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Synlett 2004(8): 1325-1333  
DOI: 10.1055/s-2004-829052
ACCOUNT
© Georg Thieme Verlag Stuttgart · New York

Synthetic Development of Radicicol and Cycloproparadicicol: Highly Promising Anticancer Agents Targeting Hsp90

Xudong Genga, Zhi-Qiang Yanga, Samuel J. Danishefsky*a,b
a Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA
Fax: +1(212)7728691; e-Mail: danishefsky@ski.mskcc.org;
b Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, USA
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Publication History

Received 5 April 2004
Publication Date:
08 June 2004 (online)

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Abstract

Molecular chaperone Hsp90 has emerged as one of the most exciting new targets for anticancer therapy. Natural product-based modulators, such as radicicol (1), inhibit Hsp90 and induce the breakdown of its client proteins, thereby blocking multiple critical oncogenic pathways. Several total synthesis endeavors directed toward radicicol have been accomplished. Cycloproparadicicol (2), a potent Hsp90 inhibitor and highly promising pre-clinical anticancer agent, was discovered through a convergent total synthesis approach. In an effort to devise a more efficient and concise route to reach 2, a novel ‘ynolide’ protocol, featuring an ynolide-bissiloxydiene Diels-Alder addition, was designed and reduced to practice. This methodology was also extended to aigialomycin D.

  • 1 Introduction

  • 2 First Total Synthesis of Radicicol

  • 3 First Generation Convergent Total Synthesis of Radicicol and the Discovery of the Promising Anticancer Agent, ­Cycloproparadicicol

  • 4 ‘Ynolide Approach’: Second Generation Total Synthesis of Cycloproparadicicol

  • 4.1 Development of ‘Ynolide’ Methodology

  • 4.2 Scope and Limitations of the New Strategy

  • 4.2.1 Extension of ‘Ynolide Approach’ to another Resorcinylic Macrolide: Aigialomycin D

  • 4.2.2 Limitations

  • 5 Conclusions and Future Directions

Key words

radicicol - cycloproparadicicol - Hsp90 - anticancer - ynolide

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Yang, Z.-Q.; Chou, T. C.; Danishefsky, S. J. unpublished results, 2004.