Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies

Bioorg Med Chem Lett. 2012 May 1;22(9):3256-60. doi: 10.1016/j.bmcl.2012.03.030. Epub 2012 Mar 13.

Abstract

A new scaffold N-(9-(ortho/meta/para-(benzyloxy)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl) isonicotinamide (H1-3) was discovered as a hSIRT1 inhibitor through virtual screening of in-house database. Based on these hits, a library of compounds were designed, synthesized and tested for in vitro hSIRT1 activity. The most potent compound 4d in the series showed a significant inhibition of SIRT1 activity. Further antitumor studies of compound 4d, showed a dose dependent increase in acetylation of p53K382 and decrease in SIRT1 with an IC(50) of 0.25 μM in MDA-MB231 breast cancer cell lines. Individual 3D-QSAR analysis using Schrödinger showed distribution of hydrophobic and non polar positive co-efficient at ortho position essential for bioactivity based on 4d.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acridines / chemistry*
  • Acridines / pharmacology
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Growth Inhibitors / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Quantitative Structure-Activity Relationship*
  • Sirtuin 1 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Acridines
  • Growth Inhibitors
  • SIRT1 protein, human
  • Sirtuin 1