Synthesis and Antitumor Properties of N^1-Acyloxymethyl Derivatives of Bis(2,6-dioxopiperazines)

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Many N^1-acyloxymethyl derivatives VI of bis(2,6-dioxopiperazine) I, ICRF-154,were prepared and tested for antitumor activity. The treatment of I with formaldehyde gave a crystalline bis(N^1-hydroxymethyl) derivative VII, which was acylated under various conditions to give bis(N^1-acyloxymethyl) derivatives VI. Antitumor activity of VI against P388 leukemia in mice was studied.Several bis(N^1-acyloxymethyl)compounds such as phenylacetyloxymethyl VI-6,methoxycarbonyloxymethyl VI-41,isobutoxycarbonyloxymethyl VI-44,and furancarboxymethyl VI-38 compounds were found to have potent antitumor activities. On the other hand, water-soluble esters having an amine or a carboxylic acid function in their acyl groups showed rather reduced activity.These bis(N-^1-acyloxymethyl) derivatives VI were presumably hydrolyzed into the parent bis(2,6-dioxopiperazine) I by nonspecific esterase in the body to exhibit their antitumor activity.
社団法人日本薬学会の論文
1989-11-25