Synthesis and Characterization of Fatty Acid Conjugates of Niacin and Salicylic Acid
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.
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The polypharmacological effect produced by simultaneous delivery of the starting chemical entities in a codrug is unique and cannot be replicated by administering multiple drugs in combinations.
“Thus, the polypharmacological effect that can be produced by the simultaneous delivery of the starting chemical entities is unique and cannot be replicated by administering multiple drugs in combinations.84”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [84]
Codrugs can provide a high level of selectivity because the two molecules are rendered essentially inactive by covalent linking.
“This process can provide a high level of selectivity because the two molecules are rendered essentially inactive by the covalent linking.84”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [84]
In codrugs, the two starting chemical entities are combined via a cleavable linker that, after enzymatic biotransformation, allows their release and individual biological effects against multiple pathways in the same target cells and at the same time.
“In fact, in codrugs the two starting chemical entities are combined via a cleavable linker, which, only after enzymatic biotransformation, allows their release and their individual biological effects against multiple pathways, in the same target cells and at the same time.84”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [84]
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- Authors
- Vu, C. B., Bemis, J. E., Benson, E., Bista, P., Carney, D., Fahrner, R., Lee, D., Liu, F., Lonkar, P., Milne, J. C., Nichols, A. J., Picarella, D., Shoelson, A., Smith, J., Ting, A., Wensley, A., Yeager, M., Zimmer, M., & Jirousek, M. R.
- Affiliations
- Catabasis Pharmaceuticals (United States) (US)
- Corresponding author
- Vu, Chi B.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-02-01
- Volume
- 59
- Issue
- 3
- Pages
- 1217-1231
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2257694034
- Cited by
- 27
- References
- 49
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- fatty acid conjugates, nicotinic acid, salicylic acid, omega-3 fatty acids, cholesterol metabolism, PCSK9, HMG-CoA reductase, ATP citrate lyase, NPC1L1, anti-inflammatory activity, NF-κB signaling, covalent conjugation
- MeSH terms
- Administration, Oral, Animals, Anti-Inflammatory Agents, Non-Steroidal, Cell Line, Dogs, Dose-Response Relationship, Drug, Fatty Acids, Humans, Hydrolysis, Liver, Niacin, Structure-Activity Relationship, Tissue Distribution, Molecular Structure, NF-kappa B, Rats, Sprague-Dawley, Salicylic Acid, Mice, Rats, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Hep G2 Cells
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