Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor), that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3-fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED50 compared to 2 for protection against glucose-induced toxicity of primary sensory neurons.

Phosphoinositide-3-kinase is a pivotal protein involved in a wide variety of signaling cascades and there has been a great deal of interest in the development of potent and selective inhibitors of this enzyme. In this review, the potency and selectivity of the known inhibitors is presented along with key structural information that helps rationalize the observed trends.

Organic chemistry Z 0200 Inhibitors of Phosphoinositide-3-kinase: A Structure-Based Approach to Understanding Potency and Selectivity -[57 refs.]. -(SUNDSTROM, T. J.; ANDERSON, A. C.; WRIGHT*, D. L.; Org. Biomol. Chem. 7 (2009) 5, 840-850; Dep. Pharm. Sci., Sch. Pharm., Univ. Conn., Storrs, CT 06269, USA; Eng.) -Lindner 23-251

We have designed a new class of non-natural furanosteroids to serve as more chemically stable analogues of the viridins, potent inhibitors of PI-3K. Central to the design is the incorporation of a nitrogen atom into the steroidal ring system to attenuate the activity of the electrophilic 2,4-diacylfuran common to these natural products. In this manuscript, we describe our initial synthetic studies on this ring system and the preparation of key intermediates for analogue generation.