Synthesis and Antitumor Activity of Duocarmycin Derivatives : A-Ring Pyrrole Compounds Bearing 5-Membered Heteroarylacryloyl Groups

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概要

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• A series of A-ring pyrrole compounds of duocarmycin bearing 5-membered heteroarylacryloyl groups (thienylacryloyl and pyrrolylacryloyl) and heteroarylcarbonyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S_3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the thienylacrylates displayed in vitro anticellular activity equivalent to 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of methoxy-thienylacrylates, compound 11b, having 4'-methoxy-2'-thienylacryloyl as segment-B (Seg-B), showed remarkably potent antitumor activity and low peripheral blood toxicity in vivo, which were equal to those of 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates, compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 10^2- to 10^3-fold stronger anticellular activity than 2'-pyrrolecarboxylates (IC_<50><0.3nM, 72 h-exposure). The 8-O-acetate and 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 2'-pyrrolylacrylates exhibited an antitumor effect at a lower dose compared with the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamate (1j). Moreover, it was expected that the antitumor activity would be increased by the strength of the extra hydrogen bond formed between the nitrogen of the pyrrole amido group and DNA, owing to the increase of the number of N-methyl-2'-pyrrolecarboxamide units. However, 2'-pyrrolylacrylates having three N-methyl-2'-pyrrolecarboxamide units showed nearly equal antitumor activity to 2'-pyrrolylacrylates having only one N-methyl-2'-pyrrolecarboxamide unit.

• 公益社団法人日本薬学会の論文
• 1999-10-15

著者

• Kobayashi E

  Pharmaceutical Research Institute Kyowa Hakko Kogyo Company Ltd.

• 斉藤 博満

  協和発酵・東京研

• AMISHIRO Nobuyoshi

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd.,

• NAGAMURA Satoru

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd.,

• KOBAYASHI Eiji

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd.,

• OKAMOTO Akihiko

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd.,

• GOMI Katsushige

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd.,

• SAITO Hiromitsu

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd.,

• Okamoto Akihiko

  Pharmaceutical Research Institute Kyowa Hakko Kogyo Company Ltd.

• Amishiro Nobuyoshi

  Pharmaceutical Research Institute Kyowa Hakko Kogyo Company Ltd.

• Saito Hideyuki

  Department Of Pharmacology College Of Pharmacy Nihon University

• Kobayashi E

  Gifu Pharmaceutical University : Gifu Prefectural Institute Of Health And Environmental Sciences

• Saito H

  Department Of Pharmacology College Of Pharmacy Nihon University

• Gomi Katsushige

  Pharmaceutical Research Institute Kyowa Hakko Kogyo Company Ltd.

• Nagamura S

  Pharmaceutical Research Institute Kyowa Hakko Kogyo Company Ltd.

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