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Novel N-oxides as Bioreductive Drugs

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A series of imidazo [1,2-a] quinoxaline mono-N-oxides and their aza- analogues have been synthesized together with analogues substituted in the 8-position. These compounds have been evaluated as bioreductively activated cytotoxins in vitro and in vivo. These compounds had differential cytotoxicities in vitro of up to 20 for 8-amino derivatives such as RB90740 and 65 for 8-aminoalkoxy derivatives such as 1,2-dihydro-8-(1-(demethylamino)ethoxy)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide, but were disappointing in vivo with a maximum growth delay of 10 days compared with 30 days for SR4233 in the RIF-1 tumor model. RB90740 is only effective at killing V79 cells at extremely low levels of oxygen, in contrast to SR4233, and this oxygen dependence can explain the poor and often variable activity of the compound in vivo. 1,2-dihydro-8-(1-(demethylamino)ethoxy)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide, as the most effective drug in vitro, remains the lead structure for any further drug development.
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Keywords: N-oxide; RB90740; bioreductive; cytotoxin; quinoxaline

Document Type: Commentary

Affiliations: Department of Medicinal Chemistry, Division of Experimental Oncology, MRC Radiobiology Unit, Chilton, Oxon, OX11 ORD, UK

Publication date: January 1, 1994

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  • Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
    Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.

    From Volume 23, Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics is Open Access under the terms of the Creative Commons CC BY-NC-ND license.

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