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
We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.
Subject(s)
Antimalarials/chemical synthesis , Chalcones/chemical synthesis , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Peroxides/chemical synthesis , Prodrugs/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Erythrocytes/drug effects , Erythrocytes/parasitology , Inhibitory Concentration 50 , Models, Molecular , Peroxides/chemistry , Peroxides/pharmacology , Plasmodium falciparum/drug effects , Prodrugs/chemistry , Prodrugs/pharmacology , Structure-Activity RelationshipABSTRACT
A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.
