ABSTRACT
Every year, students from European vet schools can apply for $5000 scholarships, which aim to 'enhance the academic experience of students'. Among last year's recipients were Jordon Egan, from the Royal Veterinary College, and Daniella Takács, from the University of Veterinary Medicine in Budapest.
ABSTRACT
BACKGROUND: The most common mechanism that reduces the efficacy of anticancer agents is overexpression of ATP-binding cassette (ABC) drug transporters. Phenothiazines and structurally-related compounds can sensitize multidrug-resistant (MDR) cells to chemotherapeutics. MATERIALS AND METHODS: Phenothiazine derivatives were investigated regarding their anticancer and MDR-reversing effect on colonic adenocarcinoma cells. The anti-proliferative and cytotoxic effects of the derivatives were assessed by the thiazolyl blue tetrazolium bromide (MTT) method, the modulation of the ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. RESULTS: All phenothiazines exhibited potent cytotoxic effect on the sensitive and MDR colon adenocarcinoma cell lines. The inhibition of the ABCB1 transporter was greater in the presence of the phenothiazine derivatives than for the known ABCB1 inhibitor verapamil. CONCLUSION: It can be concluded that these derivatives show synergism in the presence of doxorubicin and could have potential as ABCB1 inhibitors.
Subject(s)
Adenocarcinoma/genetics , Colonic Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Apoptosis/drug effects , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Doxorubicin/administration & dosage , Drug Resistance, Multiple/drug effects , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/drug effects , Humans , Phenothiazines/administration & dosage , Rhodamine 123/administration & dosage , Verapamil/administration & dosageABSTRACT
BACKGROUND/AIM: Bacterial resistance to antibiotics has become a serious problem in antibacterial chemotherapy and resistance of bacteria to chemically-unrelated anti-microbial agents can be associated with the over-expression of efflux pumps. The simultaneous therapy with efflux pump inhibitors (EPIs) could be a solution to improve the effectiveness of antibiotics. The response of an organism to an EPI often depends on how that molecule fits a particular site of a protein. Because enantiomers of a given compound rotate plane-polarized light in a solution by the same angle but in opposite directions, the rational drug design should take the chirality into account if there is a difference between the racemic compound and its enantiomers. MATERIALS AND METHODS: The main goal of the present study was to elucidate the role of chirality of N-hydroxyalkyl-2-aminophenothiazines as effective EPIs by an automated method that uses the general efflux pump substrate ethidium bromide (EB) for the assessment of AcrAB-TolC system of wild-type Escherichia coli K-12 AG100. It has been shown that the most active EPIs among the N-hydroxyalkyl-2-aminophenothiazines were the compounds rac-3i, (+)-3i, and (-)-3i by modulating the AcrAB-TolC efflux pump. CONCLUSION: Comparison of effects of enantiomeric pairs revealed that their activities were similar to that of racemic derivatives. Moreover, there was no significant difference between the racemic compounds and their enantiomers related to their antibacterial and efflux pump inhibiting effects.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Escherichia coli Proteins/antagonists & inhibitors , Phenothiazines/chemistry , Phenothiazines/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Escherichia coli K12/drug effects , Escherichia coli K12/metabolism , Microbial Sensitivity TestsABSTRACT
BACKGROUND: Phenothiazines have anticancer properties and are able to reverse the multidrug resistance of neoplastic cells by inhibiting the ATP-binding cassette, sub-family B (MDR/TAP), member 1 protein (ABCB1 or P-glycoprotein) activity. MATERIALS AND METHODS: A series of new phenothiazine derivatives was investigated regarding their ABCB1-modulating effect on multidrug resistant mouse T-lymphoma cells by rhodamine 123 accumulation assay and real-time ethidium bromide accumulation assay. RESULTS: The phenothiazine derivatives exhibited a potent anticancer effect on the parental cell line and on its multidrug-resistant mouse T-lymphoma subline overexpressing the ABCB1 transporter. The inhibition of the ABCB1 transporter in the presence of the newly-developed phenothiazines was greater than that for the known ABCB1 inhibitors thioridazine and verapamil. CONCLUSION: Based on the chemical structures and biological activity, compounds with bivalent sulfur atom in the phenothiazine ring demonstrated marked ABCB1-modulating effect, however, other derivatives with halogen or amide substitutions were ineffective.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Antineoplastic Agents/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Lymphoma, T-Cell/metabolism , Phenothiazines/pharmacology , ATP Binding Cassette Transporter, Subfamily B/genetics , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression , Lymphoma, T-Cell/genetics , Mice , Phenothiazines/chemistry , Rhodamine 123/metabolismABSTRACT
Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.
Subject(s)
Drug Resistance, Multiple/drug effects , Hepatocytes/drug effects , Phenothiazines/chemistry , Phenothiazines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amination , Animals , Cells, Cultured , Male , Phenothiazines/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfones/pharmacology , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Sulfoxides/pharmacologyABSTRACT
N-dienylphenothiazines synthesized from tetrazolo[1,5-a]pyridinium salts by treatment with phenothiazine were subjected to catalytic hydrogenation to yield N-butylphenothiazines, whereas transformation of these dienes with borane dimethyl sulfide (BH(3) × Me(2)S) resulted in selective hydroboration of one double bond and full reduction of the other double bond to give 2-hydroxybutylphenothiazines. Position of the hydroxyl group was supported by NMR spectroscopy and verified by X-ray analysis. Comparison of MDR modulatory activity of the new derivatives revealed that the hydroxybutyl compounds are promising candidates for development of novel MDR inhibitors.
Subject(s)
Amines/chemistry , Phenothiazines/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Boranes/chemistry , Cells, Cultured , Crystallography, X-Ray , Drug Resistance, Multiple/drug effects , Hepatocytes/drug effects , Male , Molecular Conformation , Phenothiazines/chemical synthesis , Phenothiazines/pharmacology , Pyrimidines/chemistry , Rats , Rats, WistarABSTRACT
BACKGROUND: Because phenothiazines inhibit efflux pumps of bacteria, forty new phenothiazine derivatives were tested for their inhibition of the efflux pump systems of Gram-positive and Gram-negative pathogenic bacteria. MATERIALS AND METHODS: Detection of efflux pump activity was conducted by a previously described automated fluorimetric method. RESULTS: Although many of the compounds significantly inhibited efflux by distinct bacteria, four compounds had exceptional activity against the efflux pump systems of the pathogenic wild type bacteria Escherichia coli, Salmonella Enteritidis, Enterococcus faecalis and Staphylococcus aureus. These four compounds were then evaluated for ability to reduce or reverse resistance of multi-drug resistant members of Escherichia coli, Salmonella and Staphylococcus aureus whose MDR phenotypes are mediated by specific over-expressed efflux pumps. One of the compounds, 2173, significantly reduced resistance of MDR Staphylococcus aureus. CONCLUSION: These results suggest possible use of compound 2173 for therapy of infections caused by this organism.
