# Design and Application of Modular and Convergent Strategies for the Synthesis of Monoterpenoid Bisindole Alkaloids and their Analogs

> **NIH NIH F31** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $48,974

## Abstract

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.

## Key facts

- **NIH application ID:** 10901726
- **Project number:** 1F31GM154462-01
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Kevin Jaime Gonzalez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901726

## Citation

> US National Institutes of Health, RePORTER application 10901726, Design and Application of Modular and Convergent Strategies for the Synthesis of Monoterpenoid Bisindole Alkaloids and their Analogs (1F31GM154462-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10901726. Licensed CC0.

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