title: Design, synthesis, cytotoxicity, HuTopoIIα inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents.
abstract: In an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue 5d showed superior cytotoxicity with an IC50value of 7.01±0.60μM for HeLa, 8.55±0.35μM for NCI-H460 and 14.31±0.90 for MCF-7 cancer cell lines. Further, compound 5d showed 70.82% inhibition of topoisomerase IIα at a concentration of 100μM with maximum docking score of -8.24. Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness properties within the ideal range.
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi 110025, India.
authors.forename: Raquib
authors.initials: R
authors.lastname: Alam
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Wahi
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Devapriya
authors.initials: D
authors.lastname: Sinha
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India; Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi 110025, India. Electronic address: rahisuddin@jmi.ac.in.
authors.lastname: Rahisuddin
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011720:Pyrazoles; D059005:Topoisomerase II Inhibitors; C031280:pyrazole; D004250:DNA Topoisomerases, Type II
keywords: Claisen-Schmidt condensation; Cytotoxicity; Docking; Michael addition; Pyrazole; Topoisomerase