Filimonov, AS, Chepanova, AA, Luzina, OA, Zakharenko, AL, Zakharova, OD, Ilina, ES, Dyrkheeva, NS, Kuprushkin, MS, Kolotaev, AV, Khachatryan, DS, Patel, J, Leung, IKH, Chand, R, Ayine-Tora, DM, Reynisson, J, Volcho, KP, Salakhutdinov, NF and Lavrik, OI (2019) New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors. Molecules, 24 (20). ISSN 1420-3049

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and evaluated as Tdp1 inhibitors. Most of these compounds were found to be potent inhibitors with IC50 values in the low nanomolar range. The activity of the compounds was verified by binding experiments and supported by molecular modeling. The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was also demonstrated. The order of administration of the inhibitor and topotecan on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitor with topotecan is the most effective.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via MPDI at - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: inhibiting activity, molecular modeling, synergetic effect, topoisomerase 1, topotecan, tyrosyl-DNA phosphodiesterase 1 (Tdp1), usnic acid
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy
Related URLs:
Depositing User: Symplectic
Date Deposited: 09 Dec 2019 12:49
Last Modified: 03 Mar 2021 10:34

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