Abstract
Curcumin has been reported to possess multiple bioactivities, such as antioxidant, anticancer, and anti-inflammatory properties, however the clinical application of curcumin has been significantly limited by its instability and poor metabolism. Modification of curcumin has led to discovery and development of lots of novel therapeutic candidates. In recent years acute and chronic inflammation has been the focus of numerous studies in various diseases. Here, we synthesized a series of asymmetrical curcumin analogs with high in vitro chemical stability, and their anti-inflammatory activity was evaluated in LPS-stimulated macrophages. According to the bio-screening results and QSAR analysis, these analogs exhibited potent activities against LPS-induced TNF-α and IL-6 release. Among the analogs of the potent anti-inflammatory activity, compounds 3b8 and 3b9 exhibited significant protection and possess enhanced anti-inflammatory activity thereby attenuated the LPS-induced septic death in mice.
Highlights
Curcumin is an active ingredient of the perennial herb Curcuma longa
We present a series of asymmetrical curcumin analogs and test their anti-inflammatory activities in mouse RAW 264.7 macrophages. We show that these asymmetrical curcumin analogs are considerably more chemically stable than curcumin in pH 7.4 buffer
Four symmetrical mono-carbonyl analogs of curcumin, 3c5, 3c6, 3d15, and 3d16, were prepared for bioactivity comparison and they are synthesized from symmetrical intermediates with propionyl or isobutyryl chloride in the presence of Et3N at room temperature, respectively
Summary
Curcumin is an active ingredient of the perennial herb Curcuma longa (commonly known as turmeric). As shown in Scheme 1, we found that several series of symmetrical mono-carbonyl analogs of curcumin lacking the β-diketone moiety exhibited enhanced stability, improved pharmacokinetic profiles [16], and enhanced anti-inflammatory activity both in vitro and in vivo [17]. As a continuation of our previous studies, we recently directed our attention to the asymmetrical mono-carbonyl curcumin analogs as novel potential anti-inflammatory candidates (Scheme 1). Different cell types are recruited, including monocytes that locally differentiate into macrophages This leads to the regulated production of various pro-inflammatory mediators, including Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), both of which play critical roles in promoting the inflammatory response and pathological development [21]. The active compound, 3b9, exhibited a beneficial effect in an LPS-induced septic mouse model
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