Recent advances in trimethoxyphenyl (TMP) based tubulin inhibitors targeting the colchicine binding site
Highlights•Crystal structures of tubulin with trimethoxyphenyl (TMP) analogs summarized.•Binding interactions between TMP analogs and tubulin discussed.•TMP analogs based on CA-4, indole, chalcone, colchicine and natural product scaffsolds.AbstractMicrotubules (composed of α- and β-tubulin heterodimers) play a pivotal role in mitosis and cell division, and are regarded as an excellent target for chemotherapeutic agents to treat cancer. There are four unique binding sites in tubulin to which taxanes, vinca alkaloids, laulimalide and colchicine bind respectively. While several tubulin inhibitors that bind to the taxane or vinca alkaloid binding sites have been approved by FDA, currently there are no FDA approved tubulin inhibitors targeting the colchicine binding site. Tubulin inhibitors that bind to the colchicine binding site have therapeutic advantages over taxanes and vinca alkaloids, for example, they can be administered orally, have less drug-drug interaction potential, and are less prone to develop multi-drug resistance. Typically, tubulin inhibitors that bind to the colchicine binding site bear the trimethoxyphenyl (TMP) moiety which is essential for interaction with tubulin. Over the last decade, a variety of molecules bearing the TMP moiety have been designed and synthesized as tubulin inhibitors for cancer treatment. In this review, we focus on the TMP analogs that are designed based on CA-4, indole, chalcone, colchicine and natural product scaffolds which are known to interact with the colchicine binding site in tubulin. The challenges and future direction of the TMP based tubulin inhibitors are also discussed in detail.Graphical abstractDownload : Download high-res image (217KB)Download : Download full-size image
پیشرفتهای اخیر در trimethoxyphenyl (TMP)مبتنی بر tubulin، محل اتصال colchicine را هدف قرار میدهد.