title: Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents.
abstract: Novel 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Kingkan
authors.initials: K
authors.lastname: Sanphanya
authors.forename: Suvara K
authors.initials: SK
authors.lastname: Wattanapitayakul
authors.forename: Orawin
authors.initials: O
authors.lastname: Prangsaengtong
authors.forename: Michiko
authors.initials: M
authors.lastname: Jo
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Shibahara
authors.forename: Aroonsri
authors.initials: A
authors.lastname: Priprem
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.forename: Opa
authors.initials: O
authors.lastname: Vajragupta
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C574963:1-((3-chloromethyl)phenyl)-3-prop-2-ynylurea; D020533:Angiogenesis Inhibitors; D014508:Urea