Targeting the colchicine site in tubulin through cyclohexanedione derivatives

Cyclohexanedione derivatives represent a new family of colchicine-site binders that were identified through a ligand-based virtual screening approach. Structural modifications have now been performed at both distal sites of our identified hit [2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (4)] in order to improve tubulin binding affinity, anti-proliferative activity and/or aqueous solubility. The results obtained indicate that the 2-methoxyphenyl ring, the fragment located closer to the αβ-tubulin interface according to docking studies, is the one that allows structural variation in order to improve the K value against tubulin (as in compound 20a with a K = 1.3 × 10 M, analogous to colchicine) or to improve aqueous solubility, as in compound 22c, being more than 10 times more soluble than the previous hit 4.M.-D. C. thanks the Fondo Social Europeo (FSE) and the JAE Predoc Programme for a predoctoral fellowship. This project has been supported by the Spanish Ministerio de Econom´ıa y Competitividad (SAF2012-39760-C02-01 to E.-M. P, M.-J. P.-P. and M.-J. C and BIO2013-42984-R to J. F. D.), and Comunidad de Madrid (BIPEDD2; ref. P2010/BMD-2457 to M.-J. C and J. F. D.). J. F. D. acknowledges networking contribution by the COST Action CM1407 “Challenging organic synthesis inspired by nature-from natural products chemistry to drug discovery” and the COST action CM1470. We also wish to thank Eef Meyen and Lizette van Berckelaer for excellent technical assistancePeer Reviewe