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Tyrosyl-DNA Phosphodiesterase 1 Inhibitors: Usnic Acid Enamines Enhance the Cytotoxic Effect of Camptothecin
- Zakharenko, Alexandra, Luzina, Olga, Koval, Olga, Nilov, Dmitry, Gushchina, Irina, Dyrkheeva, Nadezhda, Švedas, Vytas, Salakhutdinov, Nariman, Lavrik, Olga
- Journal of natural products 2016 v.79 no.11 pp. 2961-2967
- DNA, DNA damage, DNA topoisomerase, cytotoxicity, humans, inhibitory concentration 50, therapeutics, usnic acid
- Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top1) cleavage complexes and other 3′-end DNA lesions. TDP1 is a perspective target for anticancer therapy based on Top1-poison-mediated DNA damage. Several novel usnic acid derivatives with an enamine moiety have been synthesized and tested as inhibitors of TDP1. The enamines of usnic acid showed IC₅₀ values in the range of 0.16 to 2.0 μM. These compounds revealed moderate cytotoxicity against human tumor MCF-7 cells. These new compounds enhanced the cytotoxicity of the established Top1 poison camptothecin by an order of magnitude.