Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Curr Drug Targets ; 7(7): 823-41, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16842214

ABSTRACT

Bacterial plasmids have a major impact on metabolic function. Lactose fermentation of E. coli or hemolysin B transporter expressed by the plasmids that carry these respective genes could be readily obviated by heterocyclic compounds that readily bind to plasmid DNA. These compounds could also reverse the resistance to antibiotics of E. coli, Enterobacter, Proteus, Staphylococcus and Yersinia strains by eliminating plasmids. However, the frequency and extent of this effect was significantly less than might have been expected based on a complex interaction with plasmid DNA. The effects of heterocyclic compounds on the plasmids responsible for the virulence of Yersinia and A. tumefaciens, or on nodulation, nitrogen fixation of Rhizobia accounted for the elimination of 0.1 to 1.0 % of plasmids present in the populations studied. Bacterial plasmids can be eliminated from bacterial species grown as pure or mixed bacterial cultures in the presence of sub-inhibitory concentrations of non-mutagenic heterocyclic compounds. The antiplasmid action of the compounds depends on the chemical structure of amphiphillic compounds having a planar ring system with substitution in the L-molecular region. A symmetrical pi-electron conjugation at the highest occupied molecular orbitals favours the antiplasmid effect. The antiplasmid effect of heterocyclic compounds is expressed differentially in accordance with the structural form of the DNA to which they bind. In this manner "extrachromosomal" plasmid DNA that exists in a superhelical state binds more compound than its linear or open-circular form; and least to the chromosomal DNA of the bacterium, that carries the plasmid. It can also be noted that these compounds are not mutagenic and their antiplasmid effects correlate with the energy of HOMO-orbitals. Plasmid elimination is considered also to take place in ecosystems containing numerous bacterial species. This opens up a new perspective in rational drug design against bacterial plasmids. The inhibition of conjugational transfer of antibiotic resistance plasmid can be exploited to reduce the spread of antibiotic resistance plasmid in the ecosystem. Inhibition of plasmid replication at various stages, as shown in the "rolling circle" model (replication, partition, conjugal transfer) may also be the theoretical basis for the elimination of bacterial virulence in the case of plasmid mediated pathogenicity and antibiotic resistance. The large number of compounds tested for antiplasmid effects provides opportunities for QSAR studies in order to find a correlation between the antiplasmid effect and the supramolecular chemistry of these plasmid curing compounds. Plasmid elimination in vitro provides a method of isolating plasmid free bacteria for biotechnology without any risk of inducing mutations.


Subject(s)
Bacteria/drug effects , Drug Resistance, Bacterial/genetics , Intercalating Agents/pharmacology , Plasmids/genetics , Bacteria/genetics , Bacteria/growth & development , DNA Replication/drug effects , DNA Replication/genetics , Drug Design , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Intercalating Agents/chemistry , Molecular Structure , Quantitative Structure-Activity Relationship
2.
Eur J Med Chem ; 40(2): 195-202, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15694654

ABSTRACT

Various resistance mechanisms such as complex formation with DNA, tRNA and MDR1 p-glycoprotein were modified in bacteria and cancer cells in presence of pregnane, pyridoquinoline, and aza-oxafluorene derivatives. Interaction between the compounds, plasmid DNA and tRNA was shown and compared to the interaction with calf thymus DNA. Complex formation with MDR1 p-glycoprotein and drug accumulation increased in cancer cells. Both plasmid DNA and p-gp complex formation were related to the chemical structures of the resistance modifiers.


Subject(s)
DNA/metabolism , Fluorenes/chemistry , Pregnanes/chemistry , Quinolines/chemistry , RNA, Transfer/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Interactions , Drug Resistance, Neoplasm , Fluorenes/pharmacology , Genes, MDR , Humans , Molecular Structure , Plasmids/genetics , Plasmids/metabolism , Pregnanes/pharmacology , Quinolines/pharmacology
3.
Eur J Med Chem ; 39(12): 1029-38, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15571864

ABSTRACT

The synthesis of several acridine thioethers is described. These compounds were oxidized to give new sulfoxides and sulfones. Among 23 compounds prepared, 19 were tested in vitro against the human cancer cell lines panel of NCI screening. Activity is increased 5-10 times from sulfides to sulfoxides. Among substituted groups in the side chain, sulfur mustard, epoxy sulfide and sulfoxide displayed the most interesting activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Sulfides/chemical synthesis , Sulfones/chemical synthesis , Sulfoxides/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Damage/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Saccharomyces cerevisiae/drug effects , Structure-Activity Relationship , Sulfides/pharmacology , Sulfones/pharmacology , Sulfoxides/pharmacology
4.
Expert Opin Investig Drugs ; 11(8): 1023-32, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12150699

ABSTRACT

Over the past decade many well-tried chemotherapeutic agents have lost their effectiveness. This is due to a phenomenon referred to as multi-drug resistance. The most likely cause of multi-drug resistance is an increase in the activity of an efflux pump mediated through the actions of a P-glycoprotein. There is a continuing search, not only for new chemotherapeutic agents, but also for agents that can reverse the acquired resistance to existing agents.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Multiple , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Clinical Trials as Topic , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Genes, MDR , Humans , Tamoxifen/therapeutic use , Treatment Outcome
5.
Planta Med ; 68(5): 454-7, 2002 May.
Article in English | MEDLINE | ID: mdl-12058326

ABSTRACT

Seven alkaloids were isolated from Sprekelia formosissima, and five from Hymenocallis x festalis. Tazettine, lycorine, haemanthidine and haemanthamine were evaluated for antiproliferative and multidrug resistance (mdr) reversing activity on mouse lymphoma cells. Lycorine, haemanthidine and haemanthamine displayed pronounced cell growth inhibitory activities against both drug-sensitive and drug-resistant cell lines, but did not significantly inhibit mdr-1 p-glycoprotein. Thus, the tested alkaloids are apparently not substrates for the mdr efflux pump. Assays for interactions with DNA and RNA revealed that the antiproliferative effects of lycorine and haemanthamine result from their complex formation with RNA.


Subject(s)
Alkaloids/pharmacology , Amaryllidaceae Alkaloids , Antineoplastic Agents, Phytogenic/pharmacology , Magnoliopsida , Alkaloids/chemistry , Alkaloids/isolation & purification , Aniline Compounds/chemistry , Aniline Compounds/isolation & purification , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , DNA/chemistry , DNA/drug effects , Dioxoles/chemistry , Dioxoles/isolation & purification , Dioxoles/pharmacology , Drug Resistance, Multiple , Leukemia L5178/drug therapy , Leukemia L5178/pathology , Mice , Molecular Structure , Nucleic Acid Denaturation/drug effects , Phenanthridines/chemistry , Phenanthridines/isolation & purification , Phenanthridines/pharmacology , Plant Stems/chemistry , RNA, Transfer/chemistry , RNA, Transfer/drug effects , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Verapamil/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...