Chemical Modification and Structure-activity Relationships of Pyripyropenes 1. Modification at the Four Hydroxyl Groups

RIKA OBATA; TOSHIAKI SUNAZUKA; ZHUORONG LI; ZHIMING TIAN; YOSHIHIRO HARIGAYA; NORIKO TABATA; HIROSHI TOMODA; SATOSHI OMURA

doi:10.7164/antibiotics.49.1133

Chemical Modification and Structure-activity Relationships of Pyripyropenes

1. Modification at the Four Hydroxyl Groups

RIKA OBATA, TOSHIAKI SUNAZUKA, ZHUORONG LI, ZHIMING TIAN, YOSHIHIRO HARIGAYA, NORIKO TABATA, HIROSHI TOMODA, SATOSHI OMURA

Author information

RIKA OBATA
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
TOSHIAKI SUNAZUKA
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
ZHUORONG LI
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
ZHIMING TIAN
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
YOSHIHIRO HARIGAYA
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
NORIKO TABATA
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
HIROSHI TOMODA
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University
SATOSHI OMURA
Research Center for Biological Function, The Kitasato Institute and School of Pharmaceutical Sciences, The Kitasato University

JOURNAL FREE ACCESS

1996 Volume 49 Issue 11 Pages 1133-1148

DOI https://doi.org/10.7164/antibiotics.49.1133

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Abstract

Four hydroxyl groups of pyripyropenes have been modified and evaluated for their ability to inhibit microsomal acyl-CoA: cholesterol acyltransferase (ACAT) activity in vitro and to lower cholesterol absorption in vivo in a cholesterol-fed hamster. 7-O-n-Valeryl derivative (8c) improved the in vitro ACAT inhibitory activity (IC₅₀=13nM) about 7 times better than pyripyropene A. Introduction of methanesulfonyl group at 11-hydroxyl group (17a) increased both in vitro activity (IC₅₀=19nM) and in vivo efficacy (ED₅₀=10mg/kg).

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