Antitumor activity of phenothiazine-related compounds.

One of the biggest challenges in health care is the fight against tumors. 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, 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines and 1-(chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1-ureas with H, Cl and CF3 substitution at position C2. The TCID50 of phenothiazines was affected by the H, Cl and CF3 at C2. Trifluoromethyl derivative of phenothiazine showed potent (R = CF3, TCID50 = 4.7 micrograms) activity, whereas the chlorine derivative of phenothiazine (R = Cl, TCID50 = 62.5 micrograms) had a relatively weak effect. In the group of 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines, 10-[3-(phthalimido)propyl]-10H-phenothiazine (R = H, n = 3, TCID50 = 11.5 micrograms), 10-[4-(phthalimido)butyl]-10H-phenothiazine (R = H, n = 4, TCID50 = 7.8 micrograms) and 10-[3-(phthalimido)propyl]-2-trifluoromethyl-10H- phenothiazine (R = CF3, n = 3, TCID50 = 11.5 micrograms) was very effective. On the other hand, TCID50 of 10-[3-(phthalimido)propyl]-2-chloro-10H-phenothiazine (R = Cl, n = 3, TCID50 = 75.0 micrograms), 10-[4-(phthalimido)butyl]-2-chloro-10H-phenothiazine (R = Cl, n = 4, TCID50 = 31.3 micrograms) and 10-[4-(phthalimido)butyl]-2-trifluoromethyl-10H-phenothiazine (R = CF3, n = 4, TCID50 = 50.0 micrograms) were about 4-8 times less effective than 10-[4-(phthalimido)butyl]-10H-phenothiazine (R = H, n = 4, TCID50 = 7.8 micrograms). Among six 1-(chloroethyl)-3- (2-substituted-10H-phenothiazin-10-yl)alkyl-1-ureas, two chlorine compounds such as 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl)propyl-1-urea (R = Cl, n = 3, TCID50 = 6.3 micrograms), 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl) butyl-1-urea (R = Cl, n = 4, TCID50 = 7.8 micrograms), and 1-(2-chloroethyl)-3-(2-trifluoromethyl-10H-phenothiazin-10-yl)buty l-1-ur ea (R = CF3, n = 4, TCID50 = 7.8 micrograms) 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 with butylene group (-C4H8-) were lower than those with propylene group (-C3H6-) except 10-[4-(phthalimido) butyl]-2-trifuoromethyl-10H-phenothiazine and 1-(2-chloroethyl)-3-(2-chloro-10H-pheno-thiazin-10-yl) butyl-1-urea.