Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
ChemMedChem. 2024 Nov 18;19(22):e202400358. doi: 10.1002/cmdc.202400358. Epub 2024 Sep 21.
The natural and synthetic organodiselenides have garnered much research attention due to their chemotherapeutic and chemopreventive activities. Herein, we describe the synthesis of a series of benzylic diselenides, which were synthesized by coupling the in situ generated disodium diselenide with the corresponding benzylic halides. The diselenides were evaluated for their anticancer activities in the highly aggressive triple-negative breast cancer cells. Preliminary anti-proliferative activities indicated 4-cyano-substituted diselenide 7 to be most potent with an IC value of 1.9±0.3 μM. Detailed mechanistic investigations showed that diselenide 7 induces apoptosis and causes G1 phase arrest of the cell cycle. It exhibits anticancer activity by suppressing the Akt/β-catenin signaling pathway. Further control experiments with LiCl (inhibitor of GSK-3β) revealed that down-regulation of β-catenin was promoted by GSK-3β-induced phosphorylation of β-catenin and its subsequent proteasomal degradation. Moreover, the intracellular ROS was found to act as an upstream mediator for the inactivation of the Akt/β-catenin signaling pathway. The present study describing the efficient anticancer activity of a synthetic benzylic diselenide towards triple-negative breast cancer cells through the modulation of ROS-dependent Akt/β-catenin signaling pathway would certainly be helpful in the future towards the development of small-molecule organoselenium compounds for the treatment of cancer.
由于具有化学治疗和化学预防活性，天然和合成有机二硒化物引起了广泛的研究关注。在此，我们描述了一系列苄基二硒化物的合成，这些二硒化物是通过将原位生成的二硒化钠与相应的苄基卤化物偶联而合成的。评估了二硒化物在高度侵袭性三阴性乳腺癌细胞中的抗癌活性。初步的抗增殖活性表明，具有 4-氰基取代的二硒化物 7 具有最强的活性，IC 值为 1.9±0.3 μM。详细的机制研究表明，二硒化物 7 通过诱导细胞凋亡和引起细胞周期 G1 期阻滞来发挥抗癌作用。它通过抑制 Akt/β-catenin 信号通路发挥抗癌活性。用 LiCl（GSK-3β 的抑制剂）进行的进一步对照实验表明，β-catenin 的下调是由 GSK-3β 诱导的 β-catenin 磷酸化及其随后的蛋白体降解所促进的。此外，还发现细胞内 ROS 作为 Akt/β-catenin 信号通路失活的上游介质。本研究描述了通过调节 ROS 依赖性 Akt/β-catenin 信号通路，一种合成的苄基二硒化物对三阴性乳腺癌细胞具有有效的抗癌活性，这对于未来开发用于癌症治疗的小分子有机硒化合物肯定会有所帮助。
