Uses of Anthranilic Acid for the Synthesis of Dihydroquinazolin Derivatives with Antitumor, Anti-proliferative and Pim-1kinase Activities

摘要

The reaction of anthranilic acid with ethoxycarbonylisothiocyanate gave the ethyl 4-oxo-2-thioxo-1,2-dihydroquinazoline-3(4 H )-carboxylate ( 4 ). The reaction of compound 4 with hydrazine hydrate and a-halocarbonyl derivatives was found to give either hydrazono or S -alkylated products. Heterocyclization reactions of some of the S -alkylated derivatives 8 and 12 were carried out to afford thiophene, thiazole, pyran and pyridine derivatives. The cytotoxicity of the newly synthesized compounds towards the six cancer cell lines NUGC, DLD-1, HA22T, HEPG-2, HONE-1 and MCF-7 showed that compounds 8 , 10 , 16a , 19d – f , 21c , 21e , 21f , 24a and 24b showed the highest cytotoxicity. The c-Met kinase inhibition for some of the selected compounds showed that compounds 8 , 13 , 19d , 21e , 21f and 24a were the most active compounds. Screening toward tyrosine kinases revealed that compounds 13 , 21e and 24a exhibit the highest inhibitions and therefore their molecular modeling was described. In addition, compounds 13 and 24a showed the highest activities towards Pim-1 kinase.