2003年8月
Stereoselective synthesis and structure-activity relationship of novel ceramide trafficking inhibitors. (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide and its analogues
JOURNAL OF MEDICINAL CHEMISTRY
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- 巻
- 46
- 号
- 17
- 開始ページ
- 3688
- 終了ページ
- 3695
- 記述言語
- 英語
- 掲載種別
- DOI
- 10.1021/jm0300779
- 出版者・発行元
- AMER CHEMICAL SOC
New ceramide trafficking inhibitors, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12) and a series of its analogues, were synthesized in diastereomerically and enantiomerically pure forms, and the structure-activity relationship was investigated. These analogues were stereoselectively synthesized via catalytic enantioselective Mannich-type reactions using a Cu(II)-chiral diamine 4 complex. Analysis of HPA-12 analogues having various lengths of the amide side chain showed that the optimal chain length for the inhibition of sphingomyelin biosynthesis is 13 with an IC50 of similar to50 nM. Masking of the hydroxy group at the 2'- or 3-position of HPA-12 was carried out by methylation, and it was revealed that these hydroxy groups were essential for the activity. Installation of another hydroxy group onto HPA-12 at the same position as that in the natural ceramide was also conducted, but no enhancement of the activity was observed.
- リンク情報
- ID情報
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- DOI : 10.1021/jm0300779
- ISSN : 0022-2623
- Web of Science ID : WOS:000184719100016