N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, 9, Lavrentiev Ave., Novosibirsk, 630090, Russian Federation.
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk, 630090, Russian Federation.
Anticancer Agents Med Chem. 2019;19(4):463-472. doi: 10.2174/1871520619666181207094243.
The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors.
New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling.
13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549.
The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.
DNA 修复酶酪氨酰-DNA-磷酸二酯酶 1（TDP1）是目前提高癌症化疗疗效的抑制靶点。先前的研究表明，结合金刚烷和单萜片段的化合物对 TDP1 酶具有活性。本研究集中于合成 1-金刚烷羧酸的单萜衍生酯作为 TDP1 抑制剂。
通过 1-金刚烷甲酰氯与单萜醇之间的相互作用合成新的酯。测试了这些酯对 TDP1 的抑制作用，并对其与酶的结合进行了建模。
合成了 13 种新型酯基 TDP1 抑制剂，产率为 21-94%；其中 9 种酯以前没有被描述过。发现一些酯抑制 TDP1，IC50 值范围为 0.86-4.08μM。针对 TDP1 晶体结构的分子建模表明，活性酯在催化口袋中具有良好的结合，解释了它们的效力。含有 3,7-二甲基辛醇片段的无毒剂量的酯被发现增强了临床使用的抗癌药物拓扑替康对人肺腺癌细胞系 A549 的细胞毒性作用。
在所研究的浓度范围内，合成的酯对 TDP1 具有活性，这一发现得到了分子建模的证实。同时作用于 3,7-二甲基辛醇-1 和拓扑替康合成的酯显示出协同作用。
