Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors

Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors Full article

Journal

Bioorganic and Medicinal Chemistry
ISSN: 0968-0896 , E-ISSN: 1464-3391

Output data

Year: 2018, Volume: 26, Number: 15, Pages: 4470-4480 Pages count : 11 DOI: 10.1016/j.bmc.2018.07.039

Authors

Zakharova Olga ¹ , Luzina Olga ² , Zakharenko Alexandra ¹ , Sokolov Dmitry ² , Filimonov Alexandr ^2,3 , Dyrkheeva Nadezhda ¹ , Chepanova Arina ¹ , Ilina Ekaterina ¹ , Ilyina Anna ³ , Klabenkova Kristina ³ , Chelobanov Boris ^1,3 , Stetsenko Dmitry ¹ , Zafar Ayesha ⁴ , Eurtivong Chatchakorn ⁴ , Reynisson Johannes ⁴ , Volcho Konstantin ^2,3 , Salakhutdinov Nariman ^2,3 , Lavrik Olga ^1,3

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, Novosibirsk Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, Novosibirsk 630090, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland, New Zealand

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 IC(50 )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 HEK293. Compounds 6k and 6x gave very promising results. In particular, 6x has a low cytotoxicity and an IC (50) value of 63 nM, making it a valuable lead compound for the development of potent Tdp1 inhibitors for clinical use.

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 O.
Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors
Bioorganic and Medicinal Chemistry. 2018. V.26. N15. P.4470-4480. DOI: 10.1016/j.bmc.2018.07.039 WOS Scopus РИНЦ

Published print:

Aug 1, 2018

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