Synthetic studies towards penicisulfuranol B; C-H activation borylation of staurosporine; design, synthesis, and evaluation of rapamycin and everolimus analogs; design, synthesis, and evaluation of gemfibrozil analogs.

Abstract

Penicisulfuranol B and several penicisulfuranol congeners were first isolated in 2017 by Li and coworkers from the Penicillium janthinellum strain HDN13-309 found on the root of the crabapple mangrove Sonneratia caseolaris. The penicisulfuranols belong to a family of epipolythiodiketopiperazine (ETP) fungal toxins. Penicisulfuranol B shows moderate activity against HeLa and HL-60 cell lines with IC50 of 3.9 μM and 1.6 μM respectively. These interesting biological properties coupled with a number of synthetically challenging structural features led us to pursue the development of various strategies towards a total synthesis of Penicisulfuranol B. These strategies focused primarily on the initial preparation of a diketopiperazine (DKP) core that was suited for further functionalization. Staurosporine was first isolated in 1977 by Ōmura and coworkers from a streptomyces strain and has shown potent but nonspecific kinase inhibition. The latter derives from staurosporine’s ability to bind at the ATP binding sites of numerous kinases. In efforts to develop cancer therapeutics based on kinase inhibition, thousands of indolocarbazole based molecules have been prepared and studied. Out of this research numerous semi-synthetic strategies for functionalizing Staurosporine and other indolocarbazoles have been developed and one Staurosporine based drug, Midostaurin, has been approved by the FDA for acute myeloid leukemia. Interestingly, despite a vast effort in preparing analogs of indoloarbazole natural products, functionalization of the aromatic ring has been limited to electrophilic aromatic substitution (EAS) chemistry which provides regiochemical outcomes based on the electronics on the indolocarbazole. Recent advances in C-H activation chemistry and in particular the borylation have revealed that this chemistry is not governed by electronics and thus overcomes the regiochemical limitations of EAS chemistry. With regard to Staursporine this chemistry opened the door to the preparation of completely novel analogs by simple functionalization of the natural roduct. To this end, described herein are the preparation of 13 new Staurosporine analogs which possess functionality at the indolocarbozole core that is regiochemically orthogonal to known analogs. Rapamycin was first isolated from Streptomyces hydroscopicus by Vézina and coworkers and initially investigated for its antifungal activity, however this was abandoned after discovery of its potent immunosuppression capabilities through inhibiting the mammalian target of rapamycin (mTOR). Rapamycin’s immunosuppression ultimately arrests the cell cycle in the G1 phase causing an accumulation of lymphocytes and prevents proliferation of T cells through disruption of lymphokines. Many analogs of rapamycin (rapalogs) functionalized at the 40C position and rapamycin, itself, have been approved by the FDA as immunosuppressants, with rapamycin being used to prevent rejection of transplants. However, rapamycin is a difficult drug to deliver with low aqueous solubility, low bioavailability, high liver metabolism, and wide organ distribution due to lipophilicity. Within this work is the design, synthesis, and evaluation of a disulfide based cleavable linker and a fluorescent probe. Gemfibrozil is an FDA approved fibrate drug for the treatment of hyperlipidemia and hypercholesterinemia. Recently it has been discovered that gemfibrozil is an activator of soluble guanyl cyclase (sGC) which plays a crucial role in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Downstream effects of this pathway induce vasodilation which is important for the treatment of cardiac diseases. Within this work is described the design, synthesis, and evaluation of analogs of gemfibrozil for their sGC activity and vasodilatory effects.