Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity

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

The design and synthesis of simplified viridin analogs as PI3K inhibitors

Phosphoinositide-3-kinase (PI3K) plays an integral role in a cellular signaling transduction pathway which is ultimately responsible for cellular growth, differentiation, and apoptosis. This pathway is often overactivated in many types of cancers and extensive efforts in the development of PI3K inhibitors for anticancer therapy are of interest. The natural product furanosteroids, viridin and wortmannin, are potent, irreversible PI3K inhibitors with IC 50 values of 4-5 nM. The inhibitory potency is attributed to the covalent binding by Lys833 in the ATP active site which opens up the electrophilic furan ring. ^ We have developed an efficient synthetic route to analogs of viridin. Our Type I and Type II analogs were pursued to decrease the overall electrophilicity of the furan ring and improve its stability in comparison to the natural product furanosteroids. Our Type I analog contains a vinylogous amide to decrease the reactivity of the furan ring. The key building block involved the conversion of 3,4-dibromofuran to the fused tricyclic vinylogous amide core. Further conversion to the A-B-C-E furanosteroid core is discussed and will be presented herein. Our progress towards seco-B Type II analogs to relieve the furan ring strain was achieved through amide couplings and is also discussed.