Discovery of Quinic Acid Derivatives as Oral Anti-inflammatory Agents
type: CreativeWork
description: Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-κB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative 3 being the most potent. Compound 3 was named as KZ-41. The NF-kB inhibitory potency (IC50) of our most active analog KZ-41 was determined to be 2.83±1.76 mM. Further examination of the structure and activity relationship (SAR) demonstrated that acetylation of the hydroxyl groups reduced NF-κB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 mM. The dehydroxyl QA amides 18 and 20 were synthesized to retain anti-inflammatory activity while having enhanced resistance to microbial degradation. They showed NF-kB inhibition at concentration 1 mM. The extent of NF-kB inhibition was close to positive control drug dexamethasone. The dehydroxyl QA amide with a double bond 38 was also synthesized. The QA amide esters 24, 25, 29 and 33 were designed and synthesized to retain anti-inflammatory activity with additional antioxidant properties. As expected, compound 25 showed strong anti-oxidant activity. Furthermore, they were hydrolyzed by the microflora, for an example, 25 was hydrolyzed into sinapic acid (SA) and 3. Both S…
abstract: Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-κB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative 3 being the most potent. Compound 3 was named as KZ-41. The NF-kB inhibitory potency (IC50) of our most active analog KZ-41 was determined to be 2.83±1.76 mM. Further examination of the structure and activity relationship (SAR) demonstrated that acetylation of the hydroxyl groups reduced NF-κB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 mM. The dehydroxyl QA amides 18 and 20 were synthesized to retain anti-inflammatory activity while having enhanced resistance to microbial degradation. They showed NF-kB inhibition at concentration 1 mM. The extent of NF-kB inhibition was close to positive control drug dexamethasone. The dehydroxyl QA amide with a double bond 38 was also synthesized. The QA amide esters 24, 25, 29 and 33 were designed and synthesized to retain anti-inflammatory activity with additional antioxidant properties. As expected, compound 25 showed strong anti-oxidant activity. Furthermore, they were hydrolyzed by the microflora, for an example, 25 was hydrolyzed into sinapic acid (SA) and 3. Both S…
author: Zeng, Kui
keywords: anti-inflammation, orally active drug, quinic acid derivatives, Alternative and Complementary Medicine, Chemicals and Drugs, Medicinal and Pharmaceutical Chemistry, Medicine and Health Sciences, Natural Products Chemistry and Pharmacognosy, Pharmaceutical Preparations, Pharmaceutics and Drug Design, Pharmacy and Pharmaceutical Sciences
date published: 2010-05-01T07:00:00Z
date modified: 2026-07-24T05:00:23Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center