Optimizing Natural Products by Biosynthetic Engineering: Discovery of Nonquinone Hsp90 Inhibitors
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- 作者：Ming-Qiang Zhang ; Sabine Gaisser ; Mohammad Nur-E-Alam ; Lesley S. Sheehan ; William A. Vousden ; Nikolaos Gaitatzis ; Gerrard Peck ; Nigel J. Coates ; Steven J. Moss ; Markus Radzom ; Teresa A. Foster ; Rose M
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：September 25, 2008
- 年：2008
- 卷：51
- 期：18
- 页码：5494-5497
- 全文大小：190K
- 年卷期：v.51,no.18(September 25, 2008)
- ISSN：1520-4804
文摘
A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD ≥ 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.