UC Berkeley

Chapter 1. The development of inhibitors of cruzain, the major cysteine protease of the Trypanosoma cruzi parasite that causes Chagas disease, has been demonstrated to be a promising drug discovery avenue for the treatment of this neglected disease. The development of a new class of potent nonpeptidic inhibitors of cruzain is described. Application of the substrate activity screening method to cruzain resulted in the identification of a nonpeptidic substrate. Guided by a molecular replacement model, substrate cleavage efficiency was further improved by introducing additional binding interactions. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. This led to the development of a new class of nonpeptidic 2,3,5,6-tetrafluorophenoxymethyl ketone inhibitors that exhibit potent inhibitory activity against cruzain. It was also established that this class of compounds completely eradicates the T. cruzi parasite from mammalian cell culture and substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.

Chapter 2. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of the novel nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor class identified in Chapter 1. Subsequent structure-guided optimization then resulted in inhibitor analogs with improvements in potency despite minimal or no additions in molecular weight. Evaluation of these second-generation tetrafluorophenoxymethyl ketone cruzain inhibitors in cell culture is also described.

Chapter 3. The rhodium(I)-catalyzed addition of alkenylboron reagents to imines is described. The diastereoselective addition of alkenyl trifluoroborates and MIDA boronates to both aromatic and aliphatic N-tert-butanesulfinyl aldimines provides α-branched allylic amines in good yields and with very high selectivity. The chemistry is demonstrated to be compatible with a variety of electronically and sterically diverse N-sulfinyl imines and alkenyl boron reagents. This new methodology enables the general and efficient asymmetric synthesis of the important class of α-branched allylic amines from readily available and stable starting materials. Also included is a preliminary investigation into the enantioselective addition of alkenylboron reagents to activated imines.

Chapter 4. A one-pot preparation of N-tert-butanesulfinylamine diastereomer mixtures that proceeds in excellent yields for a diverse set of N-sulfinyl imine addition products is described. The method is operationally simple, and extractive isolation provides analytically pure mixtures of diastereomers as standards for stereoselectivity determinations. This method enabled the rapid and accurate determination of diastereomeric purity of the N-sulfinylamines prepared in Chapters 3 and 5.

Chapter 5. The concise total synthesis of (–)-aurantioclavine has been achieved by taking advantage of strategies for the asymmetric alkenylation of N-tert-butanesulfinyl imines. The enantiomerically pure natural product was prepared both by using the Rh-catalyzed addition of a MIDA boronate developed in Chapter 3 and by employing a Grignard reagent addition sequence. Exploration of (–)-aurantioclavine's role as an intermediate en route to the complex polyclic alkaloids of the communesin family is also described.