Synthesis and antimetastatic properties of stereoisomeric tricyclic bis(dioxopiperazines) in the Lewis lung carcinoma model.

Synthesis of trans- and cis-tetrahydrodipyrazino[1,2-a:1',2'-d] pyrazine-1,3,7,9(2H,4H,8H,10H)-tetrone analogues 10 and 11 belonging to the bis(dioxopiperazine) class of antitumor agents and their bis(morpholinomethyl) derivatives 12 and 13 are described with use of 2,5-dimethylpyrazine as the starting material. Synthetic studies utilizing 3,6-disubstituted 2,5-dioxopiperazine precursors are included. Evaluation of 10-13 in the Lewis Lung carcinoma model indicated the bis(morpholinomethyl) analogue cis-13 to be antimetastatic, whereas the trans isomer 12 was toxic at a similar dose effecting a decrease in the life span of treated mice. The parent bis(dioxopiperazines) 10 and 11 were ineffective as antitumor or antimetastatic drugs.