Herein, imidazol-4-ones are applied to the areas of methodology development, total synthesis, and small molecule design for proteasome activation. The first total synthesis of nortopsentin D is described, which was completed in 7 linear steps with an overall yield of 1.6%. This convergent synthesis involved the condensation of amidine and dione, followed by a cyclization via a pinacol-like rearrangement to produce the central imidazol-4-one ring. Additionally, a range of imidazol-4-ones were explored for their use as proteasome activators. Out of this research, a new scaffold, N-acylated fluspirilene (5-12), was discovered. This small molecule represents the Tepe lab's first proteasome activator to dock within the Îł2-3 intersubunit pocket and produce a significant increase in IDP degradation in vitro (AC200 1.9 ÎơM, max fold enhancement > 2000%) as well as in cells.
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