Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-Difluoroglutamic acid

被引:42
作者
Hart, BP
Haile, WH
Licato, NJ
Bolanowska, WE
McGuire, JJ
Coward, JK
机构
[1] UNIV MICHIGAN, DEPT CHEM, ANN ARBOR, MI 48109 USA
[2] UNIV MICHIGAN, DEPT MED CHEM, ANN ARBOR, MI 48109 USA
[3] ROSWELL PK CANC INST, GRACE CANC DRUG CTR, DEPT EXPTL THERAPEUT, BUFFALO, NY 14263 USA
关键词
D O I
10.1021/jm950515e
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The stereospecific syntheses of L-threo-gamma-fluoromethotrexate (1t) and L-threo-gamma-fluorofolic acid (3t) are reported. Compounds 1t and 3t have no substrate activity with folylpoly-gamma-glutamate synthetase isolated from CCRF-CEM human leukemia cells, and compound It inhibits human dihydrofolate reductase at similar levels as methotrexate. The synthesis of DL-3,3-difluoroglutamic acid (6) and its incorporation into DL-beta,beta-difluorofolic acid (4) are also reported. Compound 4 acts as a better substrate for human CCRF-CEM folylpoly-gamma-glutamate synthetase than folic acid (V/K = ca. 7-fold greater). Thus, replacement of the glutamate moiety of methotrexate and folic acid with 4-fluoroglutamic acid and 3,3-difluoroglutamic acid results in folates and antifolates with altered polyglutamylation activity.
引用
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页码:56 / 65
页数:10
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