Abstract:
:Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top 1) cleavage complexes and other 3'-end DNA lesions. Tdp1 is a promising target for anticancer therapy, since it can repair DNA lesions caused by Top1 inhibitors leading to drug resistance. Hence, Tdp1 inhibition should result in synergistic effect with Top1 inhibitors. Twenty nine derivatives of (+)-usnic acid were tested for in vitro Tdp1 inhibitory activity using a fluorescent-based assay. Excellent activity was obtained, with derivative 6m demonstrating the lowest IC50 value of 25 nM. The established efficacy was verified using a gel-based assay, which gave close results to that of the fluorescent assay. In addition, molecular modeling in the Tdp1 substrate binding pocket suggested plausible binding modes for the active analogues. The synergistic effect of the Tdp1 inhibitors with topotecan, a Top1 poison in clinical use, was tested in two human cell lines, A-549 and HEK-293. Compounds 6k and 6x gave very promising results. In particular, 6x has a low cytotoxicity and an IC50 value of 63 nM, making it a valuable lead compound for the development of potent Tdp1 inhibitors for clinical use.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Zakharova O,Luzina O,Zakharenko A,Sokolov D,Filimonov A,Dyrkheeva N,Chepanova A,Ilina E,Ilyina A,Klabenkova K,Chelobanov B,Stetsenko D,Zafar A,Eurtivong C,Reynisson J,Volcho K,Salakhutdinov N,Lavrik Odoi
10.1016/j.bmc.2018.07.039subject
Has Abstractpub_date
2018-08-15 00:00:00pages
4470-4480issue
15eissn
0968-0896issn
1464-3391pii
S0968-0896(18)30657-6journal_volume
26pub_type
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