Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya Sq., 394018 Voronezh, Russia.
Molecules. 2022 Jun 23;27(13):4033. doi: 10.3390/molecules27134033.
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.
本研究代表了一组新型 4,5-二氢-4,4-二甲基-1H-[1,2]二噻咯[3,4-c]喹啉-1-硫酮的混合和嵌合衍生物的设计和合成，其结构中环丙基片段线性连接或/和与另一个杂环片段缩合。使用 PASS Online 软件，在以前合成的和新的 1,2-二噻咯[3,4-c]喹啉-1-硫酮衍生物中，我们确定了 12 种具有多种活性的物质，包括化学保护和抗肿瘤活性。所有合成的衍生物都进行了抑制评估，以检测它们对多种激酶的抑制作用。在细胞中表现出突出抑制百分比的化合物（>85%）也通过 ELISA 利用索拉非尼作为参考标准来检测它们对人类激酶的抑制效率，以估计它们的 IC50 值。结果表明，化合物 2a、2b、2c 和 2q 对 JAK3 表现出显著的抑制作用（IC50=0.36μM、0.38μM、0.41μM 和 0.46μM）；此外，化合物 2a 和 2b 对 NPM1-ALK 表现出优异的活性（IC50=0.54μM、0.25μM），对 cRAF[Y340D][Y341D]，化合物 2c 表现出优异的活性，化合物 2q 表现出较弱的活性（IC50=0.78μM、5.34μM）（索拉非尼 IC50=0.78μM、0.43μM、1.95μM）。因此，为未来治疗癌症和其他多因素疾病的药物研发找到了新的有前景的首选结构。
