title: Pyrazole-oxadiazole conjugates: synthesis, antiproliferative activity and inhibition of tubulin polymerization.
abstract: A number of pyrazole-oxadiazole conjugates were synthesized and evaluated for their ability to function as antiproliferative agents on various human cancer cell lines. These conjugates are comprised of pyrazole and oxadiazole scaffolds closely attached to each other without any spacer as two structural classes. The Type I class has a trimethoxy substituent and the type II class has a 3,4-(methylenedioxy) substituent on their A rings. Among these conjugates 11a, 11d and 11f manifest potent cytotoxicity with IC50 values ranging from 1.5 μM to 11.2 μM and inhibit tubulin polymerization with IC50 values of 1.3 μM, 3.9 μM and 2.4 μM respectively. The cell cycle assay showed that treatment with these conjugates results in accumulation of cells in the G2/M phase and disrupts the microtubule network. Elucidation of zebrafish embryos revealed that the conjugates cause developmental defects. Molecular docking simulations determined the binding modes of these potent conjugates at the colchicine site of tubulin.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: Anver Basha
authors.initials: AB
authors.lastname: Shaik
authors.forename: Sowjanya
authors.initials: S
authors.lastname: Polepalli
authors.forename: Vangala Santosh
authors.initials: VS
authors.lastname: Reddy
authors.forename: G Bharath
authors.initials: GB
authors.lastname: Kumar
authors.forename: Soma
authors.initials: S
authors.lastname: Gupta
authors.forename: K V S Rama
authors.initials: KV
authors.lastname: Krishna
authors.forename: Ananthamurthy
authors.initials: A
authors.lastname: Nagabhushana
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Nishant
authors.initials: N
authors.lastname: Jain
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D011720:Pyrazoles; D014404:Tubulin; C031280:pyrazole