as a potent source of anti-cancer drugs, subject to further validations.Item Imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole: Microwave-assisted synthesis and anticancer activity via selective topoisomerase-II-? inhibition(Elsevier Ltd, 2015) Negi, Arvind; Alex, Jimi Marin; Amrutkar, Suyog M.; Baviskar, Ashish T.; Joshi, Gaurav; Singh, Sandeep; Banerjee, Uttam Chand; Kumar, RajMicrowave-accelerated synthesis and anticancer activity of novel imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole against a panel of seven cancer cell lines are reported for the first time. Compounds ARK-4, 10 and 12 in the series show promising in vitro anti proliferative activity with low micromolar IC 50 values against A-459 (lung), Hep-G2 (liver) and H-460 (liver) cancer cell lines. Compounds caused the increase in ROS levels as well as mitochondrial membrane depolarization, which might induce apoptosis. Further, mechanistic interventions on biological and molecular modeling data supported that compounds inhibited topoisomerase-II selectively.- 2015 Elsevier Ltd. All rights reserved.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 Synthesis of imine-pyrazolopyrimidinones and their mechanistic interventions on anticancer activity(2013) Baviskar, Ashish T.; Banerjee, Uttam C.; Gupta, Mukesh; Singh, Rajveer; Kumar, Sunil; Gupta, Manish K.; Kumar, Sanjeev; Rout, Satish K.; Khullar, Madhu; Singh, Sandeep; Kumar, RajDesign, synthesis and anticancer activity of a series of imine-pyrazolopyrimidinones is reported for the first time. Compounds 9d, 9n and 9o in the series show encouraging in vitro anticancer activity with low micromolar IC50 values against prostate (PC3) and breast (MCF7) cancer cell lines. Some notions about structure-activity relationships and plausible mechanism of biological activity are presented. ? 2013 Elsevier Ltd. All rights reserved.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).Item Design, microwave-mediated synthesis and biological evaluation of novel 4 aryl(alkyl)amino-3-nitroquinoline and 2,4-diaryl(dialkyl) amino-3-nitroquinolines as anticancer agents(Elsevier, 2015) Chauhan, Monika; Rana, Anil; Alex, Jimi Marin; Negi, Arvind; Singh, Sandeep; Kumar, RajDesign, microwave-assisted synthesis of novel 4-aryl (alkyl)amino-3-nitroquinoline (1a–1l) and 2,4-diaryl (dialkyl)amino-3-nitroquinolines (2a–2k and 3a) via regioselective and complete nucleophilic substitution of 2,4-dichloro-3-nitroquinoline, respectively in water are presented. The newly synthesized compounds were evaluated for the first time for antiproliferative activity against EGFR overexpressing human lung (A-549 and H-460) and colon (HCT-116-wild type and HCT-116-p53 null) cancer cell lines. Some notions about structure–activity relationships (SAR) are presented. Compounds 2e, 2f, 2j and 3a overall exhibited excellent anticancer activity comparable to erlotinib which was used as a positive control. Molecular modeling studies disclosed the recognition pattern of the compounds and also supported the observed SAR.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 Growth factors mediated cell signalling in prostate cancer progression: Implications in discovery of anti-prostate cancer agents.(Elsevier, 2015) Joshi,Gaurav; Singh, Pankaj Kumar; Negi, Arvind; Rana, Anil; Singh, Sandeep; Kumar, RajCancer is one of the leading causes of mortality amongst world’s population, in which prostate cancer is one of the most encountered malignancies among men. Globally, it is the sixth leading cause of cancer-related death in men. Prostate cancer is more prevalent in the developed world and is increasing at alarming rates in the developing countries. Prostate cancer is mostly a very sluggish progressing disease, caused by the overproduction of steroidal hormones like dihydrotestosterone or due to over-expression of enzymes such as 5-α-reductase. Various studies have revealed that growth factors play a crucial role in the progression of prostate cancer as they act either by directly elevating the level of steroidal hormones or upregulating enzyme efficacy by the active feedback mechanism. Presently, treatment options for prostate cancer include radiotherapy, surgery and chemotherapy. If treatment is done with prevailing traditional chemotherapy; it leads to resistance and development of androgen-independent prostate cancer that further complicates the situation with no cure option left. The current review article is an attempt to cover and establish an understanding of some major signalling pathways intervened through survival factors (IGF-1R), growth factors (TGF-α, EGF), Wnt, Hedgehog, interleukin, cytokinins and death factor receptor which are frequently dysregulated in prostate cancer. This will enable the researchers to design and develop better therapeutic strategies targeting growth factors and their cross talks mediated prostate cancer cell signalling.Item 1-Acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles: Exhibiting anticancer activity through intracellular ROS scavenging and the mitochondria-dependent death pathway(Wiley-VCH Verlag, 2014) Alex, Jimi M.; Singh, Sandeep; Kumar, RajA series of 17 analogs of 1-acetyl-4,5-dihydro(1H)pyrazoles (JP-1 to JP-17) bearing two aromatic rings at positions 3 and 5, either of which ought to be heterocyclic, were synthesized and evaluated for their anti-proliferative potential against breast cancer (MCF-7 and T-47D) and lung cancer (H-460 and A-549) cell lines for the first time. JP-1-7, -10, -11, -14, and -15 were observed to exhibit significant anti-proliferative activity against MCF-7 cells. Some notions about structure-activity relationships are reported. The investigated compounds were found to lower the intracellular reactive oxygen species in the H2DCFDA assay and also caused mitochondria-dependent cell death in the MCF-7 cell line, indicating a plausible mechanism of their anticancer effect. Analogs of 1-acetyl-4,5-dihydro(1H)pyrazoles (JP-1-17) were synthesized and evaluated for their anti-proliferative activity in four cancer cell lines and for their intracellular ROS scavenging properties. An attempt was made to determine the mitochondrial membrane potential of MCF-7 cells treated with JP-1 and -14, aiming to elucidate the mechanism by which proliferation was curbed. ? 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.