The generation of chemical space beyond that can be achieved by Nature is one of the main goals of synthetic chemistry and an important tenet in drug discovery research. The BN/CC isosterism (i.e., replacement of a carbon-carbon bond with a boron-nitrogen bond) has emerged as a viable strategy to increase the chemical space of compounds relevant to biomedical research. This proposal describes a medicinal chemistry program geared toward developing BN isosteres of a ubiquitous structural motif in pharmaceutical research, i.e., arenes. Potential benefits of research into these BN heterocycles (also known as azaborines) include discovery of novel azaborine-specific mechanisms of biological activity that are unattainable by conventional organic molecules and improved pharmacological profiles. While good progress has been made in the preparation of azaborines, their interactions with biomacromolecules remains virtually unexplored. Thus, this proposed research is focused on establishing 1,2-azaborine's proposed distinctive features (better aqueous solubility and NH hydrogen bonding) in a biological context. Specifically, we seek to: 1) establish the therapeutic potential of azaborines in collaboration with Novartis by directly comparing the pharmacological profiles and biological activity of known biologically active compounds (e.g., CDK-2, PPAR- ? inhibitors) to their corresponding BN isosteres. 2) develop a fundamental understanding of the hydrogen bonding interaction between the NH group of 1,2- azaborines and a protein by employing mutant T4 lysozyme as a well-defined and tunable protein model from which quantitative structural and energetic parameters can be extracted. 3) investigate how proteins accommodate incremental changes in ligand structure in discrete conformational states using a congeneric series of 1,2-azaborine ligands, taking advantage of azaborine's improved aqueous solubility. Completion of the proposed aims will yield new fundamental knowledge related to BN/CC isosterism in the context of biomedical research and at the same time promote the design and development of a new pharmacophore from which future drug candidates can be built upon.

Public Health Relevance

The expansion of structural diversity beyond what Nature can achieve is one of the main goals of synthetic chemistry and an important tenet in drug discovery efforts. This proposed work seeks to establish unnatural boron-nitrogen-containing heterocycles as a new motif for use in medicinal chemistry. New biologically active compounds with improved pharmacological profiles and new tools for biomedical research will be developed as part of this work.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094541-08
Application #
9392178
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-09-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
Edel, Klara; Yang, Xinyu; Ishibashi, Jacob S A et al. (2018) The Dewar Isomer of 1,2-Dihydro-1,2-azaborinines: Isolation, Fragmentation, and Energy Storage. Angew Chem Int Ed Engl 57:5296-5300
Giustra, Zachary X; Liu, Shih-Yuan (2018) The State of the Art in Azaborine Chemistry: New Synthetic Methods and Applications. J Am Chem Soc 140:1184-1194
Baggett, Andrew W; Liu, Shih-Yuan (2017) A Boron Protecting Group Strategy for 1,2-Azaborines. J Am Chem Soc 139:15259-15264
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; Liu, Shih-Yuan (2017) Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants. J Vis Exp :
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
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
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
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
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

Showing the most recent 10 out of 27 publications