Synthesis and biological evaluation of quinic acid derivatives as anti-inflammatory agents

Bioorg Med Chem Lett. 2009 Sep 15;19(18):5458-60. doi: 10.1016/j.bmcl.2009.07.096. Epub 2009 Jul 23.


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-kappaB). Herein, we describe the synthesis and biological testing of novel QA derivatives. Inhibition of NF-kappaB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-kappaB response element. A549-NF-kappaB cells were stimulated with TNF-alpha (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-kappaB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative being the most potent. Further examination of the SAR demonstrated that acetylation of the hydroxyl groups reduced NF-kappaB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 microM. In conclusion, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-kappaB, despite their lack of anti-oxidant activity. Mechanistic studies and pre-clinical efficacy studies in various inflammatory animal models are on-going.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Line
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Humans
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism*
  • Pulmonary Alveoli / cytology
  • Quinic Acid / chemical synthesis
  • Quinic Acid / chemistry*
  • Quinic Acid / pharmacology*
  • Uncaria / chemistry


  • Anti-Inflammatory Agents
  • NF-kappa B
  • Quinic Acid
  • Alkaline Phosphatase