Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors.,Molecular Diversity

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Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors.
Molecular Diversity ( IF 3.9 ) Pub Date : 2020-08-24 , DOI: 10.1007/s11030-020-10132-z
Kseniya Kovaleva _{1,

2} , Evgeniya Mamontova ₃ , Olga Yarovaya _{1,

2} , Olga Zakharova ₃ , Alexandra Zakharenko _{2,

3} , Olga Lavrik _{2,

3} , Nariman Salakhutdinov _{1,

2}

Affiliation

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in medicinal chemistry for the creation of cancer adjuvant therapy. Inhibition of this enzyme together with the use of anticancer chemotherapy enhances the effect of the latter. The natural mutant of TDP1, TDP1(H493R), causes severe neurodegenerative disease spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). Inhibition of TDP1(H493R) appears to be useful in containment the progression of the disease. A library of compounds was synthesized starting from dehydroabietylamine including heterocyclic pharmacophore groups in the core. To obtain the desired products, the starting dehydroabietylamine was introduced sequentially in reaction with isothiocyanate and ethyl bromoacetate. Different classes of heterocyclic derivatives—2-iminothiazolidin-4-ons and 2-thioxoimidazolidin-4-ones—were obtained depending on the addition order of reagents. 2-Iminothiazolidin-4-thiones were obtained from 2-iminothiazolidin-4-ones under the action of the Lawesson’s reagent. Effective TDP1 inhibitors were found among the obtained compounds that work in submicromolar concentrations. The inhibitor of TDP1(H493R) was also detected.

Graphic abstract

中文翻译：

基于脱氢枞胺的 thiazolidin-4-ones 和 2-thioimidazolidin-4-ones 作为新型酪氨酰 DNA 磷酸二酯酶 1 抑制剂。

抽象的

酪氨酰-DNA 磷酸二酯酶 1 (TDP1) 是一种 DNA 修复酶，在修复各种抗肿瘤药物造成的损伤中发挥着关键作用。它是药物化学领域用于创建癌症辅助疗法的一个有前途的目标。抑制这种酶与抗癌化疗的使用一起增强了后者的效果。 TDP1 的天然突变体 TDP1(H493R) 可导致严重的神经退行性疾病脊髓小脑共济失调综合征伴轴突神经病 (SCAN1)。抑制 TDP1(H493R) 似乎有助于遏制疾病的进展。从脱氢枞胺开始合成化合物库，其中核心包含杂环药效基团。为了获得所需产物，依次引入起始脱氢枞胺，使其与异硫氰酸酯和溴乙酸乙酯反应。根据试剂的添加顺序，获得了不同类别的杂环衍生物——2-亚氨基噻唑烷-4-酮和2-硫代咪唑烷-4-酮。 2-亚氨基噻唑烷-4-硫酮是由2-亚氨基噻唑烷-4-酮在Lawesson试剂作用下得到的。在所获得的化合物中发现了有效的 TDP1 抑制剂，其在亚微摩尔浓度下发挥作用。还检测到TDP1(H493R)抑制剂。

图文摘要

更新日期：2020-08-24

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