Synthesis and Discovery of Water Soluble Microtubule Targeting Agents that Bind to the Colchicine Site on Tubulin and Circumvent Pgp Mediated Resistance

摘要

Two classes of molecules were designed and synthesized based on a 6-CH3 cyclopenta[d]pyrimidine scaffold and a pyrrolo[2,3-d]pyrimidine scaffold. The pyrrolo[2,3-d]pyrimidines were synthesized by reacting ethyl 2-cyano-4,4-diethoxybutanate and acetamidine, which in turn was chlorinated and reacted with the appropriate anilines to afford >1 and >2. The cyclopenta[d]pyrimidineswere obtained from 3-methyladapic acid, followed by reaction with acetamidine to afford the cyclopenta[d]pyrimidine scaffold. Chlorination and reaction with appropriate anilines afforded (±)->3•HCl – (±)->7.HCl. Compounds >1 (add chemical compound designation) and (±)->3•HCl (add compound chemical designation) had potent antiproliferative activities in the nanomolar range. Compound (±)->3•HCl is significantly more potent than >1. Mechanistic studies showed that >1 and (±)->3•HCl cause loss of cellular microtubles, inhibit the polymerization of purified tubulin, and inhibit colchicine binding. Modeling studies show interactions of these compounds within the colchicine site. The identification of these new inhibitors that can also overcome clinically relevant mechanisms of drug resistence provides new scaffolds for colchicine site agents.