Thanatop: a novel 5-nitrofuran that is a highly active, cell-permeable inhibitor of topoisomerase II.

Abstract:

:A series of nitrofuran-based compounds were identified as inhibitors of estrogen signaling in a cell-based, high-throughput screen of a diverse library of small molecules. These highly related compounds were subsequently found to inhibit topoisomerase II in vitro at concentrations similar to that required for the inhibition of estrogen signaling in cells. The most potent nitrofuran discovered is approximately 10-fold more active than etoposide phosphate, a topoisomerase II inhibitor in clinical use. The nitrofurans also inhibit topoisomerase I activity, with approximately 20-fold less activity. Moreover, the nitrofurans, in contrast to etoposide, induce a profound cell cycle arrest in the G(0)-G(1) phase of the cell cycle, do not induce double-stranded DNA breaks, are not substrates for multidrug resistance protein-1 export from the cell, and are amenable to synthetic development. In addition, the nitrofurans synergize with etoposide phosphate in cell killing. Clonogenic assays done on a panel of human tumors maintained ex vivo in nude mice show that the most active compound identified in the screen is selective against tumors compared with normal hematopoietic stem cells. However, this compound had only moderate activity in a mouse xenograft model. This novel class of topoisomerase II inhibitor may provide additional chemotherapeutic strategies for the development of cytotoxic agents with proven clinical utility.

journal_name

Cancer Res

journal_title

Cancer research

authors

Polycarpou-Schwarz M,Müller K,Denger S,Riddell A,Lewis J,Gannon F,Reid G

doi

10.1158/0008-5472.CAN-07-0393

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

4451-8

issue

9

eissn

0008-5472

issn

1538-7445

pii

67/9/4451

journal_volume

67

pub_type

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