Design and Application of Modular and Convergent Strategies for the Synthesis of Monoterpenoid Bisindole Alkaloids and their Analogs - Project Summary: Monoterpenoid bisindole alkaloids are a broad class of natural products that includes members which have been demonstrated to disrupt protein–protein interactions in human cancer cells. These dimeric compounds consist of two independently biosynthesized monoterpenoid indole alkaloids unified by a C–C bond. Bisindole alkaloids display an assortment of biological activities, such as nitrous oxide synthase inhibition and multidrug resistance reversal, and includes the FDA-approved anticancer drugs vinblastine and vincristine. Despite their potential to serve as pharmaceuticals or lead compounds, there have been relatively few total syntheses of any members of this class; this is due to the challenges encountered with synthesizing the two complex and structurally unique monomers followed by unifying them into a sterically congested product. Furthermore, most approaches to date have relied on biomimetic strategies, which are not amenable to synthesizing analogs to explore the structure- activity relationship of these molecules. The studies described in this proposal seek to develop modular and convergent strategies for the enantioselective syntheses of bisindole dimers and non-natural analogs. The rationale for the proposed research is that efficient access to bisindole alkaloids will increase their accessibility and allow for in-depth biological evaluation. Furthermore, a modular approach can be adapted for the synthesis of analogs to enable structure activity relationship studies into this potent class of molecules. This will be realized through two specific aims centered on the synthesis and evaluation of these complex, biologically relevant molecules. In Aim 1, a robust enantioselective total synthesis of melodinine J, a never-before-synthesized bisindole dimer which has demonstrated cytotoxicity levels similar to the chemotherapeutic vinorelbine, will be developed. The route will feature a Pd-catalyzed asymmetric alkylation and target highly oxidized indole alkaloids, derivatives of which have been implicated to bind to tubulin. The synthesis will expand the scope of the Petasis reaction as a robust means to unite the two monomers in a late-stage, convergent manner. Aim 2 will involve the generation of a library of non-natural bisindole alkaloids to enable biological assays and structure- activity relationship studies. Strategies will be developed for the modular, assembly-line synthesis of analogs that can vary the nature of the linker with fine-tuned precision. This work would positively affect human health by deepening our molecular-level understanding of the roles these potent compounds and their linkers play in mediating biological processes.
