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

Standard

Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors. / Zakharova, Olga; Luzina, Olga; Zakharenko, Alexandra et al.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 15, 15.08.2018, p. 4470-4480.

Research output: Contribution to journal › Article › peer-review

Harvard

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 2018, 'Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors', Bioorganic and Medicinal Chemistry, vol. 26, no. 15, pp. 4470-4480. https://doi.org/10.1016/j.bmc.2018.07.039

APA

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. (2018). Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors. Bioorganic and Medicinal Chemistry, 26(15), 4470-4480. https://doi.org/10.1016/j.bmc.2018.07.039

Vancouver

Zakharova O, Luzina O, Zakharenko A, Sokolov D, Filimonov A, Dyrkheeva N et al. Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors. Bioorganic and Medicinal Chemistry. 2018 Aug 15;26(15):4470-4480. doi: 10.1016/j.bmc.2018.07.039

Author

Zakharova, Olga ; Luzina, Olga ; Zakharenko, Alexandra et al. / Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 15. pp. 4470-4480.

BibTeX

@article{63ece38f88c349cc83b109ae03347f39,

title = "Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors",

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.",

keywords = "TYROSYL-DNA PHOSPHODIESTERASE, EMPIRICAL SCORING FUNCTIONS, PHASE PEPTIDE-SYNTHESIS, PROTEIN-LIGAND DOCKING, BIOLOGICAL EVALUATION, NATURAL-PRODUCTS, DATA-BANK, I TDP1, ANTICANCER, ALCOHOL, Allosteric Regulation, Humans, Substrate Specificity, Structure-Activity Relationship, Cell Survival/drug effects, HEK293 Cells, Binding Sites, Furans/chemistry, Protein Structure, Tertiary, Recombinant Proteins/biosynthesis, Benzofurans/chemical synthesis, Phosphodiesterase Inhibitors/chemical synthesis, Antineoplastic Agents/chemical synthesis, DNA/chemistry, Phosphoric Diester Hydrolases/chemistry, Molecular Docking Simulation",

author = "Olga Zakharova and Olga Luzina and Alexandra Zakharenko and Dmitry Sokolov and Alexandr Filimonov and Nadezhda Dyrkheeva and Arina Chepanova and Ekaterina Ilina and Anna Ilyina and Kristina Klabenkova and Boris Chelobanov and Dmitry Stetsenko and Ayesha Zafar and Chatchakorn Eurtivong and J{\'o}hannes Reynisson and Konstantin Volcho and Nariman Salakhutdinov and Olga Lavrik",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = aug,

day = "15",

doi = "10.1016/j.bmc.2018.07.039",

language = "English",

volume = "26",

pages = "4470--4480",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd",

number = "15",

}

RIS

TY - JOUR

T1 - Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors

AU - Zakharova, Olga

AU - Luzina, Olga

AU - Zakharenko, Alexandra

AU - Sokolov, Dmitry

AU - Filimonov, Alexandr

AU - Dyrkheeva, Nadezhda

AU - Chepanova, Arina

AU - Ilina, Ekaterina

AU - Ilyina, Anna

AU - Klabenkova, Kristina

AU - Chelobanov, Boris

AU - Stetsenko, Dmitry

AU - Zafar, Ayesha

AU - Eurtivong, Chatchakorn

AU - Reynisson, Jóhannes

AU - Volcho, Konstantin

AU - Salakhutdinov, Nariman

AU - Lavrik, Olga

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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.

AB - 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.

KW - TYROSYL-DNA PHOSPHODIESTERASE

KW - EMPIRICAL SCORING FUNCTIONS

KW - PHASE PEPTIDE-SYNTHESIS

KW - PROTEIN-LIGAND DOCKING

KW - BIOLOGICAL EVALUATION

KW - NATURAL-PRODUCTS

KW - DATA-BANK

KW - I TDP1

KW - ANTICANCER

KW - ALCOHOL

KW - Allosteric Regulation

KW - Humans

KW - Substrate Specificity

KW - Structure-Activity Relationship

KW - Cell Survival/drug effects

KW - HEK293 Cells

KW - Binding Sites

KW - Furans/chemistry

KW - Protein Structure, Tertiary

KW - Recombinant Proteins/biosynthesis

KW - Benzofurans/chemical synthesis

KW - Phosphodiesterase Inhibitors/chemical synthesis

KW - Antineoplastic Agents/chemical synthesis

KW - DNA/chemistry

KW - Phosphoric Diester Hydrolases/chemistry

KW - Molecular Docking Simulation

UR - http://www.scopus.com/inward/record.url?scp=85050693421&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2018.07.039

DO - 10.1016/j.bmc.2018.07.039

M3 - Article

C2 - 30076000

AN - SCOPUS:85050693421

VL - 26

SP - 4470

EP - 4480

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 15

ER -

ID: 15945279