2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: a novel cluster of tumor-specific cytotoxins which reverse multidrug resistance

Bioorg Med Chem. 2009 Jun 1;17(11):3909-15. doi: 10.1016/j.bmc.2009.04.021. Epub 2009 Apr 17.

Abstract

A series of 2-(3-aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides 3a-l were prepared by condensation of various aryl aldehydes with 2-acetyl-3-methylquinoxaline-1,4-dioxide 2. These compounds inhibit the growth of human Molt 4/C8 and CEM T-lymphocytes and the IC(50) values are mainly in the 5-30 microM range. The quinoxaline 1,4-dioxide 3j inhibited the growth of 58 human tumor cell lines, particularly leukemic and breast cancer neoplasms. All of the compounds 3a-l reversed the multidrug resistance (MDR) properties of murine L-5178Y leukemic cells which were transfected with the human MDR1 gene. The MDR-reversing effect may be due to the conjugated pi-electron system forming a weak electron charge transfer complex with the P-glycoprotein-mediated efflux pump. The compounds in series 2 and 3 were assessed against HL-60, HSC-2, HSC-3 and HSC-4 malignant cells as well as HGF, HPC and HPLF normal cell lines which revealed that the majority of the compounds displayed a greater toxicity to neoplastic than normal cells. Various ways in which the project may be expanded are presented.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Multiple / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy
  • Oxides / chemical synthesis
  • Oxides / chemistry*
  • Oxides / pharmacology*
  • Quantitative Structure-Activity Relationship
  • Quinoxalines / chemical synthesis
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacology*

Substances

  • Oxides
  • Quinoxalines
  • 2-methylquinoxaline

Grants and funding