Amidothiazole derivatives of (+)-usnic acid effectively inhibit TDP1 and sensitize tumor cells to the effects of topotecan

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Abstract

The DNA repair enzyme tyrosyl-DNA phosphodiesterase-1 (TDP1) removes various adducts from the 3’-end of DNA, including those induced by anticancer chemotherapeutics, and as therefore considered an important therapeutic target. Previously we investigated TDP1 inhibitors as sensitizers for the anticancer drug topotecan. Now, we have demonstrated that usnic acid derivatives containing a thiazole ring with an amide linker exhibited inhibitory activity against TDP1 at micromolar and submicromolar concentrations. Moreover, the lead compound OL11-119, (R)-N-[4-(8-acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-yl)thiazol-2-yl]-4-bromobenzamide, was found to enhance topotecan-induced tumor cell death at a non-toxic concentration. Molecular docking of OL11-119 and its analog with hydrazone linker, OL9-119, a previously identified potent TDP1 inhibitor, was performed. The binding energy of OL9-119 to the enzyme active site was shown to be lower than that of OL11-119, which correlated with the higher inhibitory activity of OL9-119 against TDP1.

About the authors

A. A. Chepanova

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences; Federal Research Center Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia; Novosibirsk, 630090 Russia

A. L. Zakharenko

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

N. S. Dyrkheeva

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

I. A. Chernyshova

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences; Federal Research Center Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia; Novosibirsk, 630090 Russia

A. S. Filimonov

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

O. A. Luzina

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

M. S. Kupryushkin

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

S. A. Zhukov

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

A. V. Tsukanov

Federal Research Center Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

N. F. Salakhutdinov

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences

Novosibirsk, 630090 Russia

O. I. Lavrik

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences

Email: lavrik@niboch.nsc.ru
Novosibirsk, 630090 Russia

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