Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt.
Drug Design and Discovery Lab, Zewail City of Science and Technology, Giza, 12578, Egypt.
Chem Biol Interact. 2022 Jan 5;351:109753. doi: 10.1016/j.cbi.2021.109753. Epub 2021 Nov 19.
New semi-synthetic effective and safe anticancer agents isoeugenol derivatives were synthesized, characterized, and screened for their cytotoxic activity against MCF-7. Moreover, their selective cytotoxicity was assessed against MCF-10A. Three derivatives, 2, 8 and 10 were significantly more active than the reference drug 5-FU with IC values of 6.59, 8.07 and 9.63 and 30.93 μM, respectively. Also interestingly, these derivatives demonstrated some degree of selectivity to cancer cells over normal cells. Furthermore, derivative 2 was subjected to other in vitro experiments against MCF-7 where it inhibited colony formation by 87.5% and lowered ERα concentration to 395.7 pg/mL compared to 1129 pg/mL in untreated control cells. In continuation of the investigation, the apoptotic activity of compound 2, was assessed where it significantly enhanced total apoptotic cell death by 9.16-fold (18.70% compared to 1.64% for the untreated MCF-7 control cells) and arrested the cell cycle at the G2/M phase. Furthermore, the molecular mechanism of apoptotic activity was investigated at both the gene (RT-PCR) and protein (western plotting) levels where upregulation of pro-apoptotic and down regulation of anti-apoptotic genes was detected. Additionally, compound 2 treatment enhanced the antioxidant (GSH, CAT, SOD) activities. Finally, in vivo experiments verified the effective anticancer activity of compound 2 through inhibition of tumor proliferation by 47.6% compared to 22.9% for 5-FU and amelioration of the hematological, biochemical, and histopathological examinations near normal. In effect, compound 2 can be viewed as a promising semi-synthetic derivative of isoeugenol with some degree of selectivity for management of breast cancer through apoptotic induction and ERα downregulation.
新型半合成有效且安全的抗癌剂异丁香酚衍生物已被合成、表征，并筛选其对 MCF-7 的细胞毒性活性。此外，还评估了它们对 MCF-10A 的选择性细胞毒性。三种衍生物 2、8 和 10 的活性明显高于参考药物 5-FU，IC 值分别为 6.59、8.07 和 9.63 和 30.93μM。此外，这些衍生物对癌细胞具有一定程度的选择性，这也很有趣。此外，衍生物 2 还进行了其他针对 MCF-7 的体外实验，其中它抑制集落形成 87.5%，并将 ERα 浓度降低至 395.7pg/mL，而未处理对照细胞中的浓度为 1129pg/mL。在继续研究中，评估了化合物 2 的凋亡活性，其显著增强总凋亡细胞死亡 9.16 倍（与未处理的 MCF-7 对照细胞中的 1.64%相比为 18.70%），并将细胞周期阻滞在 G2/M 期。此外，在基因（RT-PCR）和蛋白质（western 作图）水平上研究了凋亡活性的分子机制，检测到促凋亡基因的上调和抗凋亡基因的下调。此外，化合物 2 处理增强了抗氧化剂（GSH、CAT、SOD）的活性。最后，体内实验通过抑制肿瘤增殖证实了化合物 2 的有效抗癌活性，抑制率为 47.6%，而 5-FU 的抑制率为 22.9%，并改善了血液学、生物化学和组织病理学检查接近正常。总之，化合物 2 可以被视为异丁香酚的一种有前途的半合成衍生物，通过诱导细胞凋亡和下调 ERα，对乳腺癌具有一定程度的选择性。
