RESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/síntese química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Artemisininas/farmacologia , DNA/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Polímeros/farmacologia , Pirróis/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/química , Artemisininas/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células HT29 , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Testes de Sensibilidade Parasitária , Polímeros/química , Pirróis/química , Relação Estrutura-Atividade , TermodinâmicaRESUMO
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.
Assuntos
Acridinas/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Artemisininas/farmacologia , Acridinas/síntese química , Acridinas/química , Animais , Antimaláricos/síntese química , Antineoplásicos/síntese química , Apoptose , Artemisininas/síntese química , Artemisininas/química , Ciclo Celular , Linhagem Celular Tumoral , Eritrócitos/efeitos dos fármacos , Citometria de Fluxo , Fase G1 , Células HL-60 , Humanos , Plasmodium falciparum/efeitos dos fármacosRESUMO
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.