Synthesis and biological activity of novel folic acid analogues: pteroyl-S-alkylhomocysteine sulfoximines.
Synthesis and biological activity of novel folic acid analogues: pteroyl-S-alkylhomocysteine sulfoximines.
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新型叶酸类似物：蝶酰基-S-烷基高半胱氨酸亚砜亚胺的合成和生物活性。
DOI：
10.1021/jm00085a010
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发表时间：
1992
影响因子：
7.3
通讯作者：
Kalman,TI
中科院分区：
文献类型：
--
作者：
Harvison,PJ;Kalman,TI
The synthesis of a novel series of-substituted folic acidanalogues, pteroyl-S-alkyl-DL-homocysteine (RS)-sulfoximines, and the corresponding S-methylhomocysteine sulfone is described. Side reactions of the sulfoximine groups of the amino acid ester reactants were considered. The correct structures of the isolatedtarget compounds were confirmed by NMR and FAB/MS excluding other alternatives. The replacement of the-COOH of the glutamate moiety of folicacid with S-alkylsulfoximine groups or S-methylsulfone did not affect the substrate activity of the vitamin for dihydrofolate reductase. The resulting tetrahydrofolate analogues could serve as cofactors for the thymidylate synthase cycle of murine leukemiaL1210 cells in situ. The analogues inhibited the growth of these cells in culture with 2 orders of magnitudelower IC50 values [(2-4) X 10" 4 M] than the parent folic acid.Folic acidcoenzymes play an important role in amino acid metabolism and are essential for the biosynthesis of nucleic acids. 1 They exist in the cell as tetrahydrofolyl poly-7-glutamate conjugates, which are the preferred substrates (cofactors) for most folate-requiring enzymes. 2, 3 Conversion to polyglutamates, which is catalyzed by fo-lylpolyglutamate synthetase (FPGS), contributessignificantly to the intracellular retention of tetrahydrofolate cofactors. 2 A variety of structural analogues of folic acid, exemplified by methotrexate, is capable of undergoing intracellular polyglutamylation, which may play an important role in the antitumor activity of these antifolates. 4
