N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia.
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia.
Bioorg Med Chem Lett. 2022 Oct 1;73:128909. doi: 10.1016/j.bmcl.2022.128909. Epub 2022 Jul 27.
Tyrosyl-DNA phosphodiesterase 1(TDP1) is a promising target for a new therapy in oncological disease as an adjunct to topoisomerase 1 (TOP1) drugs. In this paper, novel thiazolidin-4-one derivatives with a benzyl and monoterpene substituents were synthesized. Compounds with a monoterpene fragment attached via a phenyloxy linker were active against TDP1 with IC values in the 1 ÷ 3 μM range, while direct attachment of monoterpene moiety to the thiazolidin-4-one fragment had no activity. Molecular modelling predicted two plausible binding modes of the active compounds both effectively blocking access to the catalytic site of TDP. At non-toxic concentrations the active ligands potentiated the efficacy of the TOP1 poison topotecan in human cervical cancer HeLa cells, but not in non-cancerous HEK293A cells.
酪氨酸-DNA 磷酸二酯酶 1（TDP1）是肿瘤疾病中一种有前途的新疗法靶标，可作为拓扑异构酶 1（TOP1）药物的辅助药物。在本文中，合成了具有苄基和单萜取代基的新型噻唑烷-4-酮衍生物。通过苯氧基连接子连接单萜片段的化合物对 TDP1 具有活性，IC 值在 1μM 至 3μM 范围内，而将单萜部分直接连接到噻唑烷-4-酮片段上则没有活性。分子建模预测了两种可能的结合模式，这两种结合模式都能有效地阻止 TDP 的催化部位进入。在非毒性浓度下，活性配体增强了 TOP1 毒药拓扑替康在人宫颈癌 HeLa 细胞中的疗效，但在非癌细胞 HEK293A 细胞中没有作用。
