Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents

•Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed and synthesized.•The target compounds showed moderate to significant cytotoxic activities.•The cytotoxicity of 29a was 10.7- and 14.8-fold higher than GDC-0941 against H460 and HT-29 cell lines, respectively.•29a could inhibit HT-29 proliferation by inducing apoptosis mechanism.

Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their biological activity. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In particular, the most promising compound 29a showed the most potent antitumor activities with IC50 values of 0.081 μM, 0.058 μM, 0.18 μM, and 0.23 μM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The SAR analyses indicated that compounds with mono-halogen groups at 4-position on the terminal phenyl ring were more active than those with double-halogen groups or methyl groups. In addition, the introduction of chlorine atoms into 6,7-position of thieno[3,2-d]pyrimidine moiety led to a slight decline, but more selective activity against H460 and HT-29 cell lines.

Graphical abstractTwo series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their cytotoxicity, enzymatic assays and apoptosis analysis.Figure optionsDownload full-size imageDownload as PowerPoint slide