Carborane-Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron-Capture Therapy (BNCT) |
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Authors: | Dr. Marlon R. Lutz Jr. Sebastian Flieger Andre Colorina John Wozny Prof. Dr. Narayan S. Hosmane Prof. Dr. Daniel P. Becker |
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Affiliation: | 1. Biosynthetic Technologies, 6320 Intech Way, Indianapolis, IN 46278 USA;2. Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, IL 60660 USA;3. Regis Technologies, Inc., 8210 Austin Ave., Morton Grove, Illinois 60053 USA;4. Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115 USA |
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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. |
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Keywords: | boron neutron capture therapy (BNCT) carborane matrix metalloproteinases (MMPs) |
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