Synthesis and biological activity of novel folic acid analogues: pteroyl-S-alkylhomocysteine sulfoximines.
The synthesis of a novel series of gamma-substituted folic acid analogues, 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 isolated target compounds were confirmed by NMR and FAB/MS excluding other alternatives. The replacement of the gamma-COOH of the glutamate moiety of folic acid 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 leukemia L1210 cells in situ. The analogues inhibited the growth of these cells in culture with 2 orders of magnitude lower IC50 values [(2-4) x 10(-4) M] than the parent folic acid.
Harvison
P J
PJ
Department of Medicinal Chemistry, State University of New York at Buffalo 14260.
Kalman
T I
TI
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D005492:Folic Acid / Q000031:analogs & derivatives*; D006710:Homocysteine / Q000031:analogs & derivatives*; D007939:Leukemia L1210 / Q000473:pathology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives*; D051379:Mice; D015394:Molecular Structure; D011622:Pterins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D000970:Antineoplastic Agents; D011622:Pterins; D006710:Homocysteine; D008717:Methionine Sulfoximine; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase