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.
