Boron-containing compounds have recently emerged as useful biologically active substances with unique mechanisms of action. This proposal describes a program in synthetic chemistry geared toward developing boron-nitrogen-containing heterocycles (BN heterocycles) for use in biomedical research. Specifically, we are interested in 1,2-azaborine heterocycles, which are aromatic compounds isosteric with arenes. The broad utility and fundamental importance of arenes combined with the unique elemental and chemical features of boron make 1,2-azaborines attractive targets for biomedical investigations. Potential benefits of research into boron-based drugs include discovery of novel boron-specific mechanisms of biological activity that are unattainable by conventional organic molecules and attenuated development of drug resistance by targeted pathogens. We outline a synthetic program for the preparation of 1,2-azaborine derivatives, a physical organic program that uses a combined synthetic, structural, spectroscopic, and computational approach to address the aromaticity and reactivity of 1,2-azaborines, and a chemical biology program to establish the reactivity and interactions of BN heterocycles in a biological environment. Our proposed studies will enhance the fundamental understanding of the structure, bonding, and aromaticity the 1,2-azaborine heterocycle and illuminate the changes in the properties of classic aromatic organic molecules (e.g., benzene and indole) upon the replacement of a C=C bond with the isostructural inorganic B-N unit. The basic science resulting from the proposed work will bring new impetus to the chemistry of novel aromatics while at the same time promote the design and development of new boron-derived biologically active compounds with improved pharmacological profiles and new mechanistic tools for chemical biology.

Public Health Relevance

This proposal describes a program in synthetic chemistry geared toward developing boron-nitrogen-containing heterocycles (BN heterocycles) for use in biomedical research. Potential benefits of research into boron-based drugs include discovery of novel boron-specific mechanisms of biological activity that are unattainable by conventional organic molecules and attenuated development of drug resistance by targeted pathogens. The proposed basic research will yield new fundamental knowledge and promote the design and development of new boron-derived biologically active compounds with improved pharmacological profiles.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094541-05
Application #
8733176
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$294,377
Indirect Cost
$106,277
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Zhao, Peng; Nettleton, David O; Karki, Rajeshri G et al. (2017) Medicinal Chemistry Profiling of Monocyclic 1,2-Azaborines. ChemMedChem 12:358-361
Lee, Hyelee; Fischer, Marcus; Shoichet, Brian K et al. (2016) Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics. J Am Chem Soc 138:12021-4
Xu, Senmiao; Zhang, Yuanzhe; Li, Bo et al. (2016) Site-Selective and Stereoselective trans-Hydroboration of 1,3-Enynes Catalyzed by 1,4-Azaborine-Based Phosphine-Pd Complex. J Am Chem Soc 138:14566-14569
Edel, Klara; Brough, Sarah A; Lamm, Ashley N et al. (2015) 1,2-Azaborine: The Boron-Nitrogen Derivative of ortho-Benzyne. Angew Chem Int Ed Engl 54:7819-22
Brown, Alec N; Li, Bo; Liu, Shih-Yuan (2015) Negishi Cross-Coupling Is Compatible with a Reactive B-Cl Bond: Development of a Versatile Late-Stage Functionalization of 1,2-Azaborines and Its Application to the Synthesis of New BN Isosteres of Naphthalene and Indenyl. J Am Chem Soc 137:8932-5
Saif, Mari; Widom, Julia R; Xu, Senmiao et al. (2015) Electric Dipole Transition Moments and Solvent-Dependent Interactions of Fluorescent Boron-Nitrogen Substituted Indole Derivatives. J Phys Chem B 119:7985-93
Chrostowska, Anna; Xu, Senmiao; Mazière, Audrey et al. (2014) UV-photoelectron spectroscopy of BN indoles: experimental and computational electronic structure analysis. J Am Chem Soc 136:11813-20
Brown, Alec N; Zakharov, Lev N; Mikulas, Tanya et al. (2014) Rhodium-catalyzed B-H activation of 1,2-azaborines: synthesis and characterization of BN isosteres of stilbenes. Org Lett 16:3340-3
Abbey, Eric R; Lamm, Ashley N; Baggett, Andrew W et al. (2013) Protecting group-free synthesis of 1,2-azaborines: a simple approach to the construction of BN-benzenoids. J Am Chem Soc 135:12908-13
Knack, Daniel H; Marshall, Jonathan L; Harlow, Gregory P et al. (2013) BN/CC isosteric compounds as enzyme inhibitors: N- and B-ethyl-1,2-azaborine inhibit ethylbenzene hydroxylation as nonconvertible substrate analogues. Angew Chem Int Ed Engl 52:2599-601

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