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: Kingkan Sanphanya, Suvara K Wattanapitayakul, Orawin Prangsaengtong, Michiko Jo, Keiichi Koizumi, Naotoshi Shibahara, Aroonsri Priprem, Valery V Fokin, Opa Vajragupta
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 8 Pg. 3001-5 (Apr 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22414612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• 1-((3-chloromethyl)phenyl)-3-prop-2-ynylurea
• Angiogenesis Inhibitors
• Urea

Topics

• Angiogenesis Inhibitors (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• HeLa Cells
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Urea (analogs & derivatives, chemical synthesis, chemistry, pharmacology)