Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

Bioorg Med Chem. 2015 May 1;23(9):2010-23. doi: 10.1016/j.bmc.2015.03.017. Epub 2015 Mar 12.

Abstract

An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3- and 13-substituted derivatives 1b-q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure-activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity.

Keywords: ABCG2 modulator; Ardeemin; Multicomponent reaction; Multidrug resistance; Suzuki–Miyaura coupling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Neoplasm Proteins / antagonists & inhibitors*
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Structure-Activity Relationship

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Neoplasm Proteins
  • Pyrimidinones
  • 5-N-acetylardeemin