Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors

• Two series of thieno-pyrimidines bearing chromone moieties were designed and synthesized.
• Most of the synthesized compounds showed moderate to significant antitumor activity.
• 6-COOH substitution of chromone produced the best potency.
• Compound 16i was 7.9- to 19.1-folds more active than compound I.
• Docking study was investigated to explore the binding modes of compounds with mTOR/PI3Kalfa.

Two series of thienopyrimidine derivatives (10a–k, 16a–j) bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. Some of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound 16i showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds. Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency.

Two series of thieno-pyrimidines bearing chromone moieties were synthesized and evaluated for their activity against PI3Kα and mTOR kinase and cancer cell lines. The most promising compound 16i showed excellent in vitro antitumor activity, its IC50 values against mTOR/PI3Kα kinase, H460 and PC-3 cell lines were 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, respectively.Figure optionsDownload as PowerPoint slide