One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)thiazole: A unique, highly active antimicrotubule agent

A wide variety of small molecules with diverse molecular scaffolds inhibit microtubule formation. In this article we report a one-pot procedure for the preparation of a novel 2-(N-pyrrolidinyl)-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)thiazole in which the size of the substituent at the C-2 position of the thiazole ring plays an essential role in compound activity. The most active agent (3f) inhibited at submicromolar concentrations the growth of tumor cell lines. It also inhibited tubulin polymerization with an activity quantitatively similar to that of CA-4, and treatment of HeLa cells resulted in their arrest at the G2-M phase of the cell cycle. Furthermore, 3f was effective against multidrug resistant cancer cells and inhibited the growth of the HT-29 xenograft in a nude mouse model. This indicated that 3f is a promising new antimitotic agent with encouraging preclinical potential.

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► 2-(N-Pyrrolidinyl)-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)thiazole (3f) inhibited the growth of tumor cell lines.
► Compound 3f inhibited tubulin polymerization with an activity similar to that of CA-4.
► Derivative 3f was effective against multidrug resistant cancer cell.
► Compound 3f inhibited the growth of the HT-29 xenograft in a nude mouse model.