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Title: Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents
Authors: Sanphanya K.
Wattanapitayakul S.K.
Prangsaengtong O.
Jo M.
Koizumi K.
Shibahara N.
Priprem A.
Fokin V.V.
Vajragupta O.
Keywords: 1 [(3 chloromethyl)phenyl] 3 prop 2 ynylurea
3 prop 2 ynylurea
4 (3 (3 ethynylureido)benzyloxy) benzoate
angiogenesis inhibitor
antineoplastic agent
epidermal growth factor receptor
protein tyrosine kinase
unclassified drug
vasculotropin receptor 2
cell strain MCF 7
drug screening
drug synthesis
HeLa cell
human cell
hydrogen bond
in vitro study
Angiogenesis Inhibitors
Binding Sites
Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
HeLa Cells
Inhibitory Concentration 50
Models, Molecular
Issue Date: 2012
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. © 2012 Elsevier Ltd. All rights reserved.
ISSN: 0960894X
Appears in Collections:Scopus 1983-2021

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