# Synthesis of Antimitotic Paxilline Indole Diterpenes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $339,754

## Abstract

PROJECT SUMMARY
 Paxilline indole diterpenes (IDTs) are natural products that exhibit a variety of promising biological activities,
but lack of efficient access to the derivatives and analogs of IDTs hinders investigation of their biomedical
potential. The long-term goal is to develop new chemical methods and approaches that allow short, general
and scalable assembly of natural products with promising biological activities. The objective of this proposal is
to develop new chemical methods and approaches for efficient synthesis of IDTs and their otherwise
inaccessible analogs and to determine the molecular mechanism of action and a pharmacophore model for
inhibition of Eg5. The central hypothesis is that a controlled polycyclization will allow an efficient assembly of
the common pentacyclic core of IDTs and will provide a general entry to a broad range of congeners. This
hypothesis has been formulated on the basis of the extensive preliminary data produced in the applicant's
laboratory. These data demonstrate that a new radical-polar crossover cascade en route to the terpenoid core
provides the shortest entry to date into the IDT family. The rationale for the proposed research is that new
chemical methods and approaches are necessary to achieve efficient synthesis of IDTs and to develop new
and potent inhibitors of Eg5, which can be used as biochemical tools and potential antimitotic leads.
 The hypothesis will be tested by pursuing three specific aims: 1) development of an intermolecular
alkenylation of ketones; 2) development of a general approach to IDTs; and 3) synthesis of antimitotic IDTs
and development of potent inhibitors of Eg5. Under the first aim, a new process for intermolecular alkenylation
of ketones will be developed. This unique transformation is expected to allow efficient assembly of quaternary
centers and to provide a direct access to polycyclization precursors en route to IDTs. The preliminary data
produced in the applicant's laboratory demonstrate a proof-of-principle for this approach. Under the second
aim, a general and efficient approach to IDTs will be developed. A radical-polar crossover polycyclization is
projected to allow short and efficient assembly of the terpenoid core of IDTs. The preliminary findings from the
applicant's laboratory indicate that the key vicinal quaternary stereocenters are set in a direct and
stereoselective manner using this approach. Under the third aim, a diverse set of antimitotic IDTs and their
analogs will be synthesized and used for elucidation of structure activity relationships (SARs). These SAR data
will be used to develop chemical probes for determination of the molecular mechanism of action and to
establish a pharmacophore model for Eg5 inhibition by IDTs.
 The proposed research is significant because it will make IDTs readily available for widespread biological
studies and will allow the evaluation of these terpenoids as new leads in the treatment of cancer. The approach
is innovativ...

## Key facts

- **NIH application ID:** 9828096
- **Project number:** 5R01GM121678-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Sergey Pronin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,754
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828096

## Citation

> US National Institutes of Health, RePORTER application 9828096, Synthesis of Antimitotic Paxilline Indole Diterpenes (5R01GM121678-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828096. Licensed CC0.

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