Shaaban Saad, Hammouda Mohamed M, Althikrallah Hanan A, Al Nawah Jawaher Y, Ba-Ghazal Hussein, Sharaky Marwa, Abulkhair Hamada S, Al-Karmalawy Ahmed A
Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, 31982, Saudi Arabia.
Department of Chemistry, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt.
Curr Med Chem. 2024 Aug 12. doi: 10.2174/0109298673319340240809104237.
Organoselenium (OSe) agents and Schiff bases have demonstrated immense potential in the pharmaceutical field due to their broad spectrum of medicinal activities.
We herein report the antitumor activities of bis diselenide-based Schiff bases (3a-3c) derived from bis(4-aminophenyl)diselenide 2 and organoselenide-based Schiff bases (5a-c) derived from p-(methylselanyl)phenyl amine (4). The antitumor activity was estimated against fifteen cancer cell lines. Also, the growth inhibition percentage (GI%) of the Schiff bases tethered OSe compounds was evaluated against two normal cell lines, namely, human skin fibroblasts (HSF) and olfactory ensheathing cell line (OEC), to estimate the potential safety and selectivity. Furthermore, the cytotoxic inhibitory concentration 50 (IC50) was assessed against the cancer cell lines with the most outstanding GI% using the SRB assay.
Compounds 3a, 3b, 3c, and 5a showed the lowest IC50 values compared to those of doxorubicin (DOX) against HCT116, HEPG2, A549, MDA-MB-468, and FaDu cancer cell lines, respectively, especially against the HCT116 subtype, assuring their potential anticancer activity. On the other side, the apoptotic potentials of the most active compounds (3a, 3b, 3c, and 5a) were also evaluated for apoptosis-related genes (P53, BAX, caspases 3, 6, 8, and 9, MMP2, MMP9, and BCL-2). Interestingly, compounds 3a, 3b, 3c, and 5a upregulated P53, BAX, and caspases 3, 6, 8, and 9 by (2.66, 2.26, 2.44, and 2.57)-, (1.62, 1.52, 1.37, and 1.47)-, (1.87, 1.75, 2.02, and 1.75)-, (1.96, 1.74, 2.06, and 2.30)-, (4.25, 3.78, 3.53, and 3.96)-, and (2.04, 1.72, 1.90, and 1.63)-fold change, respectively. Furthermore, MMP2, MMP9, and BCL-2 were downregulated by (0.39, 0.51, 0.33, and 0.28)-, (0.29, 0.32, 0.37, and 0.41)-, and (0.42, 0.35, 0.29, and 0.38)-fold-change, upon treatment with compounds 3a, 3b, 3c, and 5a, respectively, assuring the apoptotic potentials. Finally, molecular docking also greatly recommends the potential activity of the examined candidates (especially 3a and 3c) against the GSTP1 receptor as a recommended mechanism for their antitumor activity.
Our findings point to significant anticancer activities of Schiff bases tethered OSe agents, suggesting their promising potential for development as effective anticancer drugs.
有机硒（OSe）试剂和席夫碱由于其广泛的药用活性，在制药领域已显示出巨大潜力。
我们在此报告了源自双（4-氨基苯基）二硒化物2的双二硒化物基席夫碱（3a - 3c）和源自对（甲基硒基）苯胺（4）的有机硒基席夫碱（5a - c）的抗肿瘤活性。针对15种癌细胞系评估了其抗肿瘤活性。此外，针对两种正常细胞系，即人皮肤成纤维细胞（HSF）和嗅鞘细胞系（OEC），评估了连接有席夫碱的OSe化合物的生长抑制率（GI%），以估计其潜在的安全性和选择性。此外，使用SRB测定法针对GI%最显著的癌细胞系评估了细胞毒性抑制浓度50（IC50）。
与阿霉素（DOX）相比，化合物3a、3b、3c和5a分别在HCT116、HEPG2、A549、MDA - MB - 468和FaDu癌细胞系中显示出最低的IC50值，尤其是针对HCT116亚型，确保了它们潜在的抗癌活性。另一方面，还针对凋亡相关基因（P53、BAX、半胱天冬酶3、6、8和9、MMP2、MMP9和BCL - 2）评估了最具活性的化合物（3a、3b、3c和5a）的凋亡潜力。有趣的是，化合物3a、3b、3c和5a分别使P53、BAX以及半胱天冬酶3、6、8和9上调了（2.66、2.26、2.44和2.57）倍、（1.62、1.52、1.37和1.47）倍、（1.87、1.75、2.02和1.75）倍、（1.96、1.74、2.06和2.30）倍以及（4.25、3.78、3.53和3.96）倍、（2.04、1.72、1.90和1.63）倍变化。此外，在用化合物3a、3b、3c和5a处理后，MMP2、MMP9和BCL - 2分别下调了（下转）（0.39、0.51、0.33和0.28）倍、（0.29、0.32、0.37和0.41）倍以及（0.42、0.35、0.29和0.38）倍变化，确保了其凋亡潜力。最后，分子对接也强烈表明所检测的候选物（尤其是3a和3c）针对GSTP1受体具有潜在活性，这是它们抗肿瘤活性的一种推荐机制。
我们的研究结果表明连接有席夫碱的OSe试剂具有显著的抗癌活性，表明它们作为有效的抗癌药物具有广阔的开发潜力。
