ABSTRACT
Greater than the sum of its parts: Artemisinins are currently in phaseâ I-II clinical trials against breast, colorectal and non-small-cell lung cancers. In an attempt to offer increased specificity, a series of hybrid artemisinin-polypyrrole minor groove binder conjugates are described. DNA binding/modelling studies and preliminary biological evaluation give insights into their mechanism of action and the potential of this strategy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/chemical synthesis , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Artemisinins/pharmacology , DNA/drug effects , Plasmodium falciparum/drug effects , Polymers/pharmacology , Pyrroles/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Artemisinins/chemistry , Binding Sites/drug effects , Cell Proliferation/drug effects , DNA/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , HT29 Cells , Humans , Models, Molecular , Molecular Conformation , Molecular Dynamics Simulation , Parasitic Sensitivity Tests , Polymers/chemistry , Pyrroles/chemistry , Structure-Activity Relationship , ThermodynamicsABSTRACT
Artemisinin-acridine hybrids were prepared and evaluated for their in vitro activity against tumour cell lines and a chloroquine sensitive strain of Plasmodium falciparum. They showed a 2-4-fold increase in activity against HL60, MDA-MB-231 and MCF-7 cells in comparison with dihydroartemisinin (DHA) and moderate antimalarial activity. Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle.
Subject(s)
Acridines/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Artemisinins/pharmacology , Acridines/chemical synthesis , Acridines/chemistry , Animals , Antimalarials/chemical synthesis , Antineoplastic Agents/chemical synthesis , Apoptosis , Artemisinins/chemical synthesis , Artemisinins/chemistry , Cell Cycle , Cell Line, Tumor , Erythrocytes/drug effects , Flow Cytometry , G1 Phase , HL-60 Cells , Humans , Plasmodium falciparum/drug effectsABSTRACT
The potency of RNA interference (RNAi) undoubtedly can be improved through chemical modifications to the small interfering RNAs (siRNA). By incorporation of the 3'-S-phosphorothiolate modification into strands of RNA, it is hoped that specific regions of a siRNA duplex can be stabilised to enhance the target binding affinity of a selected antisense strand into the activated RNA-induced silencing complex (RISC*). Oligonucleotides composed entirely of this modification are desirable so unconventional 5' --> 3' synthesis is investigated, with initial solution-phase testing proving successful. The phosphoroamidite monomer required for solid-phase synthesis has also been produced.
Subject(s)
Oligonucleotides/chemical synthesis , Phosphates/chemical synthesis , RNA Interference , Calixarenes/chemistry , Oligonucleotides/chemistry , Phosphates/chemistry , TetrazolesABSTRACT
Magnesium-ion-mediated RNA-RNA loop-receptor interactions, in conjunction with gold nanoparticles derivatized with DNA, have been used to make self-assembled nanowires. A wire located between lithographically fabricated nanoelectrodes is demonstrated that exhibits activated conduction by electron hopping at temperatures in the 150-300 K range. These techniques have the ability to link particles between devices and in the future may be used to assemble practical circuits.
Subject(s)
Gold/chemistry , Magnesium/metabolism , Nanostructures/chemistry , RNA/chemistry , RNA/metabolism , Base Sequence , Cations, Divalent/metabolism , Dimerization , Microscopy, Electron , Nanostructures/ultrastructure , Nucleic Acid Conformation , RNA/ultrastructureABSTRACT
An in-depth study into the incorporation of multiple 3-S-phosphorothiolate modifications into oligodeoxynucleotides (ODNs) and their subsequent effect on ODN/DNA and ODN/RNA duplex stability. 3-S-Phosphorothiolate linkages increase the stability of ODN/RNA duplexes and decrease the stability of ODN/DNA duplexes.
Subject(s)
DNA/chemistry , Nucleic Acid Conformation , Oligonucleotides/chemistry , Phosphorus/chemistry , RNA/chemistry , Thionucleotides/chemistry , Models, Chemical , Molecular Conformation , Nucleic Acid Heteroduplexes/chemistry , Temperature , ThermodynamicsABSTRACT
Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI50) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.
