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Structure-activity relationships for benzotriazine di-N-oxides
E M Zeman1, M A Baker, M J Lemmon
1Dept. of Radiation Oncology, Stanford University Medical Center, CA 94305.
Abstract:
SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent that selectively kills and radiosensitizes hypoxic mammalian cells in vitro and murine tumors in vivo. In an attempt to better understand the mechanism of action of the drug, and to determine whether a superior analog may exist, 15 benzotriazine-di-N-oxide analogs of SR 4233 have been evaluated to date for the following properties: hypoxic and aerobic toxicity toward CHO cells in vitro, drug-induced stimulation of oxygen consumption by incubation with respiration-inhibited cells, and acute LD50 evaluated in BALB/c mice. We noted several correlations between these biological properties of the drugs and some of their physicochemical characteristics. Both the hypoxic cytotoxicity and stimulation of oxygen consumption by respiration-inhibited cells were positively correlated with E1/2, the polarographic half-wave reduction potential, and a measure of electron affinity. The air-to-nitrogen differential cytotoxicity reached a maximum (corresponding to SR 4233) and then declined with increasing E1/2. The acute LD50 of each analog in mice decreased with increasing E1/2. One new compound, SR 4482, was found to be more toxic to hypoxic cells in vitro, but less toxic to mice, than SR 4233. It is similar in structure to SR 4233, but lacks any substituent in the 3-position of the triazine ring. This promising drug may represent a member of a new subseries of 1,2,4-benzotriazines with different structure-activity relationships.
Insights
SR 4233, a bioreductive agent, targets hypoxic cells. Researchers evaluated 15 analogs, finding correlations between biological activity and electron affinity. A new analog, SR 4482, shows promise for cancer therapy.
Area of Science:
- Biomedical research
- Pharmacology
- Medicinal chemistry
Background:
- SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent effective against hypoxic mammalian cells and murine tumors.
- Understanding its mechanism and exploring superior analogs is crucial for developing improved cancer therapies.
Purpose of the Study:
- To evaluate 15 benzotriazine-di-N-oxide analogs of SR 4233.
- To correlate physicochemical properties with biological activity (hypoxic/aerobic toxicity, oxygen consumption, in vivo toxicity).
- To identify potential superior analogs for cancer treatment.
Main Methods:
- In vitro assessment of hypoxic and aerobic cytotoxicity in CHO cells.
- Measurement of drug-induced oxygen consumption in respiration-inhibited cells.
- Determination of acute LD50 in BALB/c mice.
- Correlation analysis with polarographic half-wave reduction potential (E1/2).
Main Results:
- Hypoxic cytotoxicity and oxygen consumption stimulation positively correlated with E1/2 (electron affinity).
- Maximum air-to-nitrogen differential cytotoxicity observed at SR 4233's E1/2, decreasing with higher E1/2.
- Acute mouse LD50 decreased as E1/2 increased.
- SR 4482 demonstrated higher in vitro hypoxic cell toxicity and lower mouse toxicity than SR 4233.
Conclusions:
- Physicochemical properties, particularly E1/2, significantly influence the biological activity of benzotriazine-di-N-oxide analogs.
- SR 4482 represents a promising new analog with a potentially improved therapeutic index.
- This study suggests a new subseries of 1,2,4-benzotriazines with distinct structure-activity relationships.