Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5 H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl]benzoyl}- l-glutamic acid 4 and 11 nonclassical analogues 5- 15 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5 H-pyrrolo[3,2- d]pyrimidin-2-yl)-2,2-dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl l-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC 50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC 50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.
Gangjee
Aleem
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
Li
Wei
W
Yang
Jie
J
Kisliuk
Roy L
RL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014122:Toxoplasma / Q000201:enzymology
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase