# Antitumor Antibiotics

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $417,702

## Abstract

Abstract. Studies on the total synthesis of antitumor antibiotics are detailed, including vinblastine, vincristine,
related Vinca alkaloids and their analogs. Fundamental studies on the discovery, investigation, development,
and application of: (1) heterocyclic and acyclic azadiene cycloaddition reactions including the recently explored
1,2,3-triazines and presently unknown 1,2,3,4-tetrazines and 1,2,3,5-tetrazines, (2) the tandem Diels–Alder/1,3-
dipolar cycloaddition cascade reactions of 1,3,4-oxadiazoles, and (2) the thermal cycloadditions of
cyclopropenone ketals including those of reversibly generated -delocalized singlet vinylcarbenes will be
conducted and provide the opportunity for the introduction of new powerful synthetic methodology. We will further
examine (4) Fe(III)–NaBH4 hydrogen atom transfer (HAT) olefin functionalization reactions, (5) single-electron
transfer Fe(III)-promoted indole coupling reactions, (6) a PIFA-promoted aromatic substitution reaction that we
introduced, as well as explore (7) two new BAHA-promoted single-electron oxidative coupling reactions that we
have discovered since the grant was last reviewed. The studies target antitumor compounds that act through
selective protein (e.g., tubulin) or sequence selective DNA binding and provide well-defined challenges for the
design, synthesis, and evaluation of synthetic, mechanism-based analogs in which the structural features
responsible for their target binding affinity, selectivity, and functional reactivity will be identified, addressed,
optimized, and exploited. Efforts will provide synthetic vinblastine analogs that clarify their interaction with their
biological target, help delineate their mechanism of action, and address clinical limitations of the natural product
drug. Studies have provided synthetic vinblastine analogs now available in 3-steps from commercial materials
that are as much as 100-fold more potent than the natural product and/or that directly overcome the basis of
clinical resistance derived from Pgp overexpression and drug efflux (aka MDR). Analogs with improved potency,
selectivity, and/or such improved tumor resistance profiles can be expected to emerge from the studies that
could provide the basis for transformative new oncology drugs, representing compounds that not only could
serve as vinblastine replacements in clinic, but also offer new and effective treatment options in instances of
other multidrug resistant tumors (overexpression of Pgp) refractory to nearly all other front-line drugs.

## Key facts

- **NIH application ID:** 10816532
- **Project number:** 5R01CA042056-40
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DALE L BOGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,702
- **Award type:** 5
- **Project period:** 1986-02-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816532

## Citation

> US National Institutes of Health, RePORTER application 10816532, Antitumor Antibiotics (5R01CA042056-40). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10816532. Licensed CC0.

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