2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: A novel cluster of tumor-specific cytotoxins which reverse multidrug resistance |
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Authors: | 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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Institution: | 1. Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5C9;2. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium;3. Institute of Medical Microbiology and Immunology, University of Szeged, Szeged, Hungary;4. Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan;5. Meikai Pharmaco-Medical Laboratory (MPL), Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0238, Japan;6. Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0238, Japan |
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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. |
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