Synthesis and antitumor activities of 2-(piperidin-4-yl)-thiazole-4-carboxamides analogues of tubulysins

Abstract

Tubulysins are a family of natural products that exhibit potent antitumor activities, which have attractedmuch attention from synthetic and medicinal chemists. Previous attempts to aromatize the Tuv part of tubulysinanalogues led to a loss in antitumor activity, which suggested that the Ile and Tuv fragments of these analogues wereadopting different conformations than the natural products. In this study, a series of 2-(piperidin-4-yl)-thiazole-4-carboxamides have been prepared to investigate whether an intramolecular H-bond between key NH and OH groupsis responsible for the conformational control. The antitumor activities of these analogues have been screened usingMDA-MB-231-breast, Siha-cervical, MCF7-breast, and PC3-prostate cell lines, with ureas 5m and 5k shown to exhibitmoderate antitumor activities (IC50 values of 0.2 and 0.6 µM against MCF7 cells, respectively).