7269-15-0Relevant articles and documents
Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide
Kankanala, Jayakanth,Ribeiro, Carlos J. A.,Kiselev, Evgeny,Ravji, Azhar,Williams, Jessica,Xie, Jiashu,Aihara, Hideki,Pommier, Yves,Wang, Zhengqiang
supporting information, p. 4669 - 4682 (2019/05/17)
Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.
Aggregation effects in visible-light flavin photocatalysts: Synthesis, structure, and catalytic activity of 10-arylflavins
Da?ová, Jitka,Kümmel, Susanne,Feldmeier, Christian,Cibulková, Jana,Pa?out, Richard,Maixner, Jaroslav,Gschwind, Ruth M.,K?nig, Burkhard,Cibulka, Radek
supporting information, p. 1066 - 1075 (2013/02/23)
A series of 10-arylflavins (10-phenyl-, 10-(2′,6′- dimethylphenyl)-, 10-(2′,6′-diethylphenyl)-, 10-(2′,6′- diisopropylphenyl)-, 10-(2′-tert-butylphenyl)-, and 10-(2′,6′- dimethylphenyl)-3-methylisoalloxazine (2 a-f)) was prepared as potentially nonaggrega
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 S.,Hitchin, James R.,Hopkins, Gemma V.,Jordan, Allan M.,Maguire, Laura A.,McGonagle, Alison E.,Mould, Daniel P.,Rushbrooke, Mathew,Small, Helen F.,Smith, Kate M.,Thomson, Graeme J.,Turlais, Fabrice,Waddell, Ian D.,Waszkowycz, Bohdan,Watson, Amanda J.,Ogilvie, Donald J.
supporting information, p. 6352 - 6370 (2013/09/23)
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-activity 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.
