Monday, August 2, 2010
Pacific Concourse (Hyatt Regency San Francisco)
As part of our continuing program to identify natural product drug leads we have carried out chemical investigation of several Amycolatopsis spp. isolated from soils of the Black Water Ecosystems (BWE) in Kalimantan, Indonesia. Several of these Amycolatopsis spp. produce apoptolidins; a family of glycosylated macrolactones. The promising activity and intriguing structures has motivated us to isolate and characterize new apoptolidins from producing microorganisms. We explored the possibility to isolate new apoptolidin analogs from some strain Amycolatopsis spp. In addition we Our effort to generate new apoptolidin analogs via pathway modulation using enzyme inhibitors. Specifically, we attempted to generate new, active and stable apoptolidins that were less prone to rearrangement. Systematic studies were conducted to first optimize apoptolidin production and subsequently to examine the effect of adding the cytochrome P-450 inhibitor ancymidol to cultures of Amycolatopsis sp. ICBB 8242. The Metabolite analysis of cultures receiving ancymidol confirmed that the major compounds produces were the targeted deshydroxy species. Additionally, several new apoptolidin analogs were detected. The results indicate that inhibition of cytochrome P-450 enzymes in apoptolidin biosynthesis not only produced accumulated intermediates immediately upstream of the blocked enzymes but also led to the production of several new apoptolidins.