Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI-Center for Molecular Biosciences Innsbruck, CCB─Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
Immunobiology and Stem Cell Laboratory, Department of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.
J Med Chem. 2023 Dec 14;66(23):15916-15925. doi: 10.1021/acs.jmedchem.3c01359. Epub 2023 Nov 27.
The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[,'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (-) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: > > . In particular, was highly cytotoxic with an IC of 4.2 μM which was 6.6-fold lower than that of cisplatin (IC of 27.9 μM). In contrast, hydroxylated complexes - were almost inactive up to the highest concentration tested due to lack of cellular uptake. caused a dual mode of cell death, ferroptosis, and necroptosis, whereby at higher concentrations, ferroptosis was the preferred form. Ferroptotic morphology and the presence of ferrous iron and lipid reactive oxygen species proved the involvement of ferroptosis. was identified as a promising lead compound for the design of drug candidates inducing ferroptosis.
甲氧基和羟基在希夫碱配体中的影响氯代[,'-双（甲氧基/羟基）水杨醛-1,2-双（4-甲氧基苯基）乙二胺]铁（III）配合物对人 MDA-MB 231 乳腺癌和 HL-60 白血病细胞的影响进行了评估。甲氧基化配合物（-）以浓度依赖性方式抑制增殖、迁移和代谢活性，其抑制活性的顺序为： > > 。特别是 对细胞具有高细胞毒性，IC 为 4.2 μM，比顺铂（IC 为 27.9 μM）低 6.6 倍。相比之下，由于缺乏细胞摄取，羟基化配合物 - 直到测试的最高浓度几乎都没有活性。 引起细胞死亡的双重模式，即铁死亡和坏死性细胞死亡，在较高浓度下，铁死亡是首选形式。铁死亡形态和亚铁离子和脂质活性氧的存在证明了铁死亡的参与。 被确定为设计诱导铁死亡的候选药物的有前途的先导化合物。
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