Sarita Das and Chanakya N Kundu
KIIT University, India
Posters & Accepted Abstracts: J Cancer Sci Ther
Based on the pharmacophoric features of the natural product combretastatin A-4 (CA-4) and its synthetic analogues that inhibit tubulin polymerization, a series of novel 2-aryl-3-arylamino-imidazo-pyridines/ pyrazines as potential anti-tubulin anticancer agents were designed. They were synthesized by a one-pot method involving preparation of isocyanides from the anilines via formylation and subsequent dehydration followed by their reactions with heterocyclic-2-amidines and aldehydes. Compounds 1, 2, 14 and 15 were found to exhibit significant tubulin polymerization inhibition and disruption of tubulin�microtubule dynamics similar to that of CA-4. They showed potent anticancer activities in kidney, breast and cervical cancer cell lines, and relatively low toxicity to normal cells, compared to CA-4. The compounds induced DNA and chromosomal damage, and apoptosis via cell cycle arrest in the G2/M phase. The molecular docking and molecular dynamics (MD) simulation studies revealed that disruption of microtubule dynamics might occur by interaction of the compounds at the colchicine binding site at the a, b-tubulin hetero-dimer interface, similar to that of CA-4. Molecular modeling analysis showed that two of the three methoxy groups at ring A of all four potent compounds (1, 2, 14, and 15) were involved in bifurcated hydrogen bonding with Cysb241, an important molecular recognition interaction to show tubulin inhibitory activity. In comparison to CA-4, the bridging NH and the imidazo-pyridine/pyrazine moieties in the title compounds provide flexibility for attaining the required dihedral relationship of two aryls and additional pharmacophoric features required for the interaction with the key residues of the colchicine binding site..
Email: 18889.sarita@gmail.com
Cancer Science & Therapy received 3968 citations as per Google Scholar report
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