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

Eur J Med Chem. 2019 Jul 1;173:282-293. doi: 10.1016/j.ejmech.2019.04.022. Epub 2019 Apr 16.

Abstract

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 (IC50 = 9.36 ± 0.08 μM) and LPS-induced NO production in RAW264.7 cells (IC50 = 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.

Keywords: Andrographolide; Anti-inflammatory activity; Beckmann rearrangement; HK2.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cells, Cultured
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hexokinase / antagonists & inhibitors*
  • Hexokinase / metabolism
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mice
  • Molecular Structure
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • RAW 264.7 Cells
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Diterpenes
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Nitric Oxide
  • andrographolide
  • Hexokinase
  • hexokinase 2, mouse