title: Investigation of novel fumagillin analogues as angiogenesis inhibitors.
abstract: 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.
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. ppyun@gilead.com
authors.forename: Hyung-Jung
authors.initials: HJ
authors.lastname: Pyun
authors.forename: Maria
authors.initials: M
authors.lastname: Fardis
authors.forename: James
authors.initials: J
authors.lastname: Tario
authors.forename: Cheng Y
authors.initials: CY
authors.lastname: Yang
authors.forename: Judy
authors.initials: J
authors.lastname: Ruckman
authors.forename: Dwight
authors.initials: D
authors.lastname: Henninger
authors.forename: Haolun
authors.initials: H
authors.lastname: Jin
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol