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

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• 作者：Kingkan Sanphanya^a ; Suvara K. Wattanapitayakul^b ; Orawin Prangsaengtong^c ; Michiko Jo^c ; Keiichi Koizumi^c ; Naotoshi Shibahara^c ; Aroonsri Priprem^d ; Valery V. Fokin^e ; Opa Vajragupta^a ; ^{pyovj@mahidol.ac.th}
• 关键词：1-(Substituted)-3-prop-2-ynylurea ; Cytotoxic agents ; Tyrosine kinase inhibitors ; EGFR kinase inhibitor ; Antiangiogenic agent
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：3001-3005
• 文件大小：1705 K

摘要

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 IC₅₀ values of 1.55 渭M and 1.48 渭M, 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 渭M (for 6). The ED₅₀ of 1 and 6 were found to be 0.26 渭M and 17.52 渭M, respectively. The results from in vitro tyrosine kinase assay indicated the EGFR inhibition of 1 over other kinases (VEGFR2, FGFR1 and PDGFR尾). The cytotoxicity of 1 against EGFR overexpressing cell line A431 (IC₅₀ 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.