# STRATEGIES FOR THE SYNTHESIS OF ANTI-TUMOR COMPOUNDS

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 1992 · $293,694

## Abstract

This proposal is directed towards the development of new approaches to
the construction of naturally occurring substances with important
biological activity.  Three areas of research based on vinylogous amide
photochemistry are outlined herein: 1) the extension of the vinylogous
amide photocycloaddition/retro-Mannich fragmentation/ring closure
sequence to the synthesis of perhydroquinoline ring systems; 2) the
application of the photocycloaddition of tertiary vinylogous amides to a
construction of the recently discovered manzamine antitumor alkaloids;
and 3) a study of the scope and limitations of a novel synthesis of
heterocycles based on the photochemistry of vinylogous amides.

Taxol (NSC-125973) is an exceptionally promising cancer chemotherapeutic
agent with an unusually broad spectrum of potent antileukemic and
tumor-inhibiting activity.  It is the only plant product known to promote
the assembly of microtubules and inhibit the tubulin disassembly process
and, thus, appears to be the prototype of a new class of cancer
chemotherapeutic agents.  Two approaches for the construction of the
carbocyclic ring system of the taxane diterpenes are described in this
proposal: 1) the application of the intramolecular dioxenone
photocycloaddition to the synthesis of taxol analogs and the naturally
occurring taxusin; and 2) the development of a highly convergent approach
for the synthesis of the taxane diterpenes based on a Grob-like
fragmentation of an intramolecular ketene-olefin cycloadduct.

The strategies that are outlined herein for the synthesis of biologically
active natural products have counterparts in the Diels-Alder reaction,
cationic polyene cyclization, and arene-olefin cycloaddition reaction.
More than one carbon-carbon bond and considerable stereochemical
information is generated in a single synthetic operation.  The approaches
for the construction of the manzamine alkaloids and the taxane diterpenes
outlined in this proposal attest to the considerable potential of this
methodology for the synthesis of medicinally important substances.

## Key facts

- **NIH application ID:** 3179953
- **Project number:** 2R01CA040250-04A4
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **SAM.gov UEI:** GM1XX56LEP58
- **Principal Investigator:** JEFFREY D WINKLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $293,694
- **Award type:** 2
- **Project period:** 1992-08-01 → 1996-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179953

## Citation

> US National Institutes of Health, RePORTER application 3179953, STRATEGIES FOR THE SYNTHESIS OF ANTI-TUMOR COMPOUNDS (2R01CA040250-04A4). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179953. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*