# Developing Cyclopentadiene as a Reagent in Bioorthogonal Chemistry

> **NIH NIH F32** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $25,257

## Abstract

PROJECT SUMMARY/ABSTRACT
Bioorthogonal reactions are powerful tools capable of altering and visualizing biological processes.
Accordingly, the ability to develop organic reactions into bioorthogonal reactions has the potential to advance
biomedicine. Although a number of organic reactions have been applied in a bioorthogonal manner, most are
limited by the poor synthetic accessibility, aqueous solubility, or chemical stability of reagents, or by slow
reaction rates. A computationally guided rational design approach will be used to improve the utility and
accessibility of cyclopentadiene-based bioorthogonal reactions, ultimately making them a highly efficient tool
for applications in biological systems.
The goal of the proposed research is to develop cyclopentadiene-based bioorthogonal reactions based upon
an in silico screening procedure that evaluates reactivity and stability. First, state-of-the-art computational
methods that provide accurate activation energies will be used to evaluate the reactivity of cyclopentadienes
with known bioorthogonal 2π cycloaddends. Second, the cyclopentadienes calculated to have suitable reaction
kinetics (k > 1 M–1s–1 at room temperature in water) by computational screening will be synthesized and
evaluated experimentally as reactants. Third, the stability of these cyclopentadienes will be assessed under
physiological conditions. Finally, the cyclopentadienes that emerge from the first three aims will be used in an
in cellulo experiment to detect the nascent biosynthesis of DNA within living human cells.
This work will be carried out in the Raines group at MIT. The Raines group has solved problems in chemistry
and biology for three decades and has all of the facilities necessary to carry out the computational, chemical,
and biological aspects of the proposed research.

## Key facts

- **NIH application ID:** 10364693
- **Project number:** 5F32GM137543-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Brian Levandowski
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $25,257
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364693

## Citation

> US National Institutes of Health, RePORTER application 10364693, Developing Cyclopentadiene as a Reagent in Bioorthogonal Chemistry (5F32GM137543-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10364693. Licensed CC0.

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