Design, Synthesis And Anticancer Activity Research Of Small Molecules Via Targeting K-Ras Mutation

Human health is threatened by the cancer or tumor, and the Ras signal pathway plays a essential role in the pathogenesis and development. The Ras subfamily is one kind of low-weight GTP-binding proteins, and three members of Ras subfamily are contained, for instance, N-Ras, H-Ras and K-Ras. For the somatic carcinomas, the mutation frequency of RAS gene in human cancers is about 30%, and K-Ras mutation accounts for about 70% of these RAS gene mutation.With the development of application of benzotrizole in human disease treatment by the precursors, benzotriazole was a excellent scaffold applied in medicinal chemistry field, just like anti-cancer, anti-inflammation, anti-fungal et al. In our laboratory, we screened about 1,500 molecules in T29/T29KT1P cell lines and found that 07B11 (5-bromo-N-(2-(4-methoxyphenyl)-2H-benzotriazol-5-yl)ruran-2-carboxamide) could selectively inhibit the proliferation of T29KT1P cell line at 10 μM concentration.A series of benzotriazole analogues were designed based on the structure of 07B11 by rational drug design Through testing on the biological assay of anti-proliferation of T29 and T29KT1P cell lines, these results shown that compound 42,43,67,70 and 71 could selectively inhibit the proliferation of T29KT1P cell line at 1-5μM concentration. Through analyzing of the structure-activity relationships, these results shown that introduction of chloro or bromo-substituted acetyl moieties at the 5-amino site of 07B11 was necessary for improving the anti-proliferation activity. For the modification 4-site of 2-phenyl group of 07B11, the chloro group or methoxyl group substitution was the best function group to keep the anti-proliferation activity. Compared with the anti-proliferation assay data of 42,43,70 and 71, compound 67 could more selectively inhibit the proliferation of T29KT1P cell line than others. Through testing on the biological assay of anti-proliferation on the human cell lines, these results shown that compound 67 could selectively inhibit the proliferation of K-Ras mutation carcinoma cell lines at 5 μM concentration compared with anti-proliferation activity on the human normal cell lines and K-Ras wild type carcinoma cell lines.