Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II

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• 作者：Ali Raoof ; Paul Depledge ; Niall M. Hamilton ; Nicola S. Hamilton ; James R. Hitchin ; Gemma V. Hopkins ; Allan M. Jordan ; Laura A. Maguire ; Alison E. McGonagle ; Daniel P. Mould ; Mathew Rushbrooke ; Helen F. Small ; Kate M. Smith ; Graeme J. Thomson ; Fabrice Turlais ; Ian D. Waddell ; Bohdan Waszkowycz ; Amanda J. Watson ; Donald J. Ogilvie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6352-6370
• 全文大小：738K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure鈥揳ctivity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.