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Title: Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents
Authors: Kingkan Sanphanya
Suvara K. Wattanapitayakul
Orawin Prangsaengtong
Michiko Jo
Keiichi Koizumi
Naotoshi Shibahara
Aroonsri Priprem
Valery V. Fokin
Opa Vajragupta
Mahidol University
Srinakharinwirot University
University of Toyama
Khon Kaen University
Scripps Research Institute
Keywords: Biochemistry, Genetics and Molecular Biology;Chemistry;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 15-Apr-2012
Citation: Bioorganic and Medicinal Chemistry Letters. Vol.22, No.8 (2012), 3001-3005
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: 14643405
Appears in Collections:Scopus 2011-2015

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