Aryl-imidazothiadiazole analogues as microtubule disrupting agents. Issue 10 (15th September 2015)

• Record Type: Journal Article
• Authors: Kamal, Ahmed; Subba Rao, A. V.; Srinivasa Reddy, T.; Polepalli, Sowjanya; Shaik, Siddiq Pasha; Bagul, Chandrakant; Vishnuvardhan, M. V. P. S.; Jain, Nishant
• Is Part Of: MedChemComm. Volume 6:Issue 10(2015:Oct.)
• Page Start: 1842
• Page End: 1856
• Publication Date: 2015-09-15
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c5md00155b
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : Disruption of tubulin polymerization and the docked pose of5k in the colchicine binding site of tubulin. Abstract : Two series of 2-ethyl-6-(3′, 4′, 5′-trimethoxyphenyl)-5-aryl and 2-cyclopropyl-6-(3′, 4′, 5′-trimethoxyphenyl)-5-aryl-imidazothiadiazoles were designed, synthesized and evaluated for anti-proliferative activity in various human cancer cell lines. A common starting material 2-bromo-1-(3-, 4-, 5-trimethoxyphenyl)-ethanone was employed to generate the two scaffolds. Among them, compounds functionalized with N, N -dimethylaniline (5i and6i ) and napthyl (5k ) groups showed significant cytotoxic activity with average IC50 values of 1.7–2.9 μM, respectively. Moreover, the structure–activity relationship was elucidated by incorporating the different substitutions on the aryl moiety at the 5th position of the imidazothiadiazole ring. Treatments with5i, 6i and5k arrested cells at the G2/M phase, with cell death proceeding through an apoptotic pathway that was dependent on the activation of caspase-3. Immunocytochemical analysis revealed the loss of intact microtubule structures in treated cells. Treatments with5i, 6i and5k manifested increased mRNA and protein levels of the G2/M marker, cyclin B1. Molecular docking studies of the most potent compounds5i, 5k and6i showed that these compounds interact and bind efficiently to the active site of tubulin. This was further confirmed by a colchicine competitive binding assay.