New methodology to access small molecule proteasome inhibitors - including the total synthesis of dibromophakellin, dibromophakellstatin, and analogs

Inhibition of the proteasome has recently emerged as a valuable target in anti-cancer therapy. Bortezomib was approved as a proteasome inhibitor for the treatment of multiple myeloma in 2003. Since that time, only one additional proteasome inhibitor has been approved to treat cancer. Our lab is particularly interested in the synthesis and identification of novel small molecule proteasome inhibitors. In the past, we have successfully identified the imidazoline scaffold as a potent proteasome inhibitor. Imidazolines are readily prepared from oxazolone scaffolds, which are very versatile building blocks to access a diverse array of small heterocyclic molecules - often with interesting biological activities. From a drug discovery standpoint, development of new reactions from a common scaffold allows for rapid access into a variety of structurally diverse molecules, thus increasing the chances of discovering a new lead molecule. The first part of this dissertation describes the development of the reaction between oxazolones and carbodiimides to access 2-imino-imidazolidin-4-ones, thereby expanding the known chemistry of oxazolones. In the second part of this dissertation, the total synthesis of natural products as potential proteasome inhibitors is described. There are many known natural product proteasome inhibitors, and many synthetic proteasome inhibitors are modified derivatives of natural products. We became particularly interested in the synthesis of members of the pyrrole-2-aminoimidazole marine alkaloids due to the interesting biological activities many display, as well as the structural similarities they share with the imidazolines. The work presented in this dissertation focuses on the total synthesis of the natural products dibromophakellin and dibromophakellstatin. An NBS-mediated oxidative cyclization of guanidine directly onto electron rich olefins was developed and used to gain access to these molecules. Synthetic strategies toward the synthesis of closely related natural products is also discussed in detail. In addition to their syntheses, we have also shown that dibromophakellin, dibromophakellstatin, and various analogs are proteasome inhibitors. In collaboration with Professor Michael Groll, one of the synthesized indole-analogs was crystallized in the proteasome, and its crystal structure was elucidated. It was shown to have a mode of binding unique amongst all known proteasome inbitors, which suggests that the pyrrole-2-aminoimidazoles may be a novel group of proteasome inhibitors. Details of proteasome inhibition and binding of these compounds are presented herein. Implications of this discovery are also discussed.