Kovaleva Kseniya, Yarovaya Olga, Ponomarev Konstantin, Cheresiz Sergey, Azimirad Amirhossein, Chernyshova Irina, Zakharenko Alexandra, Konev Vasily, Khlebnikova Tatiana, Mozhaytsev Evgenii, Suslov Evgenii, Nilov Dmitry, Švedas Vytas, Pokrovsky Andrey, Lavrik Olga, Salakhutdinov Nariman
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia.
V. Zelman Institute for the Medicine and Psychology, Novosibirsk State University, Pirogova St. 1, 630090 Novosibirsk, Russia.
Pharmaceuticals (Basel). 2021 May 1;14(5):422. doi: 10.3390/ph14050422.
In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19-2.3 µM) and demonstrated low cytotoxicity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.
本文设计、合成了一系列带有金刚烷部分的新型枞酰基和脱氢枞酰基脲、硫脲、酰胺及硫代酰胺，并对其酪氨酸-DNA-磷酸二酯酶1（TDP1）抑制活性进行了评估。合成的化合物能够在微摩尔浓度（0.19 - 2.3 μM）下抑制TDP1，并在T98G胶质瘤细胞系中表现出低细胞毒性。研究了萜烯片段、连接结构和金刚烷残基对新化合物生物学性质的影响。基于分子对接结果，我们推测树脂酸的金刚烷衍生物与TDP1共价中间体结合，与Ser463形成氢键，并与Phe259、Trp590残基以及底物的寡核苷酸片段形成疏水相互作用。
