Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins

Homocamptothecin (hCPT) is an E-ring modified camptothecin (CPT) analogue b earing a methylene spacer between the alcohol and carboxyl functions of the CPT lactone. Combining pronounced inhibitory activity of topoisomerase I ( Topo I) with enhanced plasma stablility, hCPT constitutes an attractive tem plate for the elaboration of new anticancer agents. Fluorinated hCPT analog ues, prepared in enantiomerically pure form, were assayed by their stimulat ion of Topo I-mediated DNA cleavage. Translation into cytotoxicity against tumor cells was evaluated on HT29 human colon adenocarcinoma and on the mul tidrug resistant lung and bladder tumor cell lines, A549 and T24r. Good cor relation is observed between the ability of the drugs to stimulate Topo I-m ediated DNA cleavage and the respective 50% inhibitory concentrations (IC50 values) of the HT29, A549, and T24r cell growth. Fluorine substitution in the A-ring of hCPT was found to have a pronounced influence on biological a ctivity, providing several compounds which are up to 100-fold more potent t han CPT in terms of IC50. Among these, 10,11-difluoro-hCPT has been selecte d for further development.