Synthesis And Antitumor Activity Of The N-[4-(t-Butyl)-5-benzyl Thiazole-2-yl] Acetamide Derivatives

The antitumor activity research of M-(thiazole-2-yl) amide derivatives have been the focus of scholars. Physiologically active substances containing amines and heterocyclic amines widely exist in nature, which called "no nitrogen is no biological activity". Because of unique biological activity and low toxicity, heterocycles are often used as medicines and pesticides. Particularly the compounds containing piperidine, morpholine and piperazine are extensive in anticancer drugs research.In this paper, N-[4-(t-Butyl)-5-(4-chloro benzyl) thiazole-2-yl] alkyl amide was the lead compound and an NH group was inserted in the alkyl portion of the amide bond. By means of carbon chain extension, cyclization and bioisostere replacement, ?-[4-(t-Butyl)-5-benzyl thiazole-2-yl]-2-(alkyl amino) acetamides and N-[4-(t-Butyl)-5-benzyl thiazole-2-yl]-2-(nitrogen heterocycle) acetamides were designed and synth-esized. After chlorine acetylation, three kinds of 4-(t-Butyl)-5-benzyl-2-amino thiazol-es respectively reacted with the fatty amines including primary amines and secondary amines, and with the heterocycles including piperidine, morpholine and piperazine homolog. The reaction condition was that pyridine was used as the acid-binding agent, and tetrahydrofuran was used as the solvent and mole ratio of 1:2. A total of 56 new compounds were synthesized and their structures were confirmed by 1H NMR and 13C NMR.The antitumor activity of new compounds were evaluated against A549, Hela and MCF-7 cells in vitro. When R was imethyl, ethyl or n-Butyl as far as N-[4-(t-Butyl)-5-benzyl thiazole-2-yl)-2-(alkyl amino) acetamide, the antitumor activity of compounds against Hela and MCF-7 was comparable or superior to the positive control. When heterocycle was piperazine or N-alkyl piperazine as far as N-[4-(t-Butyl)-5-benzyl thiazole-2-yl]-2-(nitrogen heterocycle) acetamide, the antitumor activity of compoun-ds against Hela and MCF-7 was superior to the positive. When heterocycle was N-phenyl piperazine or N-(4-hydroxy phenyl) piperazine, the antitumor activity of compounds against Hela was superior to the positive but was weak against MCF-7.The AO/EB staining and cell cycle experiments were carried out on preferred compounds. The result confirmed the mechanism that the new compounds induced apoptosis of tumor cells. The compound B17 could inhibit the mitosis of Hela cells in the G1 phase and inhibit the mitosis of A549 cells in S phase. The compound B17 had wide range against cancer cells and had important value of further research and development.