Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents

Kingkan Sanphanya, Suvara K. Wattanapitayakul, Orawin Prangsaengtong, Michiko Jo, Keiichi Koizumi, Naotoshi Shibahara, Aroonsri Priprem, Valery V. Fokin, Opa Vajragupta

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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.

Original languageEnglish
Pages (from-to)3001-3005
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number8
DOIs
Publication statusPublished - 15 Apr 2012
Externally publishedYes

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Keywords

  • 1-(Substituted)-3-prop-2-ynylurea
  • Antiangiogenic agent
  • Cytotoxic agents
  • EGFR kinase inhibitor
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Sanphanya, K., Wattanapitayakul, S. K., Prangsaengtong, O., Jo, M., Koizumi, K., Shibahara, N., ... Vajragupta, O. (2012). Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents. Bioorganic and Medicinal Chemistry Letters, 22(8), 3001-3005. https://doi.org/10.1016/j.bmcl.2012.02.029