The first synthesis of natural disulfide bruguiesulfurol and biological evaluation of its derivatives as a novel scaffold for PTP1B inhibitors

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5061-5. doi: 10.1016/j.bmcl.2013.07.039. Epub 2013 Jul 25.

Abstract

Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymnorrhiza, was concisely synthesized for the first time in four steps, and a series of its synthetic derivatives were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to have improved pharmacological profile compared with hit 1. Among them, 5a showed the potent selectivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory activity with an IC50 value of 4.54 μM.

Keywords: Bruguiesulfurol; Derivative; PTP1B inhibitor; Selectivity; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Disulfides / chemical synthesis
  • Disulfides / chemistry
  • Disulfides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Structure-Activity Relationship
  • Thiosulfonic Acids / chemical synthesis*
  • Thiosulfonic Acids / chemistry
  • Thiosulfonic Acids / pharmacology*

Substances

  • Biological Products
  • Disulfides
  • Thiosulfonic Acids
  • bruguiesulfurol
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1