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

摘要

The reaction of anthranilic acid with ethoxycarbonylisothiocyanate gave the ethyl 4-oxo-2-thioxo-1,2-dihydroquinazoline-3(4H)-carboxylate (4). The reaction of compound 4 with hydrazine hydrate and alpha-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 thiazole, pyran and pyridine derivatives. The cytotoxicity of the newly synthesized compounds towards the six cancer cell lines NUGC, DLD-1, HA22T, HEP G-2, HONE-1 and MCF-7 showed that compounds 6, 8, 13, 19c-f, 21b-f, 24a and 24c with 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.