Synthesis and In Vitro Study of pyrimidine–phthalimide Hybrids As VEGFR2 Inhibitors With Antiproliferative Activity

Abstract

Aim: Thalidomide, a once notorious sedative, is now clinically used as an antitumor agent. We aimed to use it as a lead compound for designing pyrimidine–phthalimide hybrids. Materials & methods: Nucleophilic substitution reaction of thalidomide analog 4 with primary and/or secondary aliphatic amines afforded pyrimidine–phthalimide hybrids 5a–g, 6 and 7a–d. Results & conclusion: Compound 7c showed high antiproliferative activity against four cell lines: HepG-2 (IC50: 7.86 ± 0.5 μM), MCF-7 (IC50: 2.77 ± 0.1 μM), HCT-116 (IC50: 5.73 ± 0.4 μM) and PC-3 (IC50: 8.32 ± 0.5 μM), with selective cytotoxicity for WI-38 (IC50: 43.2 ± 2.56 μM). 7c arrested MCF-7 cells at S phase of the cell cycle and increased the total apoptotic cells by 50-fold. 7c inhibited VEGFR2 in vitro (IC50: 0.130 ± 0.02 μM). 7c was capable of binding at the VEGFR2 binding site, forming hydrogen bond interactions with Asp1046 and Glu885 in a similar way to sorafenib.

Novel Furan and Furo[2,3–d]pyrimidinone Analogues: Cytotoxicity, Antioxidant, and Bleomycin‐Dependent DNA Damage Assessment

“…Using the MTT assay, [29][30][31] the cytotoxic activity of furan and furo [2,3-d]pyrimidinone analogues (seventeen compounds) was assessed in vitro against three different types of human cell lines: HCT-116 (Colorectal carcinoma), PC3 (prostate cancer), and WI-38 (normal lung fibroblast) cell lines. The tumor and normal cell lines were acquired from the National Institute of Cancer, Cairo, Egypt.…”