title: Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates.
abstract: Two classical antifolates, a 2,4-diamino-5-substituted furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine, were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The syntheses were accomplished by condensation of 2,6-diamino-3(H)-4-oxo-pyrimidine with alpha-chloro-ketone 21 to afford two key intermediates 23 and 24, followed by hydrolysis, coupling with l-glutamate diethyl ester and saponification of the diethyl ester to afford the classical antifolates 13 and 14. Compounds 13 and 14 with a single carbon atom bridge are both substrates for folylpoly-gamma-glutamate synthetase (FPGS), the enzyme responsible for forming critical poly-gamma-glutamate antifolate metabolites with increased potency and/or increased cell retention. Compound 14 is a highly efficient FPGS substrate demonstrating that 2,4-diamino-5-substituted furo[2,3-d]pyrimidines are important lead structures for the design of antifolates with FPGS substrate activity. It retains inhibitory potency for DHFR and TS compared to the two atom bridged analog 5. Compound 13 is a poor inhibitor of purified DHFR and TS, and both 13 and 14 are poor inhibitors of the growth of CCRF-CEM human leukemia cells in culture, indicating that single carbon bridged compounds in these series though conducive to FPGS substrate activity were not potent inhibitors.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, 600 Forbes Avenue, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: John J
authors.initials: JJ
authors.lastname: McGuire
authors.forename: Roy L
authors.initials: RL
authors.lastname: Kisliuk
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008727:Methotrexate / Q000009:adverse effects; D010453:Peptide Synthases / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; C030986:pyrimidine; D008727:Methotrexate