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J Med Chem. 2008 Sep 25;51(18):5494-7. doi: 10.1021/jm8006068.

Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors.

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1
Biotica Technology Limited, Chesterford Research Park, Nr. Saffron Walden, Essex CB10 1XL, United Kingdom.

Abstract

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 > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.

PMID:
18800759
DOI:
10.1021/jm8006068
[Indexed for MEDLINE]
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