76902-97-1Relevant academic research and scientific papers
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.
Synthesis of 10-Arylpyrimidoquinoline-2,4(3H,10H)diones (10-Aryl-5-deazaflavins) and Their Use in Oxidations of Alcohols and Amines
Yoneda, Fumio,Tsukuda, Kinshiro,Shinozuka, Kazuo,Hirayama, Fumitoshi,Uekama, Kaneto,Koshiro, Akira
, p. 3049 - 3056 (2007/10/02)
Treatment of aryl-bis(6-anilino-3-methyluracil-5-yl)methanes, which were prepared by the condensation of 6-anilino-3-methyluracils with arylaldehydes, with diethyl azodicarboxylate (DAD) in the presence of sulfolane led to the formation of the corresponding 10-arylpyrimidoquinoline-2,4(3H,10H)-diones (10-aryl-5-deazaflavins).Heating of the methanes alone in sulfolane without DAD gave the corresponding 5-aryl-5-deazaalloxazines.The oxidizing abilities of the 10-aryl-5-deazaflavins thus obtained were examined from both kinetic and synthetic viewpoints.The oxidations of benzyl alcohol and benzylamine by these 5-deazaflavins have been shown to recycle automatically, and more than 100percent yield of benzaldehyde (based on the 5-deazaflavins) was obtained.Keywords - pyrimidoquinoline; 5-deazaflavin; alcohol oxidation; amine oxidation; diethyl azodicarboxylate; aryl-bis(6-anilinouracil-5-yl)methane; 5-deazaalloxazine; turn-over catalyst; biomimetic axidation.
