Synthesis of Classical, Three-Carbon-Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates

• Published in: Journal of medicinal chemistry 2004-12, Vol.47 (27), p.6893-6901
• Main Authors: Gangjee, Aleem, Zeng, Yibin, McGuire, John J, Mehraein, Farideh, Kisliuk, Roy L
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - chemical synthesis; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - pharmacology; General aspects; Humans; Medical sciences; Peptide Synthases - metabolism; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - drug effects; Thymidylate Synthase - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040123k

Bridge homologation of the previously reported classical two-carbon-bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) [which is a 6-regioisomer of LY231514 (Alimta)] and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine, afforded the three-carbon-bridged antifolates analogues 4 and 5, with enhanced inhibitory activity against tumor cells in culture (EC50 values in the 10-8−10-7 M range or less). These two analogues were synthesized via a 10-step synthetic sequence starting from methyl 4-bromobenzoate (14), which was elaborated to the α-chloromethyl ketone (8) followed by condensation with 2,6-diamino-pyrimidin-4-one (7) to afford the substituted furo[2,3-d]pyrimidine 9 and the pyrrolo[2,3-d]pyrimidine 10. Subsequent coupling of each regioisomer with diethyl-l-glutamate followed by saponification afforded 4 and 5. The biological results indicate that elongation of the C8−C9 bridge of the classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine and 6-substituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine are highly conducive to antitumor activity in vitro, despite a lack of increase in inhibitory activity against the target enzymes. This supports our original hypothesis that truncation of the B-ring of a highly potent 6−6 ring system to a 6−5 ring system can be compensated by bridge homologation to restore the overall length of the molecule.