Shaldam Moataz A, Mousa Mai H A, Tawfik Haytham O, El-Dessouki Ahmed M, Sharaky Marwa, Saleh Mohamed M, Alzahrani Abdullah Yahya Abdullah, Moussa Sana Ben, Al-Karmalawy Ahmed A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt.
Bioorg Chem. 2024 Dec;153:107843. doi: 10.1016/j.bioorg.2024.107843. Epub 2024 Sep 24.
In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful "multitarget-directed drug" for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.
在这项工作中，我们付出了额外的努力来设计基于BIBR1532的新型类似物，这些类似物具有潜在的端粒酶抑制活性，并作为多靶点抗肿瘤候选物以克服耐药性问题。因此，合成了新型取代的N-苯基-2-((6-苯基哒嗪-3-基)硫代)乙酰胺候选物(4a-n)。应用先前设计的化合物8e的先导优化策略；化合物4l显示出改善的端粒酶抑制率为64.95%，以及优异的生长抑制率为79%，表明其有潜力作为一种成功的“多靶点导向药物”用于癌症治疗。因此，进一步选择化合物4l来评估其额外的JAK1/STAT3/TLR4抑制潜力。与帕西替尼参考标准品(0.33倍变化)相比，化合物4l表现出非常有前景的JAK1抑制潜力，变化倍数为0.46倍。此外，与索拉非尼(0.33倍变化)相比，它显示出优异的STAT3抑制潜力，变化倍数为0.22倍。此外，与瑞托维德(0.29倍变化)相比，化合物4l使TLR4蛋白表达下调0.81倍。此外，还进行了分子对接，以研究优异候选物4l与四种靶标受体(端粒酶、JAK1、STAT3和TLR4)的结合模式和亲和力。此外，通过涉及植入实体艾氏癌(SEC)的雌性小鼠的体内研究，进一步探索了化合物4l作为抗肿瘤剂的治疗潜力。值得注意的是，化合物4l导致肿瘤大小和质量显著减小。生化、血液学、组织病理学和免疫组化参数的同时增强进一步证实了血管生成和炎症的抑制，阐明了化合物4l发挥其抗癌作用的其他机制。
