Open AccessDiscovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents
Author(s) -
Xiaoru Zhang,
Haowen Wang,
Wen-Lin Tang,
Yu Zhang,
Hui Yang,
De-Xuan Hu,
Azhar Ravji,
Christophe Marchand,
Evgeny Kiselev,
Kwabena Ofori-Atta,
Keli Agama,
Yves Pommier,
LinKun An
Publication year - 2018
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b00639
Subject(s) - topoisomerase , chemistry , camptothecin , cytotoxicity , dna , phosphodiesterase , dna damage , natural product , in vivo , ic50 , doxorubicin , enzyme , biochemistry , in vitro , biology , genetics , microbiology and biotechnology , chemotherapy
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 IC 50 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.