Design, synthesis and evaluation of a series of novel fumagillin analogues.
A series of fumagillin analogues targeted at understanding tolerability of MetAP2 toward substitution at C4 and C6 were synthesized. Initially, the C6 side chain was maintained as cinnamoyl ester and C4 was modified. It was concluded that replacing the natural C4 of fumagillin with a benzyl oxime at C4 resulted in moderate loss of activity toward binding to MetAP2. Placement of a primary or secondary carbamate at C6 did not improve the potency of compounds toward inhibition of MetAP2. However, the inhibitory activity against MetAP2 was gained back by placing polar groups such as piperazinyl carbamate at C6. Small alkyl substituents on the amine of piperazinyl carbamate were well tolerated.
Fardis
Maria
M
Department of Medicinal Chemistry, Gilead, 333 Lakeside Dr., Foster City, CA 94404, USA. mfardis@gilead.com
Pyun
Hyung-Jung
HJ
Tario
James
J
Jin
Haolun
H
Kim
Choung U
CU
Ruckman
Judy
J
Lin
Yun
Y
Green
Louis
L
Hicke
Brian
B
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003510:Cyclohexanes; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D012717:Sesquiterpenes; D013329:Structure-Activity Relationship
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin