TY - JOUR
T1 - Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents
AU - Sanphanya, Kingkan
AU - Wattanapitayakul, Suvara K.
AU - Prangsaengtong, Orawin
AU - Jo, Michiko
AU - Koizumi, Keiichi
AU - Shibahara, Naotoshi
AU - Priprem, Aroonsri
AU - Fokin, Valery V.
AU - Vajragupta, Opa
N1 - Funding Information:
This work was supported by the Royal Golden Jubilee Ph.D. Program (RGJ Grant No. PHD/0229/2547 ) funded by Thailand Research Fund (TRF) and the commission of Higher Education Thailand (CHE-RG 2551). The authors thank Dr. Benjamin Fraser and Dr. Neil P. Grimster for their valuable advice in some synthesis reactions.
PY - 2012/4/15
Y1 - 2012/4/15
N2 - 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.
AB - 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.
KW - 1-(Substituted)-3-prop-2-ynylurea
KW - Antiangiogenic agent
KW - Cytotoxic agents
KW - EGFR kinase inhibitor
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84859445159&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2012.02.029
DO - 10.1016/j.bmcl.2012.02.029
M3 - 学術論文
C2 - 22414612
AN - SCOPUS:84859445159
SN - 0960-894X
VL - 22
SP - 3001
EP - 3005
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 8
ER -
