В журнале Archiv der Pharmazie – Chemistry in Life Sciences (IF 4,3) по результатам работы, выполненной совместно с коллегами из Института химической биологии и фундаментальной медицины СО РАН, опубликована статья, соавторами которой являются сотрудники Института к.х.н. К.С. Ковалева (снс ЛФАВ), д.х.н. О.И. Яровая (внс ЛФАВ), д.х.н., проф., чл.-корр РАН, зав отдеом ОМХ Н.Ф. Салахутдинов, д.х.н. Ю.В. Гатилов (внс ГРСА), к.х.н. А.В. Ластовка (снс ЛМА).
Design, synthesis, and evaluation of dehydroabietyl imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones as TDP1 inhibitors and dual TDP1/TDP2 inhibitors
Kseniya S. Kovaleva, Olga I. Yarovaya, Yuriy V. Gatilov, Anastasiya V. Lastovka, Irina A. Chernyshova, Nadezhda S. Dyrkheeva, Arina A. Chepanova, Olga I. Lavrik, Nariman F. Salakhutdinov
Archiv der Pharmazie,
Volume358, Issue1 January 2025 e2400801
Published: 13 Jan 202
Abstract
Tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes involved in the repair of DNA, are regarded as promising targets for the development of new anticancer drugs. In this study, a series of imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones based on dehydroabietylamine (DHAAm) were synthesized. The inhibitory activity of the new compounds against TDP1 and TDP2, as well as their cytotoxic characteristics, were evaluated. All types of heterocyclic DHAAm derivatives demonstrated effective inhibition of TDP1 in the micromolar range, with IC50 values in the range of 0.63–4.95 µM. It was observed that only the 2-thioxoimidazolidine-4,5-diones were TDP2 inhibitors, representing the first class of dual TDP1/TDP2 inhibitors among DHAAm derivatives. The findings of this study may contribute to an enhanced comprehension of the subsequent design of novel dual TDP1/TDP2 inhibitors for the further development of new antitumor agents.
