X-ray wavefunction refinement and comprehensive structural studies on bromo-substituted analogues of...

Area of Science:

• Crystallography and Structural Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• 2-deoxy-d-glucose (2-DG) inhibits hexokinase, crucial for cancer cell metabolism and viral replication.
• 2-DG derivatives are investigated as potential anti-cancer and anti-viral drugs.
• Understanding the structural impact of substitutions is key for drug development.

Purpose of the Study:

• To characterize the crystal structures of 2-deoxy-2-bromo-d-glucose (2-BG) and 2-deoxy-2-bromo-d-mannose (2-BM).
• To investigate the influence of bromine substitution on molecular conformation and intermolecular interactions.
• To explore the potential of these derivatives as therapeutic agents.

Main Methods:

• X-ray quantum crystallography with Hirshfeld atom refinement.
• Periodic Density Functional Theory (DFT) calculations.
• Charge-density studies using electrostatic potential, Laplacian, and ELI-D.
• Nuclear Magnetic Resonance (NMR) spectroscopy.

Main Results:

• Bromine substitution at C2 minimally affects pyranose ring conformation but significantly alters crystal structure.
• Bromine atoms participate in hydrogen bonding, forming layered supramolecular structures.
• DFT calculations confirm energetic changes and support structural findings.
• Charge-density analysis validates hydrogen bonding geometry and bromine's involvement.
• Solution NMR shows similar anomeric equilibria and ring puckering to 2-DG.

Conclusions:

• Bromo-substituted 2-DG derivatives exhibit distinct crystal packing influenced by bromine.
• The structural insights support their potential as anti-cancer and anti-viral agents.
• Quantum crystallography and computational methods provide detailed understanding of intermolecular forces.