5-Cinnamoyl-6-aminouracil derivatives as novel anticancer agents. Synthesis, biological evaluation, and structure-activity relationships

A biological evaluation in the series of 5-cinnamoyl-6-aminouracils has been undertaken. These compounds have been found to be in an extended planar conformation fitting well with a possible stacking interaction between the nucleic bases of DNA; thus an eventual anticancer activity by intercalation could be hoped. 1,3-Dimethyl-5-cinnamoyl-6-aminouracil was found to be active when administered ip against ip-implanted P388 leukemia in vivo (percent T/C = 124). Two other compounds, 1,3-dimethyl-5-cinnamoyl-6-[(2-morpholinoethyl)amino]uracil and 1,3-dimethyl-5-cinnamoyl-6-[(2-piperidinoethyl)amino]uracil, bearing a hydrophilic side chain on the 6-amino group, have exhibited cytoxic activity in vitro against L1210 leukemia. Structure-activity relationships have been determined from these results and from studies of biological interactions with DNA.