Studies on the Anti-tumor Activity of Isoquinoline Derivatives. : III. On the Relationship between Toxicity and Chemical Constitution of Isoquinoline Derivatives

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Abstract
Isoquinoline derivatives were classified into five types according to the substituents at 1-position and the relationship between chemical structures and toxicities was investigated. LD50 tended to become lower with increasing degrees of hydrogenation of the isoquinoline ring. In 1-alkyl substituted isoquinoline derivatives LD50 became higher as the number of carbon branches of the 1-alkyl residue increased. Pathological changes were caused by almost all 1-alkyl substituted compounds, especially the ones possessing a tertiary alkyl residue at 1-position. In the cases of 1-aryl and 1-aralkyl substituted compounds, the swelling of liver depended on the simultaneous presence of the methylenedioxy residues at 3', 4'-position of the terminal phenyl residue of the 1-substituent and at 6, 7-position of the isoquinoline ring. However, no pathological change was observed with 1-(2-methylbutyl)-3-methyl-6, 7-methylenedioxyisoquinoline·HCl (B-15) and 1-neopentyl-3-methyl-6, 7-methylenedioxyisoquinoline·HCl (B-33). These compounds showed marked inhibitory action on the experimental tumors as described in a previous paper. From the above observation, it was suggested that the compounds possessing a methylene residue between 1-carbon of the isoquinoline ring and a secondary-or tertiary-alkyl residue in the 1-alkyl substituent would have an anti-tumor activity and little side effect.

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