Bis(haloalkyl)piperidine類の化学的反応性と抗腫瘍活性

抄録

Bis (haloalkyl) piperidine (CAP) derivatives were studied with respect to the relationship among their mode of hydrolysis in a bicarbonate buffered solution, their reactivity with Na₂S₂O₃ or 4-(p-nitrobenzyl) pyridine, and their antitumor activity on Ehrlich ascites carcinoma and rat ascites hepatoma AH-13. It was deduced that CAP derivatives rapidly formed intramolucular cyclic intermediates, an ethylene imine from the secondary amines and an ethylene imonium ion from the tertiary amines, in the process of hydrolysis. Moreover, the reactivity of these compounds was in the order of 1-methyl-2, 6-bis (halomethyl) piperidines>1-(β-haloethyl)-2-halomethylpiperidines>1-(γ-halopropyl)-2-halomethylpiperidines>2, 6-bis (halomethyl) piperidines, but there was no parallelism between the chemical reactivity and the antitumor activity. However, a significant correlation was observed between the cytotoxicity of the tertiary amine type CAP derivatives proceeded by a similar mechanism of reaction, EC₅₀ against Ehrlich ascites carcinoma cells or IC₅₀ against AH-13 cells, and the ratio of the rate constant of halogen ion release, k₁', to the rate constant of disapperance of alkylating active compounds, -k", from these amines, -k₁'/k", which seemed to be a durability of alkylating activity. On the other hand, 1-(γ-halopropyl)-2-halomethylpiperidines which showed a monofunctional chemical reaction only provided with a high therapeutic index, LD₅₀/ED₅₀, on AH-13 bearing rats, which was equal to those of cyclophosphamide and nitrogen mustard N-oxide.