Polyglutamyl and polylysyl derivatives of the lysine analogs of folic acid and homofolic acid

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Abstract
A series of N.epsilon.-poly-.alpha.-glutamyl and N.epsilon.-polylysyl derivatives of N.alpha.-pteroyllysine and N.alpha.-homopteroyllysine, analogs of the naturally occurring .gamma.-polyglutamyl forms of folate, was prepared and tested as substrates for dihydrofolate reductase and as substrates and inhibitors of thymidylate synthetase. N.alpha.-Dihydropteroyl-N.epsilon.-(tri-.alpha.-glutamyl)lysine was 1.8 times as active as N.alpha.-dihydropteroyl glutamate (dihydrofolate) as a substrate for L1210 murine leukemia dihydrofolate reductase. N.alpha.-Dihydropteroyl-N.epsilon.-(di-.alpha.-lysyl)lysine was 1.2 times as active as dihydrofolate in spite of its strong positive charge. The most active compound tested, N.epsilon.-(tert-butyloxycarbonyl)lysine, was 3.5 times as active as dihydrofolate. None of the enzymatically prepared N.alpha.-tetrahydropteroyllysine derivatives tested was as active as N.alpha.-tetrahydropteroyl glutamate (tetrahydrofolate) as a substrate for Escherichia coli thymidylate synthetase. However, there was a progressive increase in activity with the addition of each .alpha.-glutamyl residue, the N.epsilon.-(penta-.alpha.-glutamyl)lysine being 88% as active as tetrahydrofolate. N.alpha.-Tetrahydropteroyl-N.epsilon.-(di-.alpha.-lysyl)lysine was the most active thymidylate synthetase substrate of the polylysine derivatives, being 67% as active as tetrahydrofolate. Addition or deletion of lysyl residues resulted in diminished activity. Substrate activity is retained in spite of the positively charged poly(amino acid) side chain. None of the enzymatically prepared tetrahydrohomopteroyl derivatives tested was as active as N.alpha.-tetrahydrohomopteroyl glutamate (tetrahydrohomofolate) as an inhibitor of E. coli thymidylate synthetase.

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