title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: James K
authors.initials: JK
authors.lastname: Coward
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D007700:Kinetics; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D010421:Pentanoic Acids / Q000737:chemistry; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; C508807:N-((4-deoxy-4-amino-10-methyl)pteroyl)glutamate-gamma-(psiP(O)(OH))-glutarate; D010421:Pentanoic Acids; D010721:Phosphinic Acids; D011355:Prodrugs; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D000630:Aminopterin; D008727:Methotrexate