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Combretastatin A-4 inspired novel 2-aryl-3-arylamino-imidazo-pyridines/pyrazines as tubulin polymerization inhibitors, anti-mitotic and anticancer agents
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Cancer Science & Therapy

ISSN: 1948-5956

Open Access

Combretastatin A-4 inspired novel 2-aryl-3-arylamino-imidazo-pyridines/pyrazines as tubulin polymerization inhibitors, anti-mitotic and anticancer agents


Cancer Diagnostics Conference & Expo

June 13-15, 2016 Rome, Italy

Sarita Das and Chanakya N Kundu

KIIT University, India

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

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..

Biography :

Email: 18889.sarita@gmail.com

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