Structure-activity relationships for mitomycins. Application of the distance and charge analysis method.
Molecular orbital calculations based on coordinates from X-ray analysis have been performed for a set of 24 mitomycins, of which eight compounds have not been isolated so far. To prioritize the order of synthesis of these missing compounds, a new method named DISCA (distance and charge analysis) has been developed. DISCA screens correlations between spatial distribution of charge in molecules and their biological activity. The spatial distribution of charge is represented by several indexes in DISCA. LD50 and ED50 were used as measures of biological activity. DISCA has successfully extracted indexes which have significantly high correlation coefficients. The indexes with the highest correlation coefficient were common to both LD50 and ED50. By use of the correlation functions with high correlation coefficients DISCA has predicted that 9-epi-1a-N-demethylmitomycin D should have the best ED50 and a modest LD50 among the missing mitomycins.
Yoda
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Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company Ltd., Shizuoka, Japan.
Hirayama
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D008937:Mitomycins / Q000737:chemistry* / Q000633:toxicity; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D008937:Mitomycins