Evaluation of pteroyl-S-alkylhomocysteine sulfoximines as inhibitors of mammalian folylpolyglutamate synthetase.

The similarity between the reactions catalyzed by folylpoly-gamma-glutamate synthetase (FPGS), gamma-glutamylcysteine synthetase, and glutamine synthetase, as well as the susceptibility of the latter two enzymes to inhibition by methionine sulfoximine, suggest that folic acid derivatives with methionine sulfoximine or its alkyl homologs in place of the glutamate side chain of folate are good candidates to act as enzyme-generated transition state analog inhibitors of the FPGS reaction. Thus, pteroylmethionine sulfoximine, and the homologous S-ethyl-, S-propyl-, and S-butylhomocysteine sulfoximine derivatives were evaluated as inhibitors of FPGS that was partially purified from mouse liver and from mouse L1210 cells. The related compound, pteroyl-S-methylhomocysteine sulfone, which cannot undergo enzyme-mediated activation, was also investigated. Unexpectedly, none of these compounds showed significant inhibition of FPGS from these sources under a variety of conditions. These results, taken together with previously established structure-activity correlations, imply that a negative charge at the gamma-position of folate analogs may be required for initial binding to FPGS and thus constitutes a prerequisite for activity of potential mechanism-based inhibitors of this enzyme.