School Of Basic And Applied Sciences
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Item Knoevenagel/tandem knoevenagel and michael adducts of cyclohexane-1,3-dione and aryl aldehydes: Synthesis, DFT studies, xanthine oxidase inhibitory potential, and molecular modeling(American Chemical Society, 2019) Arora, S; Joshi, G; Kalra, S; Wani, A.A; Bharatam, P.V; Kumar, Pradeep; Kumar, RajXanthine oxidase (XO) plays a crucial role in the formation of uric acid by oxidative hydroxylation of purines. Herein, we report the design and synthesis of Knoevenagel/tandem Knoevenagel and Michael adducts of cyclohexane-1,3-dione and aryl aldehydes as nonpurine XO inhibitors derived from naturally occurring scaffolds. Density functional theory calculations highlighted the reaction pathways and reasoned the formation of tandem Knoevenagel and Michael adducts. The synthetics were assessed for their XO inhibitory potential, and among them, four compounds (1b, 1g, 2b, and 3a) were found to possess best IC 50 values in the range of 3.66-4.98 μM. Interestingly, Knoevenagel adducts exhibited a competitive-type inhibition, whereas tandem Knoevenagel and Michael adducts produced a noncompetitive mode of inhibition. The compounds were capable of reducing the H 2 O 2 levels induced by XO, both in normal and cancer cells with no significant cytotoxicity. Molecular modeling studies highlighted the role of interactions of compounds with residual amino acids of the XO active site and also corroborated with the observed structure-activity relationship. © 2019 American Chemical Society.Item Pd-Catalyzed Four-Component Sequential Reaction Delivers a Modular Fluorophore Platform for Cell Imaging(American Chemical Society, 2019) Ansari, A.J; Joshi, G; Sharma, P; Maurya, A.K; Metre, R.K; Agnihotri, V.K; Chandaluri, C.G; Kumar, Raj; Singh, S; Sawant, D.M.A Pd-catalyzed cascade reaction of four versatile privileged synthons is described. The sequential reaction involves the formation of five new chemical bonds by concatenating three distinct chemical steps. One of the derivatives exhibited absorption in the visible region, fluorescence with a high quantum yield, and excellent photostability. Its application is explored in live cell imaging, which exhibited cytoplasmic and mitochondrial specific staining with no toxicity. © 2019 American Chemical Society.Item 2-(2-Arylphenyl) benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation(ACS publications, 2014) Seth, Kapileswar; Garg, Sanjeev K.; Kumar, Raj; Purohit, Priyank; Meena, Vachan S.; Goyal, Rohit; Banerjee, Uttam C.; Chakraborti, Asit K.The 2-(2-arylphenyl)benzoxazole moiety has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The 2-(2-arylphenyl)benzoxazoles 3a−m have been synthesized by Suzuki reaction of 2-(2-bromophenyl)benzoxazole. Further synthetic manipulation of 3f and 3i led to 3o and 3n, respectively. The compounds 3g, 3n, and 3o selectively inhibited COX-2 with selectivity index of 3n much better than that of the COX-2 selective NSAID celecoxib. The in vivo anti-inflammatory potency of 3g and 3n is comparable to that of celecoxib and the nonselective NSAID diclofenac at two different doses, and 3o showed better potency compared to these clinically used NSAIDs.Item Microwave-assis synthesis of pyrazolo[1,5c] quinazolines and their derivatives(Elsevier, 2014) Kumar, Deependra; Kumar, RajMicrowave accelerated and expedited cyclocondensation reactions of 2-(3-aryl-1H-pyrazol-5-yl)anilines (4) with diverse aryl aldehydes/triethyl orthoformate in water/MeCN (route D) and internal cyclocondensation and aromatization of 5-(2-aminophenyl)-4,5-dihydro-3-arylpyrazole-1-carbaldehyde (7) under MeOH (route E) for the synthesis of a series of pyrazolo[1,5-c]quinazolines and their derivatives (1a–1q) are reported.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, 2014) Alex, JM; Singh, S; 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.Item Relay tricyclic Pd (ii)/Ag (i) catalysis: design of a four-component reaction driven by nitrene-transfer on isocyanide yields inhibitors of EGFR.(Royal Society of Chemistry, 2018) Sawant, D.M.; Sharma, S; Pathare, R.S; Joshi, G; Kalra, S; Sukanya, S; Maurya, A.K.; Metre, R.K; Agnihotri, V.K.; Khan, S.; Kumar, Raj; Pardasania, R. T.Synthesis of pyrazolo[1,5-c]quinazolines from four easily available precursors is presented through a one-pot tricyclic Pd(II)/Ag(I) relay catalysis. The bimetallic relay cascade forges five new chemical bonds by concatenating six discrete chemical steps. The relay catalysis enables four-component assembly of pyrazolo[1,5-c]quinazolines that selectively inhibit EGFR, exhibit apoptosis through the ROS-induced mitochondrial-mediated pathway, and arrest the cell cycle at the G1 phase.Item Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array.(Springer, 2018) Kalra, Sourav; Ludhiadch Abhilash; Shafi, Gowhar; Vashista, Rajesh; Kumar, Raj; Munshi, AnjanaCyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab.Item A review on quinoline derived scaffolds as Anti-HIV Agents.(Bentham Science, 2018) Chokkar, N.; Kalra, S; Chauhan, M; Kumar, RajAfter restricting the proliferation of CD4+T cells, Human Immunodeficiency Virus (HIV), infection persists at a very fast rate causing Acquired Immunodeficiency Syndrome (AIDS). This demands the vigorous need of suitable anti-HIV agents, as existing medicines do not provide a complete cure and exhibit drawbacks like toxicities, drug resistance, side-effects, etc. Even the introduction of Highly Active Antiretroviral Therapy (HAART) failed to combat HIV/AIDS completely. The major breakthrough in anti-HIV discovery was marked with the discovery of raltegravir in 2007, the first integrase (IN) inhibitor. Thereafter, the discovery of elvitegravir, a quinolone derivative emerged as the potent HIV-IN inhibitor. Though many more classes of different drugs that act as anti-HIV have been identified, some of which are under clinical trials, but the recent serious focus is still laid on quinoline and its analogues. In this review, we have covered all the quinoline-based derivatives that inhibit various targets and are potential anti-HIV agents in various phases of the drug discovery.Item Oxidative stress stimulates invasive potential in rat C6 and human U-87 MG glioblastoma cells via activation and cross-talk between PKM2, ENPP2 and APE1 enzymes.(Springer, 2018) Cholia, Ravi P.; Dhiman, Monisha; Kumar, Raj; Mantha, Anil K.Maintaining genomic integrity is essential for cell survival and viability. Reactive oxygen species (ROS) overproduction results in oxidative stress leading to the genomic instability via generation of small base lesions in DNA and these unrepaired DNA damages lead to various cellular consequences including cancer. Recent data support the concept "oxidative stress is an indispensable participant in fostering proliferation, survival, and migration" in various cancer cell types including glioblastoma cells. In this study we demonstrate that treatment of non-cytotoxic doses of oxidants such as amyloid beta [Aβ(25-35)] peptide, glucose oxidase (GO), and hydrogen peroxide (H2O2) for 24 h and 48 h time points found to increase the expression level and activity of a multifunctional enzyme Apurinic/apyrimidinic endonuclease (APE1), a key enzyme of base excision repair (BER) pathway which takes care of base damages; and also resulted in modulation in the expression levels of downstream BER-pathway enzymes viz. PARP-1, XRCC1, DNA polβ, and ligase IIIα was observed upon oxidative stress in C6 and U-87 MG cells. Oxidants treatment to the C6 and U-87 MG cells also resulted in an elevation in the intracellular expression of glycolytic pathway enzyme Pyruvate kinase M2 (PKM2) and the metastasis inducer protein Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) as analyzed using Western blotting and Immunofluorescence microscopic studies. Our study also reports that oxidative stress induced for 24 h and 48 h in C6 and U-87 MG cells resulted in extracellular secretion of APE1 and ENPP2 as analyzed using Western blotting in conditioned media. However, the biological significance of extracellular secreted APE1 remains elusive. Oxidative stress also elevated the ENPP2's LysoPLD activity in conditioned media of C6 and U-87 MG cells. Our results also demonstrate that oxidative stress affects the expression level and localization of APE1, PKM2, and ENPP2 in C6 and U-87 MG cells. As evidenced by the colocalization pattern at 24 h and 48 h time points, it can be attributed that oxidative stress mediates crosstalk between APE1, PKM2, and ENPP2. In addition, when C6 and U-87 MG cells were treated with lysophosphatidic acid (LPA), a bioactive lipid that negatively regulates ENPP2's LysoPLD activity at 10 μM concentration, demonstrated strong migratory potential in C6 and U-87 MG cells, and also induced migration upon oxidative stress. Altogether, the findings demonstrate the potential of C6 and U-87 MG cells to utilize three proteins viz. APE1, PKM2, and ENPP2 towards migration and survival of gliomas. Thus the knowledge on oxidative stress induced APE1's interaction with PKM2 and ENPP2 opens a new channel for the therapeutic target(s) for gliomas.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.