New insights in the structure-activity relationships of 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors

Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in Anticancer therapy. So far, many monoclonal Antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1-21 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH₃, or Cl at 8-position. Most compounds showed a promising human kinase insert domain receptor (VEGFR2/KDR/Flk-1) inhibition profile, with IC₅₀ values in the submicromolar/low micromolar range, and promising antiproliferative activity on human umbilical vein endothelial cells (HUVECs) as well as on a panel of three human tumor cell lines. The angio-kinase selectivity profile was assessed for the most promising compound 16 against a set of six human kinases. Finally, computational studies allowed clarifying at molecular level the interaction pattern established by the compounds with VEGFR2/KDR/Flk-1, highlighting key stable cation-π interactions, and thus providing the basis for further designing novel inhibitors.

Antiproliferative activity; Benzothiopyranopyrimidines; KDR kinase; Kinase inhibitors.