Sunday, August 10, 2008
P111
Mutational Biosynthesis of Geldanamycin Analogs via the Disruption of a Gene Governing Starter Unit Biosynthesis
The naturally occurring ansamycin antibiotic geldanamycin inhibits ATP-dependent chaperone activities of heat shock protein 90 (Hsp90) by binding to the amino terminal of ATP-binding domain. Because human Hsp90 client proteins, such as steroid hormone receptors, mutant p53, Raf-1, Cdk4, erb-B2, signaling kinases, transcription factors, and telomerase, are importantly involved in signal transduction and transcription on the cancer cells, geldanamycin and its derivatives have high possibilities to be potential anti-cancer chemotherapeutic agents. The biosynthesis of ansamycins, such as geldanamycin, is initiated by priming the 3-amino-5-hydroxy benzoic acid (AHBA) as a common starter unit. This is followed by the sequential addition of extender units to form a polyketide backbone, which then undergoes further downstream processing. Disruption of an AHBA biosynthetic gene has attracted the interests of those involved in improving the chemical diversity of benzoquinone ring of geldanamycin by mutational biosynthesis of geldanamycin. Here, we describe the results obtained from a mutational biosynthesis study, and demonstrate that this technique can be used to extend the structural diversity at the benzoquinone moiety of geldanamycin, which could contribute to obtain improved characteristics of Hsp90-geldanamycin binding profiles. We also show that these analogues were then evaluated for anti-proliferation activity in human cancer cell lines.
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See more of The Annual Meeting and Exhibition 2008 (August 10 - 14, 2008)
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