This research proposal involves the understanding and quantitative design of cycloadditions suitable for biomolecule labeling under physiological conditions. We will: 1. perfect computational methods to be used for accurate and routine predictions of rate constants of cycloadditions in aqueous media; 2. complete the computations of rate constants of all possible cycloadditions between cycloaddends that are known to be bioorthogonal cycloaddition reagents with a given cycloaddition partner but have not been explored in reactivities towards other cycloaddends. The resulting matrix of predicted rates for a series of dienes and 1,3-dipoles with a series of alkenes and alkynes will guide the discovery of additional useful bioorthogonal and mutually orthogonal reactions; 3. develop generalized design principles for new reagents and orthogonal reaction pairs; 4. conceive of new cycloaddition components and test them computationally in order to determine promising reactant pairs for bioorthogonal cycloadditions. 5. Compute fluorescence wavelengths and quantum yields for newly designed fluorogenic probes. The results will enhance the monitoring of biological processes and disease states.

Public Health Relevance

This research proposal involves the understanding and quantitative design of cycloadditions suitable for biomolecule labeling under physiological conditions. We will employ a variety of quantum mechanical calculations to understand what controls mutual reactions of components A and B and to assess their reactivities with components of biological systems, such as proteins, nucleic acids, and carbohydrates. We seek to understand reactions used or planned by our experimental collaborators and to predict new useful cycloaddition reactions for experimental application to the monitoring of biological processes and disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM109078-04
Application #
9387446
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2014-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shao, Zhuzhou; Liu, Wei; Tao, Huimin et al. (2018) Bioorthogonal release of sulfonamides and mutually orthogonal liberation of two drugs. Chem Commun (Camb) 54:14089-14092
Levandowski, Brian J; Gamache, Raymond F; Murphy, Jennifer M et al. (2018) Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling. J Am Chem Soc 140:6426-6431
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Levandowski, Brian J; Zou, Lufeng; Houk, K N (2018) Hyperconjugative Aromaticity and Antiaromaticity Control the Reactivities and ?-Facial Stereoselectivities of 5-Substituted Cyclopentadiene Diels-Alder Cycloadditions. J Org Chem :
Levandowski, Brian J; Herath, Dinushka; Gallup, Nathan M et al. (2018) Origin of ?-Facial Stereoselectivity in Thiophene 1-Oxide Cycloadditions. J Org Chem 83:2611-2616
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Ugur, Ilke; Agopcan Cinar, Sesil; Dedeoglu, Burcu et al. (2017) 1,3-Dipolar Cycloaddition Reactions of Low-Valent Rhodium and Iridium Complexes with Arylnitrile N-Oxides. J Org Chem 82:5096-5101
Champagne, Pier Alexandre; Houk, K N (2017) Influence of Endo- and Exocyclic Heteroatoms on Stabilities and 1,3-Dipolar Cycloaddition Reactivities of Mesoionic Azomethine Ylides and Imines. J Org Chem 82:10980-10988
Narayanam, Maruthi Kumar; Ma, Gaoyuan; Champagne, Pier Alexandre et al. (2017) Synthesis of [18 F]Fluoroarenes by Nucleophilic Radiofluorination of N-Arylsydnones. Angew Chem Int Ed Engl 56:13006-13010

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