Kingkan SanphanyaSuvara K. WattanapitayakulOrawin PrangsaengtongMichiko JoKeiichi KoizumiNaotoshi ShibaharaAroonsri PripremValery V. FokinOpa VajraguptaMahidol UniversitySrinakharinwirot UniversityUniversity of ToyamaKhon Kaen UniversityScripps Research Institute2018-06-112018-06-112012-04-15Bioorganic and Medicinal Chemistry Letters. Vol.22, No.8 (2012), 3001-3005146434050960894X2-s2.0-84859445159https://repository.li.mahidol.ac.th/handle/20.500.14594/13758Novel urea derivatives of alkynes have been designed, synthesized, and evaluated as potential cancer therapeutics leads. The most active 1-((3-chloromethyl)phenyl)-3-prop-2-ynylurea (1) exhibited cytotoxic effect against HELA and MCF-7 cell lines with IC 50 values of 1.55 μM and 1.48 μM, respectively. Further investigation on tube formation assay in human vein umbilical cells (HUVEC) demonstrated that 1 and methyl 4-(3-(3-ethynylureido)benzyloxy) benzoate (6) possess antiangiogenic activity, with minimum effective dose of 25 nM (for 1) and 6.25 μM (for 6). The ED 50 of 1 and 6 were found to be 0.26 μM and 17.52 μM, respectively. The results from in vitro tyrosine kinase assay indicated the EGFR inhibition of 1 over other kinases (VEGFR2, FGFR1 and PDGFRβ). The cytotoxicity of 1 against EGFR overexpressing cell line A431 (IC 50 36 nM) was comparable to that of erlotinib. The binding mode of 1 from docking simulation in the EGFR active site revealed that the urea motif formed hydrogen bonding with Lys745, Thr854 and Asp855 in hydrophobic pocket of EGFR. Compound 1 is considered as a potential lead for further optimization. © 2012 Elsevier Ltd. All rights reserved.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyChemistryPharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1016/j.bmcl.2012.02.029