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

Raoof, Ali; Depledge, Paul; Hamilton, Niall M.; Hamilton, Nicola; Hitchin, James R.; Hopkins, Gemma; Jordan, Allan M.; Maguire, Laura A.; McGonagle, Alison E.; Mould, Daniel P.; Rushbrooke, Mathew; Small, Helen; Smith, Kate; Thomson, Graeme; Turlais, Fabrice; Waddell, Ian D.; Waszkowycz, Bohdan; Watson, Amanda J.; Ogilvie, Donald

doi:10.1021/jm400568p

Cited by 57 publications

(89 citation statements)

References 39 publications

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“…6C), is also processed by TDP2 to liberate p -nitrophenol [154]. NPPP has begun to be used in a high-throughput screen for TDP2 inhibitors [155]. …”

Section: Tdp Inhibitorsmentioning

confidence: 99%

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

et al. 2014

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TDP1 and TDP2 were discovered and named based on the fact they process 3′- and 5′-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Yet, both enzymes have an extended spectrum of activities. TDP1 not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3′-phosphoglycolates and alkylation damage-induced DNA breaks, and excises chain terminating anticancer and antiviral nucleosides in the nucleus and mitochondria. The repair function of TDP2 is devoted to the excision of topoisomerase II- and potentially topoisomerases III-DNA adducts. TDP2 is also essential for the life cycle of picornaviruses (important human and bovine pathogens) as it unlinks VPg proteins from the 5′-end of the viral RNA genome. Moreover, TDP2 has been involved in signal transduction (under the former names of TTRAP or EAPII). The DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway. By contrast, TDP2 repair functions are coordinated with Ku and ligase IV in the non-homologous end joining pathway (NHEJ). This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents. We discuss the rationale for developing TDP inhibitors for combinations with topoisomerase inhibitors (topotecan, irinotecan, doxorubicin, etoposide, mitoxantrone) and DNA damaging agents (temozolomide, bleomycin, cytarabine, and ionizing radiation), and as novel antiviral agents.

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“…6C), is also processed by TDP2 to liberate p -nitrophenol [154]. NPPP has begun to be used in a high-throughput screen for TDP2 inhibitors [155]. …”

Section: Tdp Inhibitorsmentioning

confidence: 99%

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

et al. 2014

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“…15 It was also found that hydroxyethylaminopropyl side chains can impart inhibitory activity against tyrosyl DNA phosphodiesterase 1 and 2 (TDP1 and 2) without eliminating Top1 poisoning activity. At present, there are few reported dual inhibitors of both TDP1 and TDP2, 19, 34 and none that are potent triple inhibitors of both of these enzymes as well as poisons of Top1. Generally speaking, triple inhibitors of Top1, TDP1, and TDP2 are attractive because they not only damage DNA, they also inhibit the repair of the damage.…”

Section: Discussionmentioning

confidence: 99%

“…The concentrations of positive control 55 34 were 0.005, 0.017, 0.05, 0.15, 0.46, 1.4 μM, and the concentrations for the test compounds were 0.46, 1.4, 4.1, 12.3, 37, 111 μM (left to right). The TDP2 substrate Y19 corresponds to a 3′-end labeled DNA oligonucleotide with a 5′ phosphotyrosyl, and the TDP2 product p19 corresponds to a 3′-end labeled DNA oligonucleotide with a 5′ phosphate group (see Experimental Section).…”

Section: Figurementioning

confidence: 99%

Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Beck

Abdelmalak

et al. 2016

Bioorganic & Medicinal Chemistry

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Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds’ activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogues were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons.

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“…Expression of TDP2 is increased in nonsmall-cell lung cancer cells and is transcriptionally upregulated in mutant p53 cells 82,83 . The crystal structure of TDP2 has also been solved, and efforts to develop TDP2 inhibitors are ongoing [84][85][86][87] .…”

Section: Landmarks Of Tdp2 Researchmentioning

confidence: 99%

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

Atteya²,

2015

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The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase-induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers.

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

Cited by 57 publications

References 39 publications

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

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