A pair of sulfur-containing geldanamycin analogs, 19-S-methylgeldanamycin and 4,5-dihydro- 19-S-methylgeldanamycin, from Streptomyces hygroscopicus 17997

The Journal of Antibiotics
2011.0

Abstract

Geldanamycin (GDM) is a benzoquinone ansamycin produced by Streptomyces hygroscopicus. It is a specific inhibitor of human heat shock protein 90 (Hsp90), a molecular chaperone assisting in protein folding, cell signaling and tumor repression, and a potential cellular target for anti-tumor agents. GDM is only used as a promising lead compound for anti-cancer drug development due to its poor water solubility and severe liver toxicity. Although hundreds of semi-synthetic GDM analogs have been developed by chemical synthesis, only tens have been created by genetic manipulation of the GDM biosynthetic gene cluster, and few natural GDM analogs have been discovered. There is an urgent need for novel GDM analogs with improved pharmacological profiles and lower hepatotoxicity for developing new anti-cancer agents targeting Hsp90. The authors, interested in discovering such analogs, found that Streptomyces hygroscopicus 17997, a GDM producer, produced a red compound after maximal GDM accumulation in fermentation broth. A similar red compound was also detected in the fermentation broth of the gdmP-disrupted mutant of S. hygroscopicus 17997 (a 4,5-dihydrogeldanamycin producer). These two red compounds were proved to be a pair of sulfur-containing GDM analogs: 19-S-methylgeldanamycin (1) and 4,5-dihydro-19-S-methylgeldanamycin (2). This note reports the discovery, isolation, structure elucidation and some physicochemical properties of 1 and 2.

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