In Vivo Activity and Hydrophobicity of Cytostatic Aziridinyl Quinones

• Published in: Journal of medicinal chemistry 1996-02, Vol.39 (3), p.720-728
• Main Authors: Moret, Ed E, de Boer, Mark, Hilbers, Hans W, Tollenaere, Jan P, Janssen, Lambert H. M, Holthuis, Joost J. M, Driebergen, Reinoud J, Verboom, Willem, Reinhoudt, David N
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzoquinones - chemistry; Benzoquinones - pharmacology; Biological and medical sciences; General aspects; Leukemia L1210 - pathology; Medical sciences; Melanoma, Experimental - pathology; Mice; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9405147

For a series of 3,6-disubstituted bisaziridinylbenzoquinones the in vivo and in vitro activities against murine tumors, as well as the in vivo toxicity, are analyzed. Properties describing biochemical and physicochemical reactions are also incorporated in the analyses. The important 1-octanol/water partition coefficients were determined, using a fast variation of the shake flask method. New π‘-values were calculated for the substituents in this series. These quinone π‘-values deviate strongly from the standard π-values, especially for hydrogen-bonding substituents. To discriminate between the toxic and therapeutic activity of the compounds, principal components and partial least squares analyses were applied. Evidence is presented for selective antitumor action of the investigated compounds. The L1210 clonogenic assay only seems to relate to the general cytotoxicity and has no predictive value for in vivo activity for these compounds. The activity is correlated to the hydrophobicity of the quinones. The toxicity correlates with the ease of reduction, contrary to the hypothesis of bioreductive activation as a mechanism for selectivity.