Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue 2, Pages 770-788Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm050871p
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Funding
- NCI NIH HHS [R01 CA028097, CA28097, R01 CA028097-25] Funding Source: Medline
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Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psi P(0)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to alpha-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond. N-Alkylation of the corresponding amides derived from p-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding gamma-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding gamma-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.
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