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

The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin trifluoroacetate (7) are described. T...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-02, Vol.38 (3), p.395-401
Main Authors: Luzzio, Michael J, Besterman, Jeffrey M, Emerson, David L, Evans, Michael G, Lackey, Karen, Leitner, Peter L, McIntyre, Gordon, Morton, Bradley, Myers, Peter L, Peel, Michael, Sisco, Jay M, Sternbach, Daniel D, Tong, Wei-Qin, Truesdale, Ann, Uehling, David E, Vuong, Alan, Yates, Julie
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Camptothecin - analogs & derivatives
Camptothecin - chemical synthesis
Camptothecin - pharmacology
Cell Survival - drug effects
Female
General aspects
Humans
Medical sciences
Mice
Pharmacology. Drug treatments
Solubility
Topoisomerase I Inhibitors
Tumor Cells, Cultured
Water - chemistry
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Summary:The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00003a001