84459-35-8Relevant academic research and scientific papers
5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2
Dickens, Michael P.,Roxburgh, Patricia,Hock, Andreas,Mezna, Mokdad,Kellam, Barrie,Vousden, Karen H.,Fischer, Peter M.
supporting information, p. 6868 - 6877 (2013/11/06)
Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.
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.
, 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.
A New, General, and Convenient Synthesis of 5-Deazaflavins (5-Deazaisoalloxazines) and Bis-(5-deazaflavin-10-yl)alkanes
Nagamatsu, Tomohisa,Hashiguchi, Yuko,Yoneda, Fumio
, p. 561 - 565 (2007/10/02)
The condensation of 6-substituted aminouracils or bis(uracil-6-amino)alkanes with o-halogenobenzaldehydes in dimethylformamide led to the formation of the corresponding 5-deazaflavins or bid(5-deazaflavin-10-yl)alkanes in a single step.
A New, General, and Convenient Synthesis of 5-Deazaflavins (5-Deazaisoallooxazines)
Nagamatsu, Tomohisa,Hashigushi, Yuko,Higuchi, Masatsugu,Yoneda, Fumio
, p. 1085 - 1086 (2007/10/02)
The condensation of 6-substituted-aminouracils with o-halogenobenzaldehydes in dimethylformamide led to the formation of the corresponding 5-deazaflavins in a single step.
