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

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.
Wang Wang 1,  Yanli Wu 1,  Kaiyin Yang 2,  Canrong Wu 2,  Ruotian Tang 2,  Hua Li 3,  Lixia Chen 4
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: li_hua@hust.edu.cn.
  • 4 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: syzyclx@163.com.
PMID: 31009914 DOI: 10.1016/j.ejmech.2019.04.022
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.

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