Design, synthesis and bioevaluation of novel maleamic amino acid ester conjugates of 3,5-bisarylmethylene-4-piperidones as cytostatic agents

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6364-7. doi: 10.1016/j.bmcl.2009.09.069. Epub 2009 Sep 22.

Abstract

A novel series of maleamic amino acid ester conjugates of 3,5-bisarylmethylene-4-piperidones were prepared to investigate the efficacy of micronutrient conjugation in enhancing cytotoxic potency by improving selectivity and delivery. These compounds, prepared as anticancer agents, were expected to demonstrate enhanced selectivity towards malignant cells through the inhibition of topoisomerase IIalpha via protein thiolation. The cytostatic effects of these compounds were evaluated against three cell lines, namely murine L1210 leukemia cells, human Molt 4/C8 and CEM T-lymphocyte cells. All compounds were found to have greater potency than the reference drug melphalan. Several compounds were found to potently inhibit topoisomerase IIalpha and displayed cytostatic activity in the nanomolar range.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Crystallography, X-Ray
  • Cytostatic Agents / pharmacology*
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Esters / therapeutic use
  • HeLa Cells
  • Humans
  • Leukemia L1210
  • Mice
  • Piperidones / chemical synthesis*
  • Stereoisomerism
  • Substrate Specificity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Cytostatic Agents
  • Esters
  • Piperidones