Computer assisted design of second-generation colchicine derivatives

Abstract

Cytoskeletal proteins, such as tubulin, are a primary target for many successful anti-cancer drugs. The expression of several beta-tubulin isotypes in normal and cancerous cells provides a platform upon which to construct chemotherapeutic agents capable of differentiating between them. To test this hypothesis, we have previously designed several colchicine derivatives and computationally probed them for affinity to the beta-tubulin isotypes. Subsequent synthesis and cytotoxicity assays produced a small set of promising compounds exhibiting IC(50) values approximately 30 fold lower than values previously reported for colchicine. Here we describe the creation and testing of these first-generation colchicine derivatives and discuss the subsequent design and preliminary computational screening of a novel set of second-generation derivatives using the most promising first-generation derivatives as scaffolds.