Sunday, August 10, 2008
P81
Production of a novel progesterone receptor agonist and its analogs by fungal fermentation
Ramunas Bigelis, Li-Ping Chang, Laurel R. Barbieri, Maya P. Singh, Leonard A. McDonald, and Deborah M. Roll. Natural Products Discovery Research, Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965
Nonsteroidal progesterone receptor agonists have potential in female contraception and hormone therapy regimens, as well as in other pharmaceutical applications. In the course of screening our natural products microbial library, a fungal culture was identified that produced a new nonsteroidal natural product active in a progesterone receptor agonist screen. In addition, the culture produced 3 analogs. The original culture showed instability and morphological variability, especially after subculturing on agar media. A distinct variant strain of the fungal culture was isolated on an agar medium formulation and then shown to produce the target compound with consistency in repeated fermentations. Other isolated variants were much less productive in all liquid media investigated. The isolation of a reliable production strain permitted medium development and optimization. Both strain manipulation and optimization of nutritional variables were essential for achieving favorable fermentation yields of the novel progesterone receptor agonist and its analogs. The screening of natural products from microbial sources continues to play a significant role in drug discovery and offers opportunities for the discovery of unique compounds.
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