Chemistry Department, Faculty of Science Suez Canal University, Ismailia, 41522, Egypt.
Center for Materials Science, Zewail City of Science and Technology, 12578, Cairo, Egypt.
Chem Biol Interact. 2020 Jun 1;324:109087. doi: 10.1016/j.cbi.2020.109087. Epub 2020 Apr 12.
Despite advances in cancer treatment modalities, DNA still stands as one of the targets for anticancer agents. DNA minor groove binders (MGBs) represent an important investigational chemotherapeutic class with promising cytotoxic capacity. Herein this study reports the potent cytotoxic effect of a series of repurposed flexible bis-imidamides 1-4, triaryl bis-guanidine 5 and bis-N-substituted guanidines 6,7 having a 1,4-diphenoxybenzene scaffold backbone on MCF-7 and MDA-MB-231 breast cancer cell lines. Of these compounds, imidamide 4 was chosen for further in-vitro, in-vivo and molecular dynamics (MD) studies owing to its promising anti-tumor activity, with IC values on MCF-7 and MDA-MB-231 breast cancer cell lines of 1.9 and 2.08 μM, respectively. Annexin V/propidium iodide apoptosis assay revealed apoptosis induction on imidamide 4 treated MCF-7 cells. RT-PCR assay results demonstrated the proapoptotic effect of compound 4 through increase of mRNA levels of the pro-apoptotic genes; p53, PUMA, and Bax, and inhibiting the anti-apoptotic Bcl-2 gene expression in MCF-7 cells. Moreover, compound 4 induced a G/G cell-cycle arrest in MCF-7 in a dose-dependent manner. Corroborating in-vivo experiments on Ehrlich ascites carcinoma (EAC)-bearing mice, reflected the anticancer strength of derivative 4. For further target validation, molecular dynamics (MD) studies demonstrated an energetically favorable binding of imidamide 4 with the DNA minor groove AT rich site. In effect, imidamide 4 can be viewed as a promising hit dicationic compound with good cytotoxic and apoptotic inducing activity against breast cancer that can be adopted for future optimization.
尽管癌症治疗方法取得了进展，但 DNA 仍然是抗癌药物的目标之一。DNA 小沟结合剂（MGB）代表了一类具有有前途的细胞毒性能力的重要研究化疗药物。本研究报告了一系列具有柔性双亚咪唑酰胺 1-4、三芳基双胍 5 和双 N-取代胍 6,7 的新型化合物的强大细胞毒性作用，它们具有 1,4-二苯氧基苯骨架骨架，对 MCF-7 和 MDA-MB-231 乳腺癌细胞系。在这些化合物中，由于其有前途的抗肿瘤活性，亚咪唑酰胺 4 被选为进一步的体外、体内和分子动力学（MD）研究，其对 MCF-7 和 MDA-MB-231 乳腺癌细胞系的 IC 值分别为 1.9 和 2.08μM。 Annexin V/碘化丙啶凋亡测定显示亚咪唑酰胺 4 处理的 MCF-7 细胞诱导凋亡。RT-PCR 测定结果表明，化合物 4 通过增加促凋亡基因 p53、PUMA 和 Bax 的 mRNA 水平以及抑制 MCF-7 细胞中抗凋亡 Bcl-2 基因的表达，发挥促凋亡作用。此外，化合物 4 以剂量依赖性方式诱导 MCF-7 中的 G/G 细胞周期停滞。在荷 Ehrlich 腹水癌（EAC）的小鼠体内实验中得到证实，反映了衍生物 4 的抗癌强度。为了进一步进行靶标验证，分子动力学（MD）研究表明亚咪唑酰胺 4 与 DNA 小沟富含 AT 的位点具有有利的能量结合。实际上，亚咪唑酰胺 4 可以被视为一种有前途的双阳离子化合物，具有良好的细胞毒性和诱导凋亡活性，可用于治疗乳腺癌，并且可以进行进一步优化。
