1. Prodrug forms of N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psiP(O)(OH)]-glutarate, a potent inhibitor of folylpoly-gamma-glutamate synthetase: synthesis and hydrolytic stability.
- Author
-
Feng Y and Coward JK
- Subjects
- Aminopterin chemical synthesis, Aminopterin chemistry, Aminopterin pharmacology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, CHO Cells, Cricetinae, Cricetulus, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Esters chemical synthesis, Esters chemistry, Esters pharmacology, Hydrolysis, Kinetics, Methotrexate administration & dosage, Methotrexate chemistry, Methotrexate pharmacology, Pentanoic Acids chemistry, Phosphinic Acids chemistry, Phosphinic Acids pharmacology, Prodrugs chemistry, Prodrugs pharmacology, Structure-Activity Relationship, Aminopterin analogs & derivatives, Antineoplastic Agents chemical synthesis, Peptide Synthases antagonists & inhibitors, Phosphinic Acids chemical synthesis, Prodrugs chemical synthesis
- Abstract
Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psiP(O)(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.
- Published
- 2006
- Full Text
- View/download PDF