Original Article

The Journal of Antibiotics (2008) 61, 503–508; doi:10.1038/ja.2008.67

Selectivity of Pyripyropene Derivatives in Inhibition toward Acyl-CoA:cholesterol Acyltransferase 2 Isozyme

Taichi Ohshiro2, Satoshi Ohte2, Daisuke Matsuda2, Masaki Ohtawa2, Tohru Nagamitsu2, Toshiaki Sunazuka3, Yoshihiro Harigaya2, Lawrence L Rudel4, Satoshi O macrmura3 and Hiroshi Tomoda1

  1. 1School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
  2. 2School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
  3. 3Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
  4. 4Atherosclerosis Research Program, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

Correspondence: H. Tomoda, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. E-mail: tomodah@pharm.kitasato-u.ac.jp

Received 18 June 2008; Accepted 4 August 2008.

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Abstract

Selectivity of 96 semisynthetic derivatives prepared from fungal pyripyropene A, originally isolated as a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), toward ACAT1 and ACAT2 isozymes was investigated in the cell-based assay using ACAT1- and ACAT2-expressing CHO cells. Eighteen derivatives including PR-71 (7-O-isocaproyl derivative) showed much more potent ACAT2 inhibition (IC50: 6.0 to 62 nM) than pyripyropene A (IC50: 70 nM). Among them, however, natural pyripyropene A showed the highest selectivity toward ACAT2 with a selectivity index (SI) of > 1000, followed by PR–71 (SI, 667).

Keywords:

semisynthetic pyripyropene derivative, acyl-CoA:cholesterol acyltransferase (ACAT), ACAT isozyme, atherosclerosis

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