title: Non-glutamate type pyrrolo[2,3-d]pyrimidine antifolates. II. Synthesis and antitumor activity of N5-substituted glutamine analogs.
abstract: The glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid (1b, TNP-351) and related compounds was replaced with some N5-substituted glutamines. Antifolates (4A-S) were effectively prepared by coupling pyrrolo[2,3-d]pyrimidine carboxylic acids (11a, b) with some properly protected N5-substituted glutamine derivatives (10A-S), which were prepared by coupling Boc-Glu-OMe (7) with various amines (8A-S) using a suitable condensing reagent, followed by hydrolysis. The inhibitory effects of the resulting products on dihydrofolate reductase (DHFR), thymidylate synthetase (TS) and the growth of murine fibrosarcoma Meth A cells in culture were examined. All N5-substituted glutamine analogs (4A-S) inhibited DHFR much more strongly than TNP-351 and some analogs exhibited the same potent growth inhibition of Meth A cells as TNP-351. Some typical analogs (4Bb, 4Db, 4F, 4Oa) were also examined for inhibitory effects on the growth of methotrexate (MTX)-resistant human CCRF-CEM cells in culture and for in vivo antitumor activities against murine leukemia and solid tumors. MTX-resistant cells, with a defect in transport and decreased polyglutamylation activity, showed little cross resistance to the analog (4Oa) having a tetrazole moiety as a substituent of glutamine, which exhibited potent antitumor activities. These results demonstrate that the antifolate analogs (4) with N5-substituted glutamine in place of glutamic acid are novel potent DHFR inhibitors with activity against MTX-resistant tumors. The potent antitumor activity of these analogs (4) may result from their effective uptake via reduced folate carrier in combination with their potent inhibition of DHFR.
authors.affiliation: Pharmaceutical Research Laboratories III, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Itoh
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: K
authors.initials: K
authors.lastname: Yukishige
authors.forename: S
authors.initials: S
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Wajima
authors.forename: K
authors.initials: K
authors.lastname: Ootsu
authors.forename: H
authors.initials: H
authors.lastname: Akimoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002478:Cells, Cultured; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013940:Thymidylate Synthase; D008727:Methotrexate