<br>4,5-二氢-1H-[1,2]二硫并[3,4-c]喹啉-1-硫酮衍生物的合成及其作为蛋白激酶抑制剂的应用,Molecules

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4,5-二氢-1H-[1,2]二硫并[3,4-c]喹啉-1-硫酮衍生物的合成及其作为蛋白激酶抑制剂的应用
Molecules ( IF 4.2 ) Pub Date : 2022-06-23 , DOI: 10.3390/molecules27134033
Svetlana M Medvedeva ₁ , Khidmet S Shikhaliev ₁

Affiliation

这项研究代表了一组新的 4,5-二氢-4,4-二甲基-1 H -[1,2]二硫醇[3,4- c ]喹啉-1-硫酮的杂化和嵌合衍生物的设计和合成，其中三环片段与另一个杂环片段线性结合或/和缩合的结构。使用 PASS Online 软件，在 1,2-二硫并[3,4- c ]喹啉-1-硫酮的先前合成和新衍生物中，我们鉴定了 12 种具有多效活性的物质，包括化学保护和抗肿瘤活性。所有合成的衍生物都经过筛选，以评估其对多种激酶的抑制作用。还通过ELISA检查了在细胞中表现出显着抑制百分比(>85%)的化合物对人激酶的抑制效率，使用索拉非尼作为参考标准来估计其IC ₅₀值。结果表明，化合物2a 、 2b 、 2c和2q对JAK3具有显着的抑制作用（IC ₅₀分别为0.36 μM、0.38 μM、0.41 μM和0.46 μM）。此外，化合物2a和2b对NPM1-ALK表现出优异的活性（IC ₅₀分别为0.54 μM、0.25 μM），对cRAF[Y340D][Y341D]表现出优异的活性，化合物2c表现出优异的活性，化合物2q表现出弱活性（IC ₅₀ = 0.78 μM、5.34 μM（分别）（索拉非尼 IC ₅₀分别 = 0.78 μM、0.43 μM、1.95 μM）。因此，已经发现了新的有希望的优选结构，用于在未来创造治疗癌症和其他多因素疾病的药物。

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Synthesis of 4,5-Dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors

This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-c]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC₅₀ values. It was revealed that compounds 2a, 2b, 2c, and 2q displayed a significant inhibition JAK3 (IC₅₀ = 0.36 μM, 0.38 μM, 0.41 μM, and 0.46 μM, respectively); moreover, compounds 2a and 2b displayed excellent activities against NPM1-ALK (IC₅₀ = 0.54 μM, 0.25 μM, respectively), against cRAF[Y340D][Y341D], compound 2c showed excellent activity, and compound 2q showed weak activity (IC₅₀ = 0.78 μM, 5.34 μM, respectively) (sorafenib IC₅₀ = 0.78 μM, 0.43 μM, 1.95 μM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found.

更新日期：2022-06-23

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