2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: a novel cluster of tumor-specific cytotoxins which reverse multidrug resistance.
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.
Das
Umashankar
U
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5C9. umashankar.das@usask.ca
Pati
Hari N
HN
Panda
Atulya K
AK
De Clercq
Erik
E
Balzarini
Jan
J
Molnár
Joseph
J
Baráth
Zoltán
Z
Ocsovszki
Imre
I
Kawase
Masami
M
Zhou
Li
L
Sakagami
Hiroshi
H
Dimmock
Jonathan R
JR
D000818:Animals; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D010087:Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D010087:Oxides; D011810:Quinoxalines; C052307:2-methylquinoxaline