Synthesis And Anti-inflammatory Activity Study Of Caffeic Acid Derivatives

Inflammation is a self-protection action when living body is exposured to various kinds of stimulations outside. Inflammation is beneficial in most cases, but it would cause damage to the tissues by the excessive inflammatory reaction. Its pathological process is complex and time of duration is various, causing serious threat to patients’ health, there is a great significance in developing anti-inflammatory drugs with high efficiency and less side effect.Our group have obtained a caffeic acid derivative (HOEC) with potent anti-inflammatory activity from previous works, and its anti-inflammatory mechanism has been studied.5-Lipoxygenase (5-LOX) was identified as its potential functional target in the arachidonic cascade. However, the druggability of HOEC was restricted due to its poor in vivo pharmacokinetical property. In order to improve the pharmacokinetical property of HOEC, we designed its amide analogue HOECA by modifying the ester group. Pharmacological studies showed that HOECA possessed a potent inhibitory activity on the production of LTB4in the arachidonic acid cascade, and its IC50value is0.78μM, superior to HOEC. HOECA also showed a therapeutic effect on the collagen-induced arthritis in rats, with a dose-dependent relationship between symptom alleviation and dosage. In vivo pharmacokinetical study in rats showed that the oral bioavailability of HOECA was0.8%, higher than the lead compound. In order to find analogues with potent anti-inflammatory activity, We also designed and synthesized a batch of caffeic acid ester derivatives, and four compounds among them possessed potent inhibitory activity against the LPS-induced NO production in RAW264.7macrophages, which can be used in the anti-inflammatory study in the future.