RESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/síntesis química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Artemisininas/farmacología , ADN/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Polímeros/farmacología , Pirroles/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/química , Artemisininas/química , Sitios de Unión/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HT29 , Humanos , Modelos Moleculares , Conformación Molecular , Simulación de Dinámica Molecular , Pruebas de Sensibilidad Parasitaria , Polímeros/química , Pirroles/química , Relación Estructura-Actividad , TermodinámicaRESUMEN
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.
Asunto(s)
Acridinas/farmacología , Antimaláricos/química , Antimaláricos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Artemisininas/farmacología , Acridinas/síntesis química , Acridinas/química , Animales , Antimaláricos/síntesis química , Antineoplásicos/síntesis química , Apoptosis , Artemisininas/síntesis química , Artemisininas/química , Ciclo Celular , Línea Celular Tumoral , Eritrocitos/efectos de los fármacos , Citometría de Flujo , Fase G1 , Células HL-60 , Humanos , Plasmodium falciparum/efectos de los fármacosRESUMEN
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.
Asunto(s)
Oligonucleótidos/síntesis química , Fosfatos/síntesis química , Interferencia de ARN , Calixarenos/química , Oligonucleótidos/química , Fosfatos/química , TetrazolesRESUMEN
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.
Asunto(s)
Oro/química , Magnesio/metabolismo , Nanoestructuras/química , ARN/química , ARN/metabolismo , Secuencia de Bases , Cationes Bivalentes/metabolismo , Dimerización , Microscopía Electrónica , Nanoestructuras/ultraestructura , Conformación de Ácido Nucleico , ARN/ultraestructuraRESUMEN
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.
Asunto(s)
ADN/química , Conformación de Ácido Nucleico , Oligonucleótidos/química , Fósforo/química , ARN/química , Tionucleótidos/química , Modelos Químicos , Conformación Molecular , Ácidos Nucleicos Heterodúplex/química , Temperatura , TermodinámicaRESUMEN
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.
