Carborane-Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron-Capture Therapy (BNCT).

Abstract

Based on the previously reported potent and selective sulfone hydroxamate inhibitors SC-76276, SC-78080 (SD-2590), and SC-77964, potent MMP inhibitors have been designed and synthesized to append a boron-rich carborane cluster by employing click chemistry to target tumor cells that are known to upregulate gelatinases. Docking against MMP-2 suggests binding involving the hydroxamate zinc-binding group, key H-bonds by the sulfone moiety with the peptide backbone residues Leu82 and Leu83, and a hydrophobic interaction with the deep P1' pocket. The more potent of the two triazole regioisomers exhibits an IC50 of 3.7 nM versus MMP-2 and IC50 of 46 nM versus MMP-9.

• Authors: Marlon R Lutz Jr, Sebastian Flieger, Andre Colorina, John Wozny, Narayan S Hosmane, Daniel P Becker
• Journal: ChemMedChem (ChemMedChem) Vol. 15 Issue 20 Pg. 1897-1908 (10 19 2020) ISSN: 1860-7187 [Electronic] Germany
• PMID: 32720425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley-VCH GmbH.

Chemical References

• 1-cyclopropyl-N-hydroxy-4-(4-(4-(trifluoromethoxy)phenoxy)phenylsulfonyl)piperidine-4-carboxamide
• Boron Compounds
• Hydroxamic Acids
• Ligands
• Matrix Metalloproteinase Inhibitors
• N-hydroxy-1-(2-methoxyethyl)-4-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)piperidine-4-carboxamide
• Sulfones
• MMP2 protein, human
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Zinc

Topics

• Boron Compounds (chemical synthesis, chemistry, metabolism)
• Click Chemistry
• Enzyme Assays
• Humans
• Hydroxamic Acids (chemical synthesis, chemistry, metabolism)
• Ligands
• Matrix Metalloproteinase 2 (chemistry, metabolism)
• Matrix Metalloproteinase 9 (chemistry)
• Matrix Metalloproteinase Inhibitors (chemical synthesis, chemistry, metabolism)
• Molecular Docking Simulation
• Sulfones (chemical synthesis, chemistry, metabolism)
• Zinc (chemistry)