Identification of 6-demethoxy-6-methylgeldanamycin and its implication of geldanamycin biosynthesis

摘要

Geldanamycin (1, Figure 1), the first member of benzoquinone ansamycins, was isolated from Streptomyces hygroscopicus in 1970. Although exhibiting potent cytotoxicity against various cancer cells, 1 is not a clinical compound due to its severe hepatotoxicity and poor water solubility. 17-AAG (17-allylamino-17-demethoxy-geldanamycin) as a semisynthetic derivative of 1 with much improved water solubility is currently under clinical trial for breast cancer treatment. Many new analogs or derivatives of 1 have been created or discovered in the past few years.We are interested in natural 1 analogs and understanding their synthetic mechanisms. We identified such analogs as 4,5-dihydro-4-hydroxygeldanamycins, thiazinogeldanamycin and 19-S-methylgelda-namycin from S. hygroscopicus 17997 and characterized their synthetic mechanisms. We also discovered a minor component 7-descarbamoyl-7-hydroxygeldanamycin from a gdmN disruption mutant of S. hygroscopicus 17997, which presented an additional proof for C-7 carbamoylation taking place before C-4,5 oxidation in 1 biosynthesis.