Design and synthesis of Azolidinedione/Thiazolidinediones teth-ered benzo[f]chromene derivatives and there in silico evaluation as tubulin inhibitors

Abstract

The small molecules that target microtubules is an attractive and an active area in cancer drug discovery.1‒4 These molecules bind to the tubulin, an α, βheterodimer and disrupt the dynamics of microtubule. Microtubule targeting agents can be classified into two categories. Microtubule stabilizing agents such as paclitaxel, docetaxel, epothilones, and discodermolide binds to the tubulin polymer and stabilize the microtubules. Microtubule destabilizing agents such as vinca alkaloids, colchicine and combretastatins binds to tubulin dimers and cause destabilization.5 The equilibrium between tubulin and microtubule is altered, which results in disruption of mitotic spindle. This effects a critical transition in the cell cycle, leading to cell death. Out of these different pockets on tubulin, colchicine is a significant source of inspiration for the design of new drugs as the colchicine binding site inhibitors binds with high affinity at the interface of α and β-tubulin. These are effective against multidrug mechanisms but however, the potential clinical applications of colchicine site tubulin inhibitors have been nullified by the significant toxicities against the normal cells, low solubility, and low bioavailability.6,7 The increase in resistance of cancer cells against current clinical drugs and poor tolerance of the existing anticancer drugs, intensifies the need to identify new molecules as anticancer drugs with high potency, minimal side effects.