Synthesis of novel, nonclassical 2-amino-4-oxo-6-(arylthio)ethylpyrrolo[2,3-d] pyrimidines as potential inhibitors of thymidylate synthase

• Published in: Journal of heterocyclic chemistry 2001-03, Vol.38 (2), p.349-354
• Main Authors: Gangjee, Aleem, Dubash, Nauzer P., Kisliuk, Roy L.
• Format: Article
• Language: English
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.5570380205

A novel series of 14 nonclassical 6‐substituted pyrrolo[2,3‐d]pyrimidines 2a ‐ 2n were designed as potential inhibitors of thymidylate synthase, based on previously reported 2‐amino‐4‐oxopyrrolo[2,3‐d]‐pyrimidines 1a and 1b. The synthesis of the target compounds 2a‐2n was accomplished by nucleophilic displacement of the mesylate 11 with appropriately substituted aromatic thiols. Most of the target compounds did not show inhibition of either Escherichia coli thymidylate synthase or recombinant human thymidylate synthase at the concentrations tested. However, compounds 2h (2,4‐dichloro), 2j (3,4‐dichloro) and 2m (4‐nitro) did show 25%, 40% and 35% inhibition of human thymidylate synthase at 23 μM, 23 μM and 24 μM, respectively. These observations are in accordance with previous reports, which suggest that strong electron withdrawing substituents on the side chain aromatic ring are conducive to inhibition of thymidylate synthase.