Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase I

Article abstract of DOI:10.1021/jm00003a001

The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-<(4-methylpiperazino)methyl>-10,11-(methylenedioxy)-(20S)-camptothecin trifluoroacetate (6) and 7-<(4-methylpiperazino)methyl>-10,11-(ethylenedioxy)-(20S)-camptothecin trifluoroacetate (7) are described.The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to <0.003 mg/mL for camptothecin in the same buffer.In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan.In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM.Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.