Structure-Activity Relationship Study and Total Synthesis of Pyripyropene A as a Potent ACAT2-Selective Inhibitor

• Ohtawa Masaki

• Omura Satoshi

• Tomoda Hiroshi

• Nagamitsu Tohru

  Graduate School of Pharmacy, Kitasato University

Bibliographic Information

Other Title

• 新規脂質異常症予防治療薬を指向したACAT2選択的阻害剤ピリピロペンAの構造活性相関研究
• シンキ シシツ イジョウショウ ヨボウ チリョウヤク オ シコウ シタ ACAT2 センタクテキ ソガイザイ ピリピロペン A ノ コウゾウ カッセイ ソウカン ケンキュウ

Abstract

Fungal pyripyropene A (PPPA, 1), consisting of pyridine, α-pyrone, and sesquiterpene moieties, is the only potent and selective inhibitor of acyl-CoA: cholesterol acyl transferase 2 (ACAT2) isozyme. In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on 1. We have successfully developed novel 1,11-O-o-substituted benzylidene-7-p-cyanobenzoyloxy PPPA derivatives that exhibit significantly more potent ACAT2 inhibitory activity and much higher isozyme selectivity than 1.<br>Furthermore, we have achieved a stereocontrolled total synthesis of 1. Key features of the synthetic strategy included an intramolecular Ti(III)-mediated radical cyclization for construction of the A-ring, stereoselective β-epoxide formation/Peterson olefination for preparation of the functional groups on the B-ring, and stereoselective intramolecular cyclization through hetero-Michael addition for C-ring formation. Extension of this chemistry to the synthesis of an A-ring truncated PPPA analog for structure-activity relationship studies has also been achieved.

Journal

• Journal of Synthetic Organic Chemistry, Japan

  Journal of Synthetic Organic Chemistry, Japan 71 (8), 830-843, 2013

  The Society of Synthetic Organic Chemistry, Japan

Keywords

• pyripyropene A
• ACAT2
• ACAT2-selective inhibitor
• anti-atherosclerotic agent
• structure-activity relationship
• total synthesis

Details

• CRID: 1390001205339989504
• NII Article ID: 10031191019
• NII Book ID: AN0024521X
• DOI: 10.5059/yukigoseikyokaishi.71.830
• COI: 1:CAS:528:DC%2BC3sXhtlSgtbvL
• ISSN: 18836526
• ISSN: 00379980
• NDL BIB ID: 024817337
• Web Site: http://id.ndl.go.jp/bib/024817337
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I024817337
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed