Abstract
We describe a new type of barbiturate-based matrix metalloproteinase (MMP) inhibitor incorporating a nitric oxide (NO) donor/mimetic group (series 1). The compounds were designed to inhibit MMP at enzyme level and to attenuate MMP-9 secretion arising from inflammatory signaling. To detect effects related to the nitrate, we prepared and studied an analogous series of barbiturate C5-alkyl alcohols that were unable to release NO (series 2). Both series inhibited recombinant human MMP-2/9 activity with nanomolar potency. Series 1 consistently inhibited the secretion of MMP-9 from TNFα/IL1β stimulated Caco-2 cells at 10 μM, which could be attributed to NO related effects because the non-nitrate panel did not affect enzyme levels. Several compounds from series 1 (10 μM) inhibited tumor cell invasion but none from the non-nitrate panel did. The work shows that MMP-inhibitory barbiturates are suitable scaffolds for hybrid design, targeting additional facets of MMP pathophysiology, with potential to improve risk-benefit ratios.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Barbiturates / chemical synthesis*
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Barbiturates / chemistry
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Barbiturates / pharmacology
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Cell Line
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Cell Movement / drug effects
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Cell Survival / drug effects
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Collagen
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Drug Combinations
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Drug Design
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Humans
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Interleukin-1beta / pharmacology
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Laminin
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinase Inhibitors*
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Models, Molecular
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Molecular Mimicry
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Neoplasm Invasiveness
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Nitric Oxide Donors / chemical synthesis*
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Nitric Oxide Donors / chemistry
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Nitric Oxide Donors / pharmacology
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Proteoglycans
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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Barbiturates
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Drug Combinations
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Interleukin-1beta
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Laminin
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Matrix Metalloproteinase Inhibitors
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Nitric Oxide Donors
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Proteoglycans
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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matrigel
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Collagen
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9