Geldanamycin

IUPAC: (4E, 6Z, 8R, 9R, 10E, 12R, 13S, 14R, 16S ) - 9 - [( aminocarbonyl ) oxy ] - 13 -hydroxy -8 ,14,19 -trimethoxy - 4,10,12,16 - tetramethyl- 2- azabicyclo [ 16.3.1 ] docosa - 4,6,10,18,21 - pentaene - 3,20,22 -trione

Yellow to orange solid

• Insoluble in water
• Soluble in DMSO

2500 mg · kg -1 ( LD50, rat, oral)

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Geldanamycin is a biologically active chemical compound, specifically a benzochinoides ansamycin that is produced by the bacterium Streptomyces hygroscopicus. It specifically binds to and alters the function of HSP90 Hitzschockprotein. HSP90 client proteins play important roles in the regulation of cell cycle, cell growth, cell survival, apoptosis, angiogenesis, and oncogenesis. By binding of geldanamycin to Hsp90 target proteins, such as tyrosine kinases, steroid receptors, transcription factors and cell cycle - regulating kinases are degraded. It induces the inactivation, destabilization and ultimately the degradation of HIF- 1α.

Geldanamycin induces degradation of the preferred proteins that are mutated in cancer cells compared to the normal proteins, such as at v - src, bcr-abl and p53. This effect is mediated by HSP90. Despite its high antitumor potential, shows geldanamycin some disadvantages as drug candidate, in particular hepatotoxicity, which gave rise to develop geldanamycin analogs, especially those whose position is derivatized 17: