J Med Chem. 2008 Jul 8. [Epub ahead of print]
The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents-
Gangjee A, Jain HD, Queener SF, Kisliuk RL.
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, Department of Pharmacology and Toxicology, School of Medicine, Indiana University, Indianapolis, Indiana 46202, Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111 firstname.lastname@example.org.
Novel classical antifolates ( 3 and 4) and 17 nonclassical antifolates ( 11- 27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11- 27 were 2,4-diamino-5-alkylsubstituted-7 H-pyrrolo[2,3- d]pyrimidines, 31 and 38, prepared by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I 2. The condensation of alpha-hydroxy ketones with malonodinitrile afforded the furans. For the classical analogues 3 and 4, the ester precursors were deprotected, coupled with diethyl- l-glutamate, and saponified. Compounds 3 (IC 50 = 60 nM) and 4 (IC 50 = 90 nM) were potent inhibitors of human DHFR. Compound 3 inhibited tumor cells in culture with GI 50 = 10 (-7) M. Nonclassical 17 (IC 50 = 58 nM) was a potent inhibitor of Toxoplasma gondii ( T. gondii) DHFR with >500-fold selectivity over human DHFR. Analogue 17 was 50-fold more potent than trimethoprim and about twice as selective against T. gondii DHFR.
PMID: 18605720 [PubMed - as supplied by publisher]