Stresgenin B

A new NADH oxidase, useful for the regeneration of NAD+, was isolated and characterized from Lactobacillus brevis. In crude extracts the activity was from 10-15 U mg(-1). After purification by four chromatographic steps, an activity of 116 U mg(-1) was obtained with 14% yield. Highest activity was from pH 5.5-7 and at 40 degrees C. The enzyme requires dithiothreitol to prevent oxidative deactivation. The Km value for NADH was 24 microM.

We report the first total synthesis of the reported structure of the heat shock protein expression inhibitor stresgenin B. The synthesis features (1) diastereoselective cyanation of an oxocarbenium intermediate en route to the synthetically challenging α-amido dioxolane, (2) Pd-catalyzed hydration of an unstable nitrile, and (3) late-stage Au-catalyzed Meyer-Schuster rearrangement or Ce-mediated Peterson olefination to furnish the exocyclic α,β-unsaturated ester. Our synthetic endeavors allowed us to conclude that the structure of stresgenin B requires revision.

Heat-shock protein 90 (Hsp90) is an essential, cytosolic protein. Its overexpression in a wide variety of malignant tumors makes it a candidate target for pharmacological intervention. The association with Hsp90 stabilizes key regulatory proteins like Fak, Bcr-Abl, ErbB2, mutant p53 and Raf-1. The disruption of these heterocomplexes by Hsp90 inhibitors causes the rapid degradation of Hsp90-client proteins by the proteasome. Benzoquinone ansamycins were the first group of compounds for which interference with Hsp90 function was shown to be the major mechanism of action. They are in the early phase of clinical development. Radicicol and its derivatives are functional analogues of benzoquinone ansamycins without structural similarity. Flavonoids and stresgenin B share the ability to suppress heat-shock protein synthesis. Recently, it became apparent that coumarin antibiotics, cisplatin and paclitaxel also bind to Hsp90. The clinical value of the newly characterized agents with activity towards Hsp90 remains to be determined.