Fardis Maria, Pyun Hyung-Jung, Tario James, Jin Haolun, Kim Choung U, Ruckman Judy, Lin Yun, Green Louis, Hicke Brian
Department of Medicinal Chemistry, Gilead, 333 Lakeside Dr., Foster City, CA 94404, USA.
Bioorg Med Chem. 2003 Nov 17;11(23):5051-8. doi: 10.1016/j.bmc.2003.08.031.
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.
合成了一系列旨在了解甲硫氨酸氨肽酶2（MetAP2）对C4和C6位取代耐受性的烟曲霉素类似物。最初，C6侧链保持为肉桂酰酯，C4位进行修饰。得出的结论是，在C4位用苄基肟取代烟曲霉素的天然C4会导致与MetAP2结合的活性适度丧失。在C6位引入伯或仲氨基甲酸酯并没有提高化合物对MetAP2的抑制效力。然而，通过在C6位引入极性基团如哌嗪基氨基甲酸酯，对MetAP2的抑制活性得以恢复。哌嗪基氨基甲酸酯胺上的小烷基取代基具有良好的耐受性。
