title: Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.
abstract: We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC(50) < or = 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.forename: Yibin
authors.initials: Y
authors.lastname: Zeng
authors.forename: John J
authors.initials: JJ
authors.lastname: McGuire
authors.forename: Roy L
authors.initials: RL
authors.lastname: Kisliuk
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005663:Furans; C503905:N-(4-(4-(2,4-diaminofuro(2,3-d)pyrimidin-5-yl)butyl)benzoyl)glutamic acid; C503904:N-(4-(4-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimidin-6-yl)butyl)benzoyl)glutamic acid; D011743:Pyrimidines; D011744:Pyrimidinones; D011758:Pyrroles; D018698:Glutamic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase