title: Non-glutamate type pyrrolo[2,3-d]pyrimidine antifolates. III. Synthesis and biological properties of N(omega)-masked ornithine analogs.
abstract: The glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-g lutamic acid (1b, TNP-351) and the related compound (1a), was replaced with various N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-2,omega-diaminoalkanoic acids, and the inhibitory effects of the resulting products (9, 11, 14, 18, 21, 23, 25, 30, 36) on dihydrofolate reductase (DHFR), the growth of murine fibrosarcoma Meth A cells, and methotrexate-resistant human CCRF-CEM cells, were examined. Compounds (9a-f) acylated with a hemiphthaloyl group were efficiently synthesized by coupling pyrrolo[2,3-d]pyrimidine carboxylic acids (7a,b) and N(omega)-phthaloyl 2,omega-diaminoalkanoic acid methyl esters (6a-c) and subsequent hydrolysis. The other N(omega)-acyl- and sulfonyl-ornithine analogs (21, 23, 25) were synthesized by acylation of free amino intermediates (19a,b) derived from tert-butoxycarbonyl-ornithine analogs (17a,b). A free ornithine analog (18) did not strongly inhibit Meth A cell growth, whereas all N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-ornithine analogs (9, 11, 21, 23, 25, 30, 36) exhibited much more potent inhibitory activities against both DHFR and Meth A cell growth. In particular, compounds 9c, 21k and 36a also showed remarkable growth-inhibitory activities against methotrexate-resistant CCRF-CEM cells. These results demonstrate that the potent inhibitory activities of N(omega)-masked ornithine analogs against the growth of Meth A cells and methotrexate-resistant CCRF-CEM cells, results from effective uptake via reduced folate carrier and their potent DHFR inhibition.
authors.affiliation: Medicinal Chemistry Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan. Itoh_Fumio@takeda.co.jp
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: K
authors.initials: K
authors.lastname: Ootsu
authors.forename: H
authors.initials: H
authors.lastname: Akimoto
mesh_terms: D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate