Abstract
This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
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Anti-Inflammatory Agents, Non-Steroidal / chemistry*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cell Line
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Dogs
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Dose-Response Relationship, Drug
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Fatty Acids / chemistry*
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Hep G2 Cells
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Humans
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Hydrolysis
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Liver / drug effects
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Liver / metabolism
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Mice
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Molecular Structure
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Niacin / administration & dosage
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Niacin / chemistry*
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Niacin / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Salicylic Acid / administration & dosage
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Salicylic Acid / chemistry*
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Salicylic Acid / pharmacology*
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Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Sterol Regulatory Element Binding Protein 2 / antagonists & inhibitors
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Sterol Regulatory Element Binding Protein 2 / metabolism
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Fatty Acids
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NF-kappa B
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SREBF1 protein, human
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SREBF2 protein, human
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Niacin
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Salicylic Acid