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 µM, 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 µM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 µM). 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.

Synthesis, characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents.

Thymidylate synthase (TS), one of folate-dependent enzymes, is a key and well-recognized target for anticancer agents. In this study, a series of 6-aryl-5-cyano thiouracil derivatives were designed and synthesized in accordance with essential pharmacophoric features of known TS inhibitors. Nineteen compounds were screened in vitro for their anti-proliferative activities toward HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Compounds [Formula: see text], [Formula: see text], and 24 exhibited high anti-proliferative activity, comparable to that of 5-fluorouracil. Additionally, ten compounds with potent anti-proliferative activities were further evaluated for their ability to inhibit TS enzyme. Six compounds ([Formula: see text], [Formula: see text], [Formula: see text], 22, 23 and 24) demonstrated potent dose-related TS inhibition with [Formula: see text] values ranging from 1.57 to [Formula: see text]. The in vitro TS activity results were consistent with those of the cytotoxicity assay where the most potent anti-proliferative compounds of the series showed good TS inhibitory activity comparable to that of 5-fluorouracil. Furthermore, molecular docking studies were carried out to investigate the binding pattern of the designed compounds with the prospective target, TS (PDB-code: 1JU6).