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New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors.

Reynisson, Johannes

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Abstract

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.

Citation

Reynisson, J. (2019). New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors. Molecules, https://doi.org/10.3390/molecules24203711

Acceptance Date Oct 12, 2019
Publication Date Oct 15, 2019
Journal Molecules
Publisher MDPI
DOI https://doi.org/10.3390/molecules24203711
Keywords inhibiting activity, molecular modeling, synergetic effect, topoisomerase 1, topotecan, tyrosyl-DNA phosphodiesterase 1 (Tdp1), usnic acid
Publisher URL http://doi.org/10.3390/molecules24203711

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