ANTITRYPANOSOMAL ACTIVITY OF CAMPTOTHECIN ANALOGS - STRUCTURE-ACTIVITY CORRELATIONS

African trypanosomes (Trypanosoma brucei species) are parasitic protoz oa that cause lethal diseases in humans and cattle. Previous studies s howed that camptothecin, a potent and specific inhibitor of DNA topois omerase I, is cytotoxic to African trypanosomes and related pathogenic hemoflagellates (Bodley AL and Shapiro TA, Proc Natl Acad Sci USA 92: 3726-3730, 1995). In this study, a series of camptothecin analogs was tested against axenically cultured, bloodstream form, T. brucei. Modi fications to the pentacyclic nucleus of camptothecin ablated antiparas itic activity. In contrast, activity could be increased by substituent s added to the parent ring system (e.g. 10,11-methylenedioxy or ethyle nedioxy groups; alkyl additions to carbon 7; or g-amino or g-chloro su bstituents), Cytotoxicity was correlated with the level of cleavable c omplexes in trypanosomes, implicating topoisomerase I as the intracell ular target for these compounds. To obtain some indication of selectiv e toxicity, ten compounds were also tested against L1210 mouse leukemi a cells. The 9-substituted-10,11-methylenedioxy analogs caused a dispr oportionate increase in antiparasitic activity, compared with mammalia n cell toxicity. These findings provide a basis for designing further structural modifications and for selecting camptothecin analogs to tes t in animal models of trypanosomiasis.