Contributions of the D-Ring to the Activity of Etoposide against Human Topoisomerase II伪: Potential Interactions with DNA in the Ternary Enzyme鈥揇rug鈥揇NA Complex
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- 作者：Steven L. Pitts ; Michael J. Jablonksy ; Maria Duca ; Daniel Dauzonne ; Claude Monneret ; Paola B. Arimondo ; Clemens Anklin ; David E. Graves ; Neil Osheroff
- 刊名：Biochemistry
- 出版年：2011
- 出版时间：June 7, 2011
- 年：2011
- 卷：50
- 期：22
- 页码：5058-5066
- 全文大小：954K
- 年卷期：v.50,no.22(June 7, 2011)
- ISSN：1520-4995
文摘
Etoposide is a widely prescribed anticancer drug that stabilizes covalent topoisomerase II-cleaved DNA complexes. The drug contains a polycyclic ring system (rings A鈥揇), a glycosidic moiety at C4, and a pendant ring (E-ring) at C1. Interactions between human topoisomerase II伪 and etoposide in the binary enzyme鈥揹rug complex appear to be mediated by substituents on the A-, B-, and E-rings of etoposide. These protein鈥揹rug contacts in the binary complex have predictive value for the actions of etoposide within the ternary topoisomerase II伪鈥揹rug鈥揇NA complex. Although the D-ring of etoposide does not appear to contact topoisomerase II伪 in the binary complex, etoposide derivatives with modified D-rings display reduced cytotoxicity against murine leukemia cells [Meresse, P., et al. (2003) Bioorg. Med. Chem. Lett. 13, 4107]. This finding suggests that alterations in the D-ring may affect etoposide activity toward topoisomerase II伪 in the ternary enzyme鈥揹rug鈥揇NA complex. Therefore, to address the potential contributions of the D-ring to the activity of etoposide, we characterized drug derivatives in which the C13 carbonyl was moved to the C11 position (retroetoposide and retroDEPT) or the D-ring was opened (D-ring diol). All of the D-ring alterations decreased the ability of etoposide to enhance DNA cleavage mediated by human topoisomerase II伪 in vitro and in cultured cells. They also weakened etoposide binding in the ternary enzyme鈥揹rug鈥揇NA complex and altered sites of enzyme-mediated DNA cleavage. On the basis of these findings, we propose that the D-ring of etoposide has important interactions with DNA in the ternary topoisomerase II cleavage complex.