title: Design and synthesis of pyrazole/isoxazole linked arylcinnamides as tubulin polymerization inhibitors and potential antiproliferative agents.
abstract: As pyrazole and isoxazole based derivatives are well-known for displaying a considerable biological profile, an attempt has been made to unravel their cytotoxic potential. In this context, a number of pyrazole/isoxazole linked arylcinnamide conjugates (15a-o and 21a-n) have been synthesized by employing a straight forward route. The basic structure comprised three ring scaffolds (A, B and C): methoxyphenyl rings as A and C rings and a five membered heterocyclic ring (pyrazole or isoxazole) as the B-ring. To achieve clear understanding, these derivatives are categorized as pyrazole-phenylcinnamides (PP) and isoxazole-phenylcinnamides (IP). These compounds have been evaluated for their ability to inhibit the growth of various human cancer cell lines such as HeLa, DU-145, A549 and MDA-MB231 and most of them exhibit considerable cytotoxic effects. Some of them like 15a, 15b, 15e, 15i and 15l exhibit promising cytotoxicity in HeLa cells (IC50 = 0.4, 1.8, 1.2, 2.7 and 1.7 μM). Amongst them 15a, 15b and 15e were taken up for detailed biological studies, they were found to arrest the cells in the G2/M phase of the cell cycle. Moreover, they were investigated for their effect on the microtubular cytoskeletal system by using a tubulin polymerization assay, immunofluroscence and molecular docking studies; interestingly they demonstrate a significant inhibition of tubulin polymerization.
authors: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India. ahmedkamal@iict.res.in.
authors: Ahmed
authors: A
authors: Kamal
authors: Anver Basha
authors: AB
authors: Shaik
authors: Bala Bhaskara
authors: BB
authors: Rao
authors: Irfan
authors: I
authors: Khan
authors: G
authors: G
authors: Bharath Kumar
authors: Nishant
authors: N
authors: Jain
mesh_terms: 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; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; 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*
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D007555:Isoxazoles; D011720:Pyrazoles; D014404:Tubulin; D050257:Tubulin Modulators; C031280:pyrazole