Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents

Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 +/- 0.16 and 4.10 +/- 0.45 mu M, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 +/- 0.03 mu M, that is equal to that of reference, sorafenib (IC50 = 0.23 +/- 0.04 mu M). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.

Automated summary

Novel thieno[2,3-d]pyrimidine derivatives with structural similarity to VEGFR-2 inhibitors were designed and synthesized, showing promising anticancer activities against human cancer cell lines. Compound 17f exhibited the highest cytotoxic activities against HCT-116 and HepG2 cell lines and displayed high inhibitory activity against VEGFR-2, comparable to the reference drug sorafenib. ADMET and toxicity assessments revealed that most compounds had low BBB penetration levels and were non-toxic, except for compounds 17b and 20b.