Synthesis of novel andrographolide beckmann rearrangement derivatives and evaluation of their HK2-related anti-inflammatory activities.

Two series of andrographolide derivatives with introduction of amide moiety into ring A by Beckmann rearrangement were synthesized. In series 1, the ring A was converted to caprolactam, and an amide moiety was linked to C-19 of ring A in series 2. Among them, compound 8h exhibited obvious inhibition on HK2 enzyme activity (IC 50 = 9.36 ± 0.08 μM) and LPS-induced NO production in RAW264.7 cells (IC 50 = 22.38 ± 3.57 μM), and potent binding affinity with HK2 (Kd = 5.12 ± 0.82 μM). The preliminary structure-activity relationships (SARs) suggested that the formation of caprolactam of ring A and esterification of C-19-hydroxyl could improve the inhibitory effects on HK2 enzyme of andrographolide derivatives. Furthermore, compound 8h significantly reduced the levels of IL-1β and IL-6, down-regulated the expressions of iNOS and COX-2. Its anti-inflammatory effect was related to the inhibition of both NF-κB pathway and glycolysis enzyme HK2. Since HK2 could be a novel and effective target for anti-inflammation, compound 8h might be a new anti-inflammatory agent targeting at HK2, or serve as a lead compound to design and synthesize more HK2 inhibitors with better inflammatory effects. Image 1 • Two series of andrographolide derivatives with introduction of amide moiety into ring A were synthesized. • Compound 8h exhibited obvious inhibition of HK2 enzyme activity. • Compound 8h also could reduce LPS-induced NO, IL-1β and IL-6 production in RAW264.7 cells. • The anti-inflammatory action mechanism of 8h was related to the inhibition of both NF-κB signal pathway and HK2. [ABSTRACT FROM AUTHOR]