ANTITUMOR-ACTIVITY OF PHENOTHIAZINE-RELATED COMPOUNDS

One of the biggest challenges in health care is the fight against tumo rs. Some phenothiazines have antitumor activity on HEp-2 tumor cells. In this study, we tested the antitumor effects of three series such as 10-nonsubstituted phenothiazines, hthalimido)alkyl]-2-substituted-10H -phenothiazines and 2-substituted-10H-phenothiazin-10-yl)alkyl-1-ureas with H, Cl and CF3 substitution at position C2. The TCID50 of phenoth iazines was affected by the H, Cl and CF3 at C2. Trifluoromethyl deriv ative of phenothiazine showed potent (R=CF3, TCID50=4.7 mu g) activity , whereas the chlorine derivative of phenothiazine (R=Cl, TCID50=62.5 mu g) had a relatively weak effect. In the group of thalimido)alkyl]-2 -substituted-10H-phenothiazines, 10-[3-(phthalimido)propyl]-10H-phenot hiazine (R=H, n=3, TCID50=11.5 mu g), was very effective. On the other hand, TCID50 of [3-(phthalimido)propyl]-2-chloro-10H-phenothiazine (R =Cl, n=3, TCID50=75.0 mu g), -[4-(phthalimido)butyl]-2-chloro-10H-phen othiazine (R=Cl, n=4, TCID50=31.3 mu g) and alimido)butyl]-2-trifluoro methyl-10H-phenothiazine (R=CF3, n=4, TCID50=50.0 mu g) were about 4-8 times less effective than 10-[4-(phthalimido)butyl]-10H-phenothiazine (R=H, n=4, TCID50=7.8 mu g). Among six -substituted-10H-phenothiazin- 10-yl)alkyl-1-ureas, two chlorine compounds such as )-3-(2-chloro-10H- phenothiazin-10-yl)propyl-1-urea (R=Cl, n=3, TCID50=7.8 mu g), and rif luoromethyl-10H-phenothiazin-10-yl)butyl-1-urea (R=CF3, n=4, TCID50=7. 8 mu g) were significantly active. Tests showed that the substitution at 2C position apparently affected the anti-HEp-2 tumor cell activity; that the length of the aliphatic side chain at 10N contributes to the anti-tumor activity; and that the TCID50 values of the derivatives wi th butylene group (-C4H8-) were lower than those with propylene group (-C3H6-) except 10-[4-(phthalimido) butyl]-2-trifuoromethyl-10H-phenot hiazine and -chloroethyl)-3-(2-chloro-10H-pheno-thiazin-10-yl) butyl-1 -urea.