Browsing by Author "Chauhan, Monika"

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A comprehensive review on bioactive fused heterocycles as purine-utilizing enzymes inhibitors
(Birkhauser Boston, 2015) Chauhan, Monika; Kumar, Raj
Purine-utilizing enzymes (PUEs) are involved in the control of biological actions of nitrogen-containing bases, purines and pyrimidines, by participating in their catabolism, and this has made them a topic of considerate interest. The heterocyclics, as purine-utilizing enzyme inhibitors (PUEIs), play a vital role in a number of diseases, e.g., malaria, cancer, rheumatoid arthritis, inflammation, tissue rejection, and autoimmune disorders. The present review is first of its kind covering the literature up to 2014 on the advances in broad-spectrum medicinal activities exhibited by heterocycles as PUEIs. The drug designing of the purine and pyrimidine antimetabolites is based on the structural mimicking of the existing compounds. The basic consideration during the designing of this class is the introduction of small structural changes without the alteration of basic skeleton of pharmacophore. The balance between the existing empirical approach and rational approach is yet to be maintained during the design and synthesis of new PUEIs by combining in vivo, in vitro, and in silico methods. The data compiled in the present manuscript on SARs, IC50s, Kis, Km, in silico studies, and their reported X-ray co-crystal structures with PUEs will offer the researchers the rational approaches for the design and development of selective and specific PUEIs devoid of adverse effects. ? 2014 Springer Science+Business Media.
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, Raj
Design, 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.
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, Raj
Based 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.
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, Raj
Background: 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.
Identification of new insulin growth factor receptor-1 (IGF-1R) inhibitors via exploring ATPas kinase domain of IGF-1R through virtual screening
(Birkhauser Boston, 2017) Garg, Mansi; Chauhan, Monika; Kumar, Raj
Insulin growth factor receptor-1 is a trans-membrane tyrosine kinase receptor that mediates the polypeptide protein hormone insulin growth factor-1, responsible for normal function and growth of human cells. The overexpression of insulin growth factor receptor-1 has been associated with a variety of cancers. A number of small molecule inhibitors of insulin growth factor receptor-1 are discovered by various researchers but all of them get failed in preclinical trials due to less potency and resistance. In the present paper, we have identified new insulin growth factor receptor-1 inhibitors through virtual screening based on ATPase kinase domain having phosphate, sugar and hydrophobic regions lined with amino acid residues such as Asp 1150, Lys 1003, Phe 1124 and Lys 1033. A total of 7659 compounds were selected from PubChem database. Then on applying, the rule of five, 4482 compounds were enlisted and downloaded. Further on performing high throughput virtual screening, standard precision and extra precision three best scoring compounds were identified, which could be taken further for drug development. ? 2016, Springer Science+Business Media New York.
Medicinal attributes of pyrazolo[3,4-d]pyrimidines: A review
(2013) Chauhan, Monika; Kumar, Raj
Pyrazolopyrimidines are the fused heterocyclic ring systems which structurally resemble purines which prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The advent of their first bioactivity as adenosine antagonistic property divulged their medicinal potential. Radioactivity test on mice cells, morphometric and serological tests on rat hepatocytes, antitumor testing against L1210 and P388 leukemias in mice threw light on their biophysical aspects of significance. Biochemical properties were explored via xanthine oxidase assay, antioxidant enzyme assays, Western blot analysis, mRNA expression of apoptopic genes, receptor binding assays, and tryptan blue exclusion cytotoxicity evaluation. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, cardiovascular system, cancer, inflammation etc. The present manuscript to the best of our knowledge is the first compilation on synthesis and medicinal aspects including structure-activity relationships of pyrazolo[3,4-d]pyrimidines reported to date. ? 2013 Elsevier Ltd. All rights reserved.
Pyrazoloquinazolines: Synthetic strategies and bioactivities
(2015) Garg, Mansi; Chauhan, Monika; Singh, Pankaj Kumar; Singh, Pankaj Kumar; Alex, Jimi Marin; Kumar, Raj
Numerous N-heterocycles are indisputably evidenced to exhibit myriad biological activities. In the recent past, attempts made to condense the various heterocycles have resulted in derivatives possessing better bioactivities. Among many such condensed heterocycles, pyrazoloquinazolines have managed to hold the attention of many researchers, owing to the broad spectrum of activities they portray. This review is the first of its kind to congregate the various pyrazoloquinazolines reported until now and categorizes these structurally isomeric classes into eleven different groups based on the fusion pattern of the ring such as [1,5-c], [5,1-b], [4,3-h], etc. Furthermore, this review is a concerted effort to highlight design, synthetic strategies as well as biological activities of each class of this condensed heterocycle. Structure-activity relationship studies and in silico approaches wherever reported have also been discussed. In addition, manuscript also offers scope for design, synthesis and generation of libraries of unreported classes of pyrazoloquinazolines for the biological evaluation. Copyright ? 2014 Elsevier Masson SAS. All rights reserved.
SYNTHESIS AND ANTICANCER EVALUATION OF NOVEL HETEROCYCLICS DERIVED FROM IMIDAZOLE AND QUINOLINE SCAFFOLDS
(Central University of Punjab, 2018) Chauhan, Monika; Kumar, Raj
Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations
(Springer Verlag, 2016) Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj
Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed. ? 2015, Springer-Verlag Berlin Heidelberg.