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  3. Design, synthesis and structural-activity relationship studies of phanginin A derivatives for regulating SIK1-cAMP/CREB signaling to suppress hepatic gluconeogenesis

Design, synthesis and structural-activity relationship studies of phanginin A derivatives for regulating SIK1-cAMP/CREB signaling to suppress hepatic gluconeogenesis

  • Eur J Med Chem. 2022 Mar 15;232:114171. doi: 10.1016/j.ejmech.2022.114171.
Xing-De Wu 1,  Suling Huang 2,  Yu Shi 3,  Yu Shen 2,  Wen-Chao Tu 4,  Ying Leng 5,  Qin-Shi Zhao 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650500, Yunnan, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: [email protected].
PMID: 35152093 DOI: 10.1016/j.ejmech.2022.114171
Abstract

Persistent activation of hepatic gluconeogenesis is a main cause of fasting hyperglycemia in patients with type 2 diabetes (T2D), and the salt-induced kinase 1 (SIK1) acts as a key modulator in regulating hepatic gluconeogenesis. Recently, we first reported phanginin A (PA, 1), a natural cassane diterpenoid isolated from the seeds of Caesalpinia sappan, exhibited potent anti-diabetic effect through activation of SIK1 and increasing PDE4 activity to inhibit hepatic gluconeogenesis pathway by suppressing the cAMP/PKA/CREB pathway in the liver. In present study, we designed and prepared 25 PA derivatives and their structure-activity relationship (SAR) for gluconeogenesis inhibitory activity were established. Among them, compound 7 exhibited remarkable inhibitory activity on hepatic gluconeogenesis by enhancing the SIK1 phosphorylation and ameliorated the hyperglyceamia of type 2 diabetic mice. Our results supported that compound 7 could be served as a potential candidate for the treatment of T2D.

Keywords

Hepatic gluconeogenesis; Phanginin A derivatives; SIK1; Structural-activity relationship; Type 2 diabetes.

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