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

Umashankar Das, Hari N. Pati, Atulya K. Panda, Erik De Clercq, Jan Balzarini, Joseph Molnár, Zoltán Baráth, Imre Ocsovszki, Masami Kawase, Li Zhou, Hiroshi Sakagami, Jonathan R. Dimmock

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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 IC50 values are mainly in the 5-30 μM 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 π-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.

Original languageEnglish
Pages (from-to)3909-3915
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number11
DOIs
Publication statusPublished - jún. 1 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Das, U., Pati, H. N., Panda, A. K., Clercq, E. D., Balzarini, J., Molnár, J., Baráth, Z., Ocsovszki, I., Kawase, M., Zhou, L., Sakagami, H., & Dimmock, J. R. (2009). 2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: A novel cluster of tumor-specific cytotoxins which reverse multidrug resistance. Bioorganic and Medicinal Chemistry, 17(11), 3909-3915. https://doi.org/10.1016/j.bmc.2009.04.021