ABSTRACT
Eighteen analogues of the nonintercalative DNA topoisomerase II (topo II)-active epipodophyllotoxin-ellipticine hybrid, azatoxin, were synthesized and evaluated for their ability to induce topo II-mediated DNA strand breaks in vitro. In general, the SAR profile of the azatoxins showed more homology with that of the epipodophyllotoxins than with the ellipticines. Of the compounds studied, only fluoro substitution at the 8-, 9, and 10-positions of azatoxins enhanced activity, with 9-fluoroazatoxin being the most active compound in this series.
Subject(s)
DNA Topoisomerases, Type II/metabolism , DNA/metabolism , Indoles/pharmacology , Hydrolysis , Indoles/chemistry , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment , Structure-Activity RelationshipABSTRACT
The endoperoxide sesquiterpene lactone, artemisinin, and its derivatives have become increasingly important as antimalarial drugs with impressive activity against multidrug resistant forms of Plasmodium falciparum. Artemisinin has a novel structure among known antimalarial compounds with a unique 1,2,4-trioxane ring that is essential for activity. This paper gives an overview of the chemistry of artemisinin and comments on future prospects for artemisinin and its derivatives.
Subject(s)
Antimalarials/chemistry , Antiprotozoal Agents/chemistry , Artemisinins , Sesquiterpenes/chemistry , Antimalarials/chemical synthesis , Antiprotozoal Agents/chemical synthesis , Sesquiterpenes/chemical synthesisABSTRACT
The effect of mammalian and bacterial topoisomerase II inhibitors on Leishmania promastigotes was studied in vitro. Parasites were incubated with drugs, and cytotoxicity was assessed on the basis of the loss of flagellar motility and cell lysis after 48 h. 9-Aminoacridines, which are structurally related to the known antileishmanial compounds quinacrine and chlorpromazine, showed activity against the parasite at concentrations in the range of 10 to 20 microM. Adriamycin showed far less activity, while etoposide and several quinolones were inactive at 100-microM concentrations. These results demonstrate that a particular structural class of compounds is cytotoxic to Leishmania species. The unique structure-activity relationship discovered suggests that leishmanial topoisomerase II could be a useful target for chemotherapy.
