Improving physical properties via C-H oxidation: chemical and enzymatic approaches.

Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle-type leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of C-H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water-soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds.

Improvement of sordarin production through process optimization: combining traditional approaches with DOE.

BMS-353645, also known as sordarin, was of interest based on its activity against pathogenic fungi. The objective of these studies was to provide high quality starting substrate for chemical modification aimed at further improving biological activity, with particular interest in the inhibition of Aspergillus. In the work presented here, Design of Experiments, or DOE, was successfully combined with traditional approaches to significantly improve sordarin yields in fermentation flasks. Overall, yields were increased 25-fold from <100 microg/g to as high as 2,609 microg/g in flasks through the use of various medium and conduction changes supplemented with DOE. The improved process was then successfully scaled to pilot plant tanks with the best batch producing 2,389 microg/g sordarin at the 250-l scale.

Sordarin oxazepine derivatives as potent antifungal agents.

The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.