title: Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases.
abstract: The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a classical antifolate inhibitor of tumor cells in culture. The compounds were designed as conformationally restricted analogues of trimetrexate. The synthesis was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2, 4-diamino-6-hydroxypyrimidine to afford regiospecifically 2, 4-diamino-5,6,7,8-tetrahydropyrido[4',3':4,5]furo[2, 3-d]pyrimidine-7-hydrobromide (16). This in turn was alkylated with the appropriate benzyl halide to afford the target compounds 1-6. The classical antifolate 7 utilized 4-(chloromethyl)benzoyl-l-glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation, followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. The classical analogue 7 was 88-fold more potent against M. avium DHFR than against rat liver DHFR. The classical analogue was also inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gangjee
authors.forename: E
authors.initials: E
authors.lastname: Elzein
authors.forename: S F
authors.initials: SF
authors.lastname: Queener
authors.forename: J J
authors.initials: JJ
authors.lastname: McGuire
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000494:pharmacology; D009162:Mycobacterium avium / Q000201:enzymology; D011010:Pneumocystis / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014122:Toxoplasma / Q000201:enzymology; D014407:Tumor Cells, Cultured
chemical_list: C111911:2,4-diamino-5,6,7,8-tetrahydro-7-(4'-benzoylglutamic acid)pyrido(4',3'-4,5)furo(2,3-d)pyrimidine; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D018698:Glutamic Acid; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate