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 the Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Molecules. 2022 May 24;27(11):3374. doi: 10.3390/molecules27113374.
Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane-monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (-)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives - and - showed activity against TDP1 at a low micromolar range with IC ~5-6 μM, whereas camphor-containing compounds and were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.
抑制酪氨酰-DNA 磷酸二酯酶 1（TDP1）是提高现有抗肿瘤疗法效果的一种有前途的策略，因为它可以去除抗癌药物与拓扑异构酶 1（TOP1）形成的共价复合物引起的 DNA 损伤。在这里，合成了具有 1,2,4-三唑或 1,3,4-噻二唑连接子核心的新型金刚烷-单萜缀合物，其中（+）-和（-）-莰烯和（+）-樟脑衍生物用作单萜片段。莰烯衍生物 - 和 - 在低微摩尔范围内对 TDP1 表现出活性，IC~5-6 μM，而含樟脑的化合物 和 则无效。令人惊讶的是，所有合成的化合物都与拓扑替康（一种 TOP1 抑制剂）表现出明显的协同作用，无论它们抑制 TDP1 的能力如何。这些发现表明，除了抑制 TDP1 之外，还可以实现增强拓扑替康毒性的不同途径。
