Non-glutamate Type Pyrrolo[2,3-d]pyrimidine Antifolates. III. Synthesis and Biological Properties of N^ω-Masked Ornithine Analogs

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概要

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• 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 the related compound (1a), was replaced with various N^ω-acyl-, sulfonyl-, carbamoyl- and aryl-2,ω-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^ω-phthaloyl 2,ω-diaminoalkanoic acid methyl esters (6a-c) and subsequent hydrolysis. The other N^ω-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^ω-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^ω-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.

• 公益社団法人日本薬学会の論文
• 2000-09-01

著者

• Itoh F

  Division Of Gastroenterology And Hepatology Department Of Internal Medicine St Marianna University S

• Itoh Fumio

  Division Of Gastroenterology And Hepatology Department Of Internal Medicine St Marianna University S

• 吉田 茂男

  The Institute Of Physical And Chemical Research

• Itoh Fumio

  Medicinal Chemistry Research Laboratories Takeda Chemical Industries Ltd.

• Yoshida S

  Biological Research Laboratories Sankyo Co. Ltd.

• Akimoto H

  Intellectual Property Department Takeda Chemical Industries Ltd.

• YOSHIOKA Yoshio

  Medicinal Chemistry Research Laboratories, Takeda Chemical Industries, Ltd.,

• YUKISHIGE Koichi

  Pharmaceutical Business Development Department Takeda Chemical Industries, Ltd.,

• YOSHIDA Sei

  Discovery Research Laboratories III, Takeda Chemical Industries, Ltd.,

• OOTSU Koichiro

  Takeda RABICS Takeda Chemical Industries, Ltd.,

• AKIMOTO Hiroshi

  Intellectual Property Department, Takeda Chemical Industries, Ltd.,

• Ootsu K

  Takeda Rabics Takeda Chemical Industries Ltd.

• Ypshioka Y

  Medicinal Chemistry Research Laboratories Takeda Chemical Industries Ltd.

• Yukishige K

  Pharmaceutical Business Development Department Takeda Chemical Industries Ltd.

• AKIMOTO Hiroshi

  Intellectual Property Department, Takeda Chemical Industries, Ltd.

• OOTSU Koichiro

  Takeda RABICS Takeda Chemical Industries, Ltd.

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