Drug resistance reversal, anti-mutagenicity and antiretroviral effect of phthalimido- and chloroethyl-phenothiazines.
The effect of substituted phenothiazines was studied in three different systems; bacteria and cancer cells and reverse transcriptase enzyme of Moloney leukemia virus. F'lac and hemolysin plasmids were eliminated by some substituted phenothiazines from E. coli at a very low frequency. The same phenothiazine derivatives also were synergistic with tetracycline in bacteria and shown antimutagenic effect in Ames test. No mutagenic effects were observed in TA 98 strain of Salmonella typhimunium. Chloroethyl-substituted phenothiazines showed antimutagenicity equivalent to the parent compounds; however, phthalimido-substituted phenothiazines had higher antimutagenicity of 50%. P-glycoprotein responsible for multidrug resistance was also inhibited in tumor cells. The accumulation of the fluorescent rhodamine 123 in the phenothiazine treated multi-drug resistant tumor cells was measured by flow cytometry. Some of the substituted phenothiazines were effective P-glycoprotein blockers, while some compounds had moderate activity, but others were without effect as compared to 5 microM verapamil. On the basis of computer analysis there are some correlations between the biological activities and the dipole moments, and entropy of the studied molecules. Our results suggest that the inhibition of Hly+ plasmid replication and P-glycoprotein function may depend partly on similar electronic properties of the studied phenothiazine derivatives. The activity of Moloney leukemia virus reverse transcriptase was inhibited by the substituted phenothiazines, however, no basic differences were found in the activities of phthalimido- and chloroethyl substituted phenothiazines.
Motohashi
N
N
Department of Medicinal Chemistry, Meiji College of Pharmacy, Tokyo, Japan.
Kurihara
T
T
Kawase
M
M
Hevér
A
A
Tanaka
M
M
Szabo
D
D
Nacsa
J
J
Yamanaka
W
W
Kerim
A
A
Molnár
J
J
D016587:Antimutagenic Agents; D000970:Antineoplastic Agents / Q000737:chemistry; D000998:Antiviral Agents / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018432:Drug Resistance, Multiple; D004926:Escherichia coli / Q000187:drug effects; D015394:Molecular Structure; D008979:Moloney murine leukemia virus / Q000201:enzymology; D009153:Mutagens; D010640:Phenothiazines / Q000494:pharmacology*; D010957:Plasmids; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013752:Tetracycline / Q000008:administration & dosage
D016587:Antimutagenic Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009153:Mutagens; D010640:Phenothiazines; D018894:Reverse Transcriptase Inhibitors; D013752:Tetracycline