Potential CNS antitumor agents-phenothiazines II: fluphenazine analogs.

Fluphenazine was found to possess moderate reproducible activity against the intraperitoneal L-1210 and P-388 leukemia murine tumor models. Seven ether derivatives of fluphenazine and eight compounds in which the terminal side-chain hydroxyl group was replaced by an amine function were prepared and evaluated in the intraperitoneal L-1210, P-388, and B16 melanoma systems as well as the intracerebral L-1210 and ependymoblastoma brain tumor models. While no substantial intracerebral activity was observed, seven derivatives possessed reproducible activity in the intraperitoneal L-1210 or P-388 system. Several gave T/C values of 150%. No B16 melanoma activity was observed. These compounds were also tested for their cytotoxic properties in culture against L-1210, P-388, and KB cells. The amine isosteres, while possessing little in vivo activity, were the most cytotoxic of the compounds prepared, with several having ED50 values less than 1 microgram/ml.