Shaaban Saad, Alabdali Aya Yaseen Mahmood, Mousa Mai H A, Ba-Ghazal Hussein, Al-Faiyz Yasair S, Elghamry Ibrahim, Althikrallah Hanan A, Khatib Arwa Omar Al, Alaasar Mohamed, Al-Karmalawy Ahmed A
Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Mashreq, Baghdad, Iraq.
Drug Dev Res. 2025 Apr;86(2):e70075. doi: 10.1002/ddr.70075.
Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids (5-19) via modifications of the lead, N-(4-selaneylphenyl)-2-selaneylacetamide. The OSe-based thiazol 9 showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered N-chloroacetamide 5 and Schiff base 19 showed a cytotoxic effect with an IC of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme-linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds 5 and 19 in the A549 cancer cells both showed promising inhibitory activities with IC values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds 5 and 19 showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds 5 and 19 described the downregulation of the examined inflammatory proteins: COX2, IL-6, and IL-1β. In addition, OSe compound 19 showed potential cell cycle arrest at the G0, S, and G2-M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound 19 showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.
在此，我们报告了通过对先导化合物N-(4-硒基苯基)-2-硒基乙酰胺进行修饰而设计、合成和表征的新型有机硒（OSe）杂化物（5-19）。相对于阳性对照多柔比星（DOX），基于OSe的噻唑9显示出最高的生长抑制率（GI%），为64.72%，而DOX的GI%为79.5%。此外，与所使用的正常细胞系相比，新型OSe衍生物显示出较低的GI%值，证明了它们的选择性。与OSe相连的N-氯乙酰胺5和席夫碱19对A549肿瘤细胞系分别具有细胞毒性作用，IC值分别为（25.07和11.61 μM），对HELA癌细胞系的IC值分别为（34.22和20.12 μM）。通过酶联免疫吸附测定法研究OSe化合物5和19在A549癌细胞中对JAK1和STAT3的抑制潜力，结果均显示出有前景的抑制活性，IC值分别为25.07和11.61 μM。对A549癌细胞系中OSe化合物5和19的蛋白质表达分析显示，凋亡蛋白P53、BAX以及半胱天冬酶3、6、8和9上调。然而，这两种化合物均使抗凋亡蛋白（BCL2、MMP2和MMP9）下调。此外，OSe化合物5和19使所检测的炎症蛋白COX2、IL-6和IL-1β下调。另外，OSe化合物19显示出在G0、S和G2-M期的潜在细胞周期阻滞，且细胞水平增加。最后，OSe化合物19的分子对接研究显示其对JAK1和STAT3靶受体具有最有前景的抑制潜力，结合分数和相互作用超过了JAK1共结晶抑制剂。
