title: 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.
abstract: 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-7H-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 I2. 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 (IC50 = 60 nM) and 4 (IC50 = 90 nM) were potent inhibitors of human DHFR. Compound 3 inhibited tumor cells in culture with GI50 <or= 10(-7) M. Nonclassical 17 (IC50 = 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.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.forename: Hiteshkumar D
authors.initials: HD
authors.lastname: Jain
authors.forename: Sherry F
authors.initials: SF
authors.lastname: Queener
authors.forename: Roy L
authors.initials: RL
authors.lastname: Kisliuk
mesh_terms: D000478:Alkylation; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / 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*
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; D013762:Tetrahydrofolate Dehydrogenase