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

Research output: Contribution to journalArticle

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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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Angiogenesis Inhibitors
Urea
Assays
Cells
Cell Line
Umbilical Veins
Alkynes
Benzoates
MCF-7 Cells
Hydrogen Bonding
Cytotoxicity
Protein-Tyrosine Kinases
Catalytic Domain
Hydrogen bonds
Phosphotransferases
Derivatives
Neoplasms
Therapeutics
Erlotinib Hydrochloride
In Vitro Techniques

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

Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents. / Sanphanya, Kingkan; Wattanapitayakul, Suvara K.; Prangsaengtong, Orawin; Jo, Michiko; Koizumi, Keiichi; Shibahara, Naotoshi; Priprem, Aroonsri; Fokin, Valery V.; Vajragupta, Opa.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 8, 15.04.2012, p. 3001-3005.

Research output: Contribution to journalArticle

Sanphanya, K, Wattanapitayakul, SK, Prangsaengtong, O, Jo, M, Koizumi, K, Shibahara, N, Priprem, A, Fokin, VV & Vajragupta, O 2012, 'Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 8, pp. 3001-3005. https://doi.org/10.1016/j.bmcl.2012.02.029
Sanphanya K, Wattanapitayakul SK, Prangsaengtong O, Jo M, Koizumi K, Shibahara N et al. Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents. Bioorganic and Medicinal Chemistry Letters. 2012 Apr 15;22(8):3001-3005. https://doi.org/10.1016/j.bmcl.2012.02.029
Sanphanya, Kingkan ; Wattanapitayakul, Suvara K. ; Prangsaengtong, Orawin ; Jo, Michiko ; Koizumi, Keiichi ; Shibahara, Naotoshi ; Priprem, Aroonsri ; Fokin, Valery V. ; Vajragupta, Opa. / Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 8. pp. 3001-3005.
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