Investigation of novel fumagillin analogues as angiogenesis inhibitors.
Modification of fumagillin was conducted to develop MetAP-2 inhibitors with desirable pharmacological properties. Replacement of the C4 side chain by benzyloxime preserves the inhibitory activity against MetAP-2 enzyme. Fumagillin analogues containing the C4 benzyloxime moiety were found to be very sensitive to the nature of the C6 substituent on the inhibition activity of HUVEC proliferation. This lack of correlation between MetAP-2 and HUVEC activities might be due to the cellular metabolism of the compounds by epoxide hydrolase, which is present in the cell. Compound (E)-3d, containing ethylpiperazinyl carbamate at C6 position, exhibited antiangiogenic effects similar to TNP-470 on matrigel plug assay and rat corneal micropocket assay.
Pyun
Hyung-Jung
HJ
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. ppyun@gilead.com
Fardis
Maria
M
Tario
James
J
Yang
Cheng Y
CY
Ruckman
Judy
J
Henninger
Dwight
D
Jin
Haolun
H
Kim
Choung U
CU
D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol