Cytotoxic 3,5-bis(benzylidene)piperidin-4-ones and N-acyl analogs displaying selective toxicity for malignant cells

Eur J Med Chem. 2008 Jan;43(1):1-7. doi: 10.1016/j.ejmech.2007.03.010. Epub 2007 Apr 3.

Abstract

A series of 3,5-bis(benzylidene)piperidin-4-ones 1, 1-acryloyl-3,5-bis(benzylidene)piperidin-4-ones 2 and adducts of 2 with sodium 2-mercaptoethanesulfonate (mesna), namely series 3, were prepared as candidate cytotoxic agents. These compounds were examined against neoplastic HSC-2, HSC-4 and HL-60 cells as well as HGF, HPC and HPLF normal cell lines and many of the compounds displayed selective toxicity for malignant cells. The CC50 values of the analogs in series 2 towards the cancer cell lines were mainly submicromolar. The relative potencies, selectivity and logP values were in the order of 2>1>3. The sulfonic acid group of a representative compound in series 3 was replaced by a thiol function to produce 4 leading to substantial increases in cytotoxic potencies and hydrophobicity indicating that the presence of a hydrophilic sulfonic acid group was disadvantageous in terms of potency. Molecular modeling suggested that the superior cytotoxicity of various members of series 1-3 over an acyclic analog 5 may have been due to the greater torsion angles theta1 and theta2 created between the arylidene aryl rings and the adjacent olefinic groups in series 1-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzylidene Compounds / chemistry*
  • Benzylidene Compounds / toxicity*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytotoxins / chemistry*
  • Cytotoxins / toxicity*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Biological
  • Neoplasms / pathology*
  • Piperidones / chemistry*
  • Piperidones / toxicity*
  • Sensitivity and Specificity

Substances

  • Benzylidene Compounds
  • Cytotoxins
  • Piperidones