89525-47-3Relevant academic research and scientific papers
Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents
Zhang, Xiao-Ru,Wang, Hao-Wen,Tang, Wen-Lin,Zhang, Yu,Yang, Hui,Hu, De-Xuan,Ravji, Azhar,Marchand, Christophe,Kiselev, Evgeny,Ofori-Atta, Kwabena,Agama, Keli,Pommier, Yves,An, Lin-Kun
, p. 9908 - 9930 (2018)
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)-DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC50 value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future efforts for the discovery of natural product-based TOP1 and TDP1 inhibitors.
OXYNITIDINE DERIVATIVES USEFUL AS INHIBITORS OF TOPOISOMERASE IB (Top1) AND TYROSYL-DNA PHOSPHODIESTERASE 1 (Tdp1)
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Paragraph 0143-0144; 0146-0147; 0149; 0195-0196, (2020/02/16)
Compounds and pharmaceutically acceptable salts thereof of Formula I are disclosed. Certain compounds and salts of Formula I are active as Topl and / or Tdpl inhibitors. The disclosure provides pharmaceutical compositions containing a compound of Formula I as the only active agent, or optionally containing one or more additional active agents. Methods of using compounds of Formula I to treat cancer are provided in this disclosure. The disclosed compounds of Formula I may be used alone to treat cancer, but may also be used in combination with another active agent, such as a Topl inhibitor, for example, camptothecin or a camptothecin analogue.
