Ravichandiran Palanisamy, Martyna Aleksandra, Kochanowicz Elżbieta, Maroli Nikhil, Kubiński Konrad, Masłyk Maciej, Boguszewska-Czubara Anna, Ramesh Thiyagarajan
R&D Education Center for Whole Life Cycle R&D of Fuel Cell Systems, Jeonbuk National University, Jeonju, Jeollabuk-do, 54896, Republic of Korea.
Department of Life Science, Department of Energy Storage/Conversion Engineering of Graduate School, Hydrogen and Fuel Cell Research Center, Jeonbuk National University, Jeonju, Jeollabuk-do, 54896, Republic of Korea.
ChemMedChem. 2024 Dec 16;19(24):e202400495. doi: 10.1002/cmdc.202400495. Epub 2024 Oct 15.
A novel library of naphthoquinone derivatives (3-5 aa) was synthesized and evaluated for their anticancer properties. Specifically, compounds 5 i, 5 l, 5 o, 5 q, 5 r, 5 s, 5 t, and 5 v demonstrated superior cytotoxic activity against the cancer cell lines that were studied. All the studied compounds exhibited a higher selectivity index (SI) and a favourable safety profile than the standard drug doxorubicin. Notably, compound 5 v displayed a greater cytotoxic effect on MCF-7 cells (IC=1.2 μM, and 0.9 μM at 24 h and 48 h, respectively) compared to the standard drug doxorubicin (IC=2.4 μM, and 2.1 μM at 24 h and 48 h, respectively). To further investigate the mechanism of cytotoxic effect, additional anticancer studies were conducted with 5 v in MCF-7 cells. The studies are including morphological changes, AO/EB (acridine orange/ethidium bromide) double staining, apoptosis analysis, cell colony assay, SDS-PAGE and Western blotting, cell cycle analysis, and detecting reactive oxygen species (ROS) assay. The findings showed that 5 v triggered cytotoxic effects in MCF-7 cells through the initiation of cell cycle arrest at the G1/S phase and necrosis. In vivo ecotoxicity studies indicated that 5 v had lower toxicity towards zebrafish larvae (LC=50.15 μM) and had an insignificant impact on cardiac functions. In vivo xenotransplantation of MCF-7 cells in zebrafish larvae demonstrated a significant reduction in tumour volume in the xenograft. Approximately 95 % of the zebrafish larvae with 5 v xenografts survived after 10 days of the treatment. Finally, a computational modelling study was conducted on four protein receptors, namely ER, EFGR, BRCA1, and VEFGR2. The findings highlight the importance of the aminonaphthoquinone moiety, amide linkage, and propyl thio moiety in enhancing the anticancer properties. 5 v exhibited superior drug-likeness features and docking scores (-9.1, -7.1, -8.9, and -10.9 kcal/mol) compared to doxorubicin (-7.2, -6.1, -6.9, and -7.3 kcal/mol) against ER, EFGR, BRCA1, and VEGFR2 receptors, respectively. Therefore, the notable antitumor effects of naphthoquinone derivatives (3-5 aa) suggest that these molecular frameworks may play a role in the development of promising anticancer agents for cancer treatment.
合成了一个新型萘醌衍生物库（3-5 aa），并对其抗癌特性进行了评估。具体而言，化合物5 i、5 l、5 o、5 q、5 r、5 s、5 t和5 v对所研究的癌细胞系表现出优异的细胞毒性活性。所有研究的化合物均表现出比标准药物阿霉素更高的选择性指数（SI）和良好的安全性。值得注意的是，与标准药物阿霉素（24小时和48小时的IC分别为2.4 μM和2.1 μM）相比，化合物5 v对MCF-7细胞表现出更大的细胞毒性作用（24小时和48小时的IC分别为1.2 μM和0.9 μM）。为了进一步研究细胞毒性作用的机制，在MCF-7细胞中对5 v进行了额外的抗癌研究。这些研究包括形态学变化、AO/EB（吖啶橙/溴化乙锭）双重染色、凋亡分析、细胞集落测定、SDS-PAGE和蛋白质印迹、细胞周期分析以及活性氧（ROS）检测。结果表明，5 v通过引发细胞周期在G1/S期停滞和坏死，在MCF-7细胞中触发细胞毒性作用。体内生态毒性研究表明，5 v对斑马鱼幼虫的毒性较低（LC=50.15 μM），对心脏功能的影响不显著。在斑马鱼幼虫中对MCF-7细胞进行体内异种移植表明，异种移植瘤的肿瘤体积显著减小。用5 v进行异种移植的斑马鱼幼虫在治疗10天后，约95%存活。最后，对四种蛋白质受体，即雌激素受体（ER）、表皮生长因子受体（EFGR）、乳腺癌1号基因（BRCA1）和血管内皮生长因子受体2（VEFGR2）进行了计算建模研究。研究结果突出了氨基萘醌部分、酰胺键和丙基硫部分在增强抗癌特性方面的重要性。与阿霉素（分别针对ER、EFGR、BRCA1和VEGFR2受体的对接分数为-7.2、-6.
