title: Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents.
abstract: Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds 3 and 4 were obtained from 2,4-diamino-5-methylpyrrolo[2,3-d]pyrimidine 7 and 2-amino-4-oxo-5-methylpyrrolo[2,3-d]pyrimidine 12, respectively, in a concise three-step sequence. Compound 3 is the first example, to our knowledge, of a 2,4-diamino classical antifolate that has potent inhibitory activity against both human dihydrofolate reductase (DHFR) and human thymidylate synthase (TS). Compound 4 was a dual DHFR-TS inhibitor against the bifunctional enzyme derived from Toxoplasma gondii (tg). Further evaluation of the mechanism of action of 3 implicated DHFR as its primary intracellular target. Both 3 and 4 were folylpolyglutamate synthetase (FPGS) substrates. Compound 3 also inhibited the growth of several human tumor cell lines in culture with GI50 < 10(-8) M. This study shows that the pyrrolo[2,3-d]pyrimidine scaffold is conducive to dual DHFR-TS and tumor inhibitory activity, and the potency is determined by the 4-position substituent.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Roy L
authors.initials: RL
authors.lastname: Kisliuk
authors.forename: John J
authors.initials: JJ
authors.lastname: McGuire
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014122:Toxoplasma / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005971:Glutamates; C507025:N-(4-((2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-6-yl)thio)benzoyl)glutamic acid; C507026:N-(4-((2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-6-yl)thio)benzoyl)glutamic acid; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase