School of Science and Technology, The University of Georgia, Tbilisi, Georgia.
Pharmaceutical Sciences Research Center, Health Institute, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Toxicology. 2023 Aug 15;495:153609. doi: 10.1016/j.tox.2023.153609. Epub 2023 Aug 3.
Two Ga(III) complexes (C1) and (C2) were prepared by the one-pot reaction of pyridine-2,6-dicarboxylic acid and aminopyridine derivatives with gallium(III) nitrate octahydrate. The compounds were characterized by single-crystal X-ray diffraction. The distorted octahedral geometry was confirmed by crystallographic data for both complexes. The study of the in vitro cytotoxicity of the compounds showed that the presence of different extra-nuclear cations can affect the cytotoxicity of the same anionic complexes. The most significant antiproliferative activity was observed for C1 (IC = 0.69 μM, MAE = 73.96%) and C2 (IC = 3.78 μM, MAE = 60.35%) (where MAE represents the maximal antiproliferative effect) against A431 cell line. The mechanistic study evidenced the same pathway for the death of A431 cells treated with the complexes, although the results for C2 were obtained at approximately five times the concentration of C1. According to the study, both complexes induced cell cycle arrest in G2/M phase in A431 cells by upregulating the levels of p21, p27, p-cdc25C, and p-cdc2 and downregulating the levels of cdc25C, cdc2, and cyclin B1. In addition, apoptosis via a caspase-dependent mitochondrial pathway was confirmed by a decrease in Bcl-2 family proteins and an increase in the expression of procaspase-9 and 3. Also, the complexes induced autophagic cell death by activating the RAGE /PI3KC3/Beclin 1 pathway in A431 cells. DATA AVAILABILITY: CCDC 874052 and 874055 contain the supplementary crystallographic data for C1 and C2, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/services/structures?pid=ccdc:874052,874055&sid=CCDCManual, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
两个 Ga(III) 配合物（C1）和（C2）通过吡啶-2,6-二羧酸和氨基吡啶衍生物与硝酸镓（III）八水合物的一锅反应制备。通过单晶 X 射线衍射对化合物进行了表征。通过对两个配合物的晶体数据的分析，证实了扭曲的八面体几何形状。对化合物的体外细胞毒性研究表明，不同的核外阳离子的存在会影响相同的阴离子配合物的细胞毒性。C1（IC = 0.69 μM，MAE = 73.96%）和 C2（IC = 3.78 μM，MAE = 60.35%）（其中 MAE 代表最大的增殖抑制作用）对 A431 细胞系表现出最强的抗增殖活性。机制研究表明，尽管 C2 的结果是在大约 C1 浓度的五倍时获得的，但用配合物处理 A431 细胞导致细胞死亡的途径相同。根据该研究，两种配合物均通过上调 p21、p27、p-cdc25C 和 p-cdc2 的水平，下调 cdc25C、cdc2 和 cyclin B1 的水平，导致 A431 细胞的细胞周期停滞在 G2/M 期，从而诱导细胞凋亡。此外，通过 Bcl-2 家族蛋白的减少和 procaspase-9 和 3 的表达增加，证实了 caspase 依赖性线粒体途径的凋亡。此外，该配合物通过激活 A431 细胞中的 RAGE/PI3KC3/Beclin 1 通路诱导自噬性细胞死亡。数据可用性：CCDC 874052 和 874055 分别包含 C1 和 C2 的补充晶体学数据。这些数据可以通过以下网址免费获得：http://www.ccdc.cam.ac.uk/services/structures?pid=ccdc:874052,874055&sid=CCDCManual，或从剑桥晶体学数据中心，12 联合路，剑桥 CB2 1EZ，英国；传真：（+44）1223-336-033；或电子邮件：deposit@ccdc.cam.ac.uk。
