El-Metwally Souad A, Elkady Hazem, Hagras Mohamed, Husein Dalal Z, Ibrahim Ibrahim M, Taghour Mohammed S, El-Mahdy Hesham A, Ismail Ahmed, Alsfouk Bshra A, Elkaeed Eslam B, Metwaly Ahmed M, Eissa Ibrahim H
Department of Basic Science, Higher Technological Institute 10th of Ramadan City Egypt.
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt
RSC Adv. 2023 Aug 4;13(33):23365-23385. doi: 10.1039/d3ra03128d. eCollection 2023 Jul 26.
In this work, new thieno[2,3-]pyrimidine-derived compounds possessing potential anticancer activities were designed and synthesized to target VEGFR-2. The thieno[2,3-]pyrimidine derivatives were tested for their abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two types of cancer cells, MCF-7 and HepG2. Compound 18 exhibited the strongest anti-VEGFR-2 potential with an IC value of 0.084 μM. Additionally, it displayed excellent proliferative effects against MCF-7 and HepG2 cancer cell lines, with IC values of 10.17 μM and 24.47 μM, respectively. Further studies revealed that compound 18 induced cell cycle arrest in G2/M phase and promoted apoptosis in MCF-7 cancer cells. Apoptosis was stimulated by compound 18 by increasing BAX (3.6-fold) and decreasing Bcl-2 (3.1-fold). Additionally, compound 18 significantly raised the levels of caspase-8 (2.6-fold) and caspase-9 (5.4-fold). Computational techniques were also used to investigate the VEGFR-2-18 complex at a molecular level. Molecular docking and molecular dynamics simulations were performed to assess the structural and energetic features of the complex. The protein-ligand interaction profiler analysis identified the 3D interactions and binding conformation of the VEGFR-2-18 complex. Essential dynamics (ED) study utilizing principal component analysis (PCA) described the protein dynamics of the VEGFR-2-18 complex at various spatial scales. Bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-18 complex. In addition, the DFT studies provided insights into the structural and electronic properties of compound 18. Finally, computational ADMET and toxicity studies were conducted to evaluate the potential of the thieno[2,3-]pyrimidine derivatives for drug development. The results of the study suggested that compound 18 could be a promising anticancer agent that may provide effective treatment options for cancer patients. Furthermore, the computational techniques used in this research provided valuable insights into the molecular interactions of the VEGFR-2-18 complex, which may guide future drug design efforts. Overall, this study highlights the potential of thieno[2,3-]pyrimidine derivatives as a new class of anticancer agents and provides a foundation for further research in this area.
在本研究中，设计并合成了具有潜在抗癌活性的新型噻吩并[2,3 - ]嘧啶衍生物，以靶向血管内皮生长因子受体 - 2（VEGFR - 2）。测试了噻吩并[2,3 - ]嘧啶衍生物抑制VEGFR - 2以及阻止两种癌细胞（MCF - 7和HepG2）生长的能力。化合物18表现出最强的抗VEGFR - 2潜力，IC值为0.084 μM。此外，它对MCF - 7和HepG2癌细胞系显示出优异的增殖抑制作用，IC值分别为10.17 μM和24.47 μM。进一步研究表明，化合物18诱导MCF - 7癌细胞在G2/M期发生细胞周期阻滞并促进其凋亡。化合物18通过增加BAX（3.6倍）和降低Bcl - 2（3.1倍）来刺激凋亡。此外，化合物18显著提高了caspase - 8（2.6倍）和caspase - 9（5.4倍）的水平。还使用计算技术在分子水平上研究VEGFR - 2 - 18复合物。进行了分子对接和分子动力学模拟，以评估该复合物的结构和能量特征。蛋白质 - 配体相互作用分析确定了VEGFR - 2 - 18复合物的三维相互作用和结合构象。利用主成分分析（PCA）的主成分动力学（ED）研究描述了VEGFR - 2 - 18复合物在不同空间尺度上的蛋白质动力学。二维投影分析证实了VEGFR - 2 - 18复合物的正确结合。此外，密度泛函理论（DFT）研究提供了关于化合物18的结构和电子性质的见解。最后，进行了计算药物代谢动力学、药效学及毒性研究，以评估噻吩并[2,3 - ]嘧啶衍生物用于药物开发的潜力。研究结果表明，化合物18可能是一种有前景的抗癌药物，可为癌症患者提供有效的治疗选择。此外，本研究中使用的计算技术为VEGFR - 2 - 18复合物的分子相互作用提供了有价值的见解，这可能会指导未来的药物设计工作。总体而言，本研究突出了噻吩并[2,3 - ]嘧啶衍生物作为一类新型抗癌药物的潜力，并为该领域的进一步研究奠定了基础。
