Stereoselective antitumor properties in the Lewis lung carcinoma model using bis(morpholinomethyl) derivatives of tricyclic bis(dioxopiperazines).
Witiak DT, Trivedi BK, Schmid FA.
Geometric isomers of 2,11-bis(morpholinomethyl)tetrahydrodipyrazino[1,2-a:2',1'-c]pyraz ine-1, 3,10,12-(2H,4H,9H,11H)-tetrone (3 and 4) and the parent bisimides (1 and 2) were studied for their stereoselective antimetastatic activity in the Lewis Lung carcinoma model. The morpholinomethyl cis-syn-trans isomer 4 was more effective as an inhibitor of metastasis than the other three analogues. Using a postamputation protocol, the order of decreasing activity was cis morpholinomethyl analogue 4 greater than trans morpholinomethyl analogue 3 greater than parent cis imide 2 greater than parent trans imide 1. Increased activity observed for the morpholinomethyl derivatives may reflect differences in solubility and delivery (prodrug) or an intrinsic antitumor activity of the morpholinomethyl-N functionality.