title: Design and synthesis of pyrazole-oxindole conjugates targeting tubulin polymerization as new anticancer agents.
abstract: A series of twenty one compounds with pyrazole and oxindole conjugates were synthesized by Knoevenagel condensation and investigated for their antiproliferative activity on different human cancer cell lines. The conjugates are comprised of a four ring scaffold; the structural isomers 12b and 12c possess chloro-substitution in the D ring. Among the congeners 12b, 12c, and 12d manifested significant cytotoxicity and inhibited tubulin assembly. Treatments with 12b, 12c and 12d resulted in accumulation of cells in G2/M phase, disruption of microtubule network, and increase in cyclin B1 protein. Zebrafish screening revealed that 12b, and 12d caused developmental defects. Docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Anver Basha
authors.initials: AB
authors.lastname: Shaik
authors.affiliation: Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Nishant
authors.initials: N
authors.lastname: Jain
authors.affiliation: Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Chandan
authors.initials: C
authors.lastname: Kishor
authors.affiliation: CSIR - Centre for Cellular and Molecular Biology, Hyderabad 500007, India; CoE in Epigenetics, IISER-Pune, Pune 411021, India.
authors.forename: Ananthamurthy
authors.initials: A
authors.lastname: Nagabhushana
authors.affiliation: Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Bhukya
authors.initials: B
authors.lastname: Supriya
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: G
authors.initials: G
authors.lastname: Bharath Kumar
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Sumit S
authors.initials: SS
authors.lastname: Chourasiya
authors.affiliation: Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Yerramsetty
authors.initials: Y
authors.lastname: Suresh
authors.affiliation: CSIR - Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: anthony@iict.res.in.
authors.forename: Anthony
authors.initials: A
authors.lastname: Addlagatta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000078183:Oxindoles; D058105:Polymerization / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015027:Zebrafish / Q000196:embryology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011720:Pyrazoles; D014404:Tubulin; D050257:Tubulin Modulators; C022960:2-oxindole; C031280:pyrazole
keywords: Pyrazole–oxindole conjugates; Tubulin depolymerization; Zebrafish screening and molecular modeling