# Chemical Synthesis and Biology of Complex Alkaloids

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $541,163

## Abstract

PROJECT SUMMARY
 From Vinblastine to Morphine, alkaloid natural products have contributed enormously to the treatment of
human health and their impact has touched nearly every area of disease biology. Despite past successes, the
number of new FDA-approved medicines derived from, or inspired by, complex alkaloids are waning. The
multifarious and not-easily-manipulated chemical structures of intricate alkaloids, combined with complex, and
often unknown, cellular target profiles has contributed to the abandonment of many natural product-based drug
discovery programs. High-throughput screening approaches now dominate the hit-to-lead process. Yet there is
growing concern over the lack of diverse three-dimensional complexity in many screening libraries, and natural
products, and their derivatives, are recognized as filling an important area in bioactive compound space. This
proposal seeks to address such limitation through both advances in synthetic chemistry pathways as well as
cutting-edge chemoproteomics platforms to map the protein targets of a variety of judiciously chosen alkaloid
natural products. The targets selected for this program represent both state of the art challenges for efficient
complex molecule synthesis as well as scaffolds ideal for further medicinal chemistry discovery. Despite their
small size, and potential to treat a variety of diseases, members of the altemicidin alkaloids require roughly thirty
steps to prepare. The need to prepare new antibiotics is critical and many successful antibiotic classes
have been derived from natural products, often ones with one or more nitrogen atom. The curvulamine
alkaloids represent a promising new antibiotic class with reported activity against both gram negative
and positive pathogens and possess a completely novel chemical structure. Finally, covalently acting alkaloids
derived from tyrosine show potent anti-cancer effects yet their biological targets are unknown. Overall this
work will utilize innovative synthetic chemistry approaches to synthesize complex alkaloid natural products
and their derivatives in an efficient manner and with unprecedented structural diversity for further biological
evaluation. Using cutting-edge chemoproteomics platforms, we will determine the cellular targets responsible
for a given phenotype. In the process of carrying out this work, students and post-docs will be provided with
rigorous and intellectually stimulating training in synthetic chemistry and chemical biology and will be
well prepared for careers in biomedical research and drug discovery.

## Key facts

- **NIH application ID:** 10130574
- **Project number:** 5R01GM136945-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Thomas John Maimone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $541,163
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130574

## Citation

> US National Institutes of Health, RePORTER application 10130574, Chemical Synthesis and Biology of Complex Alkaloids (5R01GM136945-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130574. Licensed CC0.

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