N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia.
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., 630090 Novosibirsk, Russia.
Molecules. 2021 May 24;26(11):3128. doi: 10.3390/molecules26113128.
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC values in the 0.35-0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative , α-pinene-derived compounds , and and the citronellic acid derivative were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.
酪氨酸-DNA 磷酸二酯酶 1（Tdp1）是一种很有前途的抗癌治疗靶点，因为它能够抵消拓扑异构酶 1（Top1）毒剂（如拓扑替康）的作用，从而降低其疗效。我们合成了含有金刚烷和单萜残基的化合物，通过 1,2,4-三唑或 1,3,4-噻二唑连接子连接，并对 Tdp1 进行了测试。所有衍生物在低微摩尔或纳摩尔浓度下表现出抑制作用，最有效的抑制剂的 IC 值在 0.35-0.57 µM 范围内。在 HeLa、HCT-116 和 SW837 癌细胞系中测定了细胞毒性；从中等 CC（µM）值到 100 µM 时无影响。此外，柠檬醛衍生物 、α-蒎烯衍生化合物 、 和 以及香茅酸衍生物 与拓扑替康联合使用时，在 HeLa 宫颈癌和结肠腺癌 HCT-116 细胞系中表现出增敏作用。这些配体被预测与 Tdp1 的催化口袋结合，并具有有利的物理化学性质，可进一步开发为与 Top1 毒剂联合的潜在辅助治疗方法。
