Design, Synthesis, and Biological Evaluation of Beauveriolide Analogues Bearing Photoreactive Amino Acids
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- Masuda Yuichi
- Graduate School of Pharmaceutical Sciences, Tohoku University
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- Aoyama Kazumasa
- Graduate School of Pharmaceutical Sciences, Tohoku University
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- Yoshida Masahito
- Graduate School of Pharmaceutical Sciences, Tohoku University
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- Kobayashi Keisuke
- Graduate School of Pharmaceutical Sciences, Kitasato University
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- Ohshiro Taichi
- Graduate School of Pharmaceutical Sciences, Kitasato University
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- Tomoda Hiroshi
- Graduate School of Pharmaceutical Sciences, Kitasato University
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- Doi Takayuki
- Graduate School of Pharmaceutical Sciences, Tohoku University
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Beauveriolides I and III, which are naturally occurring cyclodepsipeptides, have been reported to bind to sterol O-acyltransferase (SOAT), inhibiting its ability to synthesize cholesteryl esters. To facilitate an analysis of the binding site(s) of these compounds, we designed beauveriolide analogues 1a–d wherein the Leu or D-allo-Ile residue was replaced by photoreactive amino acids possessing methyldiazirine or trifluoromethyldiazirine in the side chains. The methyldiazirine moiety was installed by reaction of methyl ketones with liquid ammonia to provide imine intermediates, followed by treatment with hydroxylamine-O-sulfonic acid to provide the diaziridines. Subsequent oxidation gave methyldiazirines. In contrast, trifluoromethyldiazirine derivatives were prepared from trifluoromethyl ketones via the oxime intermediates, which were transformed into diaziridines. Subsequent oxidation afforded trifluoromethyldiazirines. The synthesized photoreactive amino acids 3a–d were coupled with 3-hydroxy-4-methyloctanoic acid 4 and dipeptide 5, followed by macrolactamization to provide beauveriolide analogues 1a–d. The SOAT inhibitory activities of 1a–d were found to be as potent as those of beauveriolides I and III. Moreover, 1a–d inhibited SOAT1 selectively rather than SOAT2, which was also consistent with the behavior of beauveriolides I and III.
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 64 (7), 754-765, 2016
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390001204177399168
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- NII論文ID
- 130005160040
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- NII書誌ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 027451451
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- PubMed
- 27020600
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
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- 使用不可