Design, synthesis and antitumor activity of novel thiophene- triazine derivatives bearing arylurea unit as potent PI3K/mTOR inhibitorss

In this article, we designed and synthesized a series of novel thiophene-triazine derivatives bearing arylurea unit as potent dual PI3K/mTOR inhibitors. The cytotoxicity of all the target compounds were evaluated against nine cancer cell lines (breast cancer cell line MCF-7, lung cancer cell lines A549, NCI-H460, H2228 and H1975, cervical cancer cell lines Hela and Hela-MDR, ovarian cancer cell lines Ovcar-2 and glioma U87MG) and the kinase inhibitory activity against PI3K/mTOR kinases was also tested. The results demonstrated that most of the target compounds exhibited moderate to excellent activity and high selectivity against one or more cancer cell lines. Among them, seven compounds displayed better activity than lead compound GDC-0941. The inhibitory activity of the most promising compound on nine cancer cell lines was 302.5 times better than that of GDC-0941 with the IC50 values as low as 0.008 +/- 0.002 mu M, and the inhibitory activity against PI3K alpha and mTOR kinase was excellent, with the IC50 values of 177.41 and 12.24 nM, respectively, indicating that it was a potential dual PI3K alpha/mTOR inhibitor. The Structure-Activity Relationships (SARs) indicated that the introduction of the arylurea group significantly improved the cellular and kinase activities of the target compounds. Moreover, the results of toxicity and hemolysis experiments demonstrated that the most promising compound had low toxicity and good safety. The results of PCR assay and molecular docking modes showed that it was a potential PI3K/ mTOR inhibitor, which was worthy of further study.

Automated summary

In this study, we developed and synthesized a series of novel thiophene-triazine derivatives containing arylurea unit as potent dual PI3K/mTOR inhibitors. We evaluated their cytotoxicity against nine cancer cell lines and their kinase inhibitory activity against PI3K/mTOR kinases. Most of the target compounds showed excellent activity and selectivity against one or more cancer cell lines. The most promising compound exhibited significantly better activity than the lead compound GDC-0941 with excellent inhibitory activity against PI3K alpha and mTOR kinase. Its introduction of the arylurea group improved the cellular and kinase activities of the target compounds. Additionally, it demonstrated low toxicity and good safety in toxicity and hemolysis experiments.