DRUG-RESISTANCE REVERSAL, ANTI-MUTAGENICITY AND ANTIRETROVIRAL EFFECTOF PHTHALIMIDO-PHENOTHIAZINES AND CHLOROETHYL-PHENOTHIAZINES

The effect of substituted phenothiazines was studied in three differen t systems; bacteria and cancer cells and reverse transcriptase enzyme of Moloney leukemia virus. F'lac and hemolysin plasmids were eliminate d by some substituted phenothiazines from E. coli at a very low freque ncy. The same phenothiazine derivatives also were synergistic with tet racycline in bacteria and shown antimutagenic effect in Ames test. No mutagenic effects were observed in TA 98 strain of Salmonella typhimun ium. Chloroethyl-substituted phenothiazines showed antimutagenicity eq uivalent to the parent compounds; however, phthalimido-substituted phe nothiazines had higher antimutagenicity of 50%. P-glycoprotein respons ible for multidrug resistance was also inhibited in tumor cells. The a ccumulation of the fluorescent rhodamine 123 in the phenothiazine trea ted multi-drug resistant tumor cells was measured by flow cytometry. S ome of the substituted phenothiazines were effective P-glycoprotein bl ockers, while some compounds had moderate activity, but others were wi thout effect as compared to 5 mu M verapamil. On the basis of computer analysis there are some correlations between the biological activitie s and the dipole moments, and entropy of the studied molecules. Our re sults suggest that the inhibition of Hly(+) plasmid replication and P- glycoprotein function may depend partly on similar electronic properti es of the studied phenothiazine derivatives. The activity of Moloney l eukemia virus reverse transcriptase was inhibited by the substituted p henothiazines, however, no basic differences were found in the activit ies of phthalimido- and chloroethyl substituted phenothiazines.