Lysosome-Targeted Chemotherapeutics: Half-Sandwich Ruthenium(II) Complexes That Are Selectively Toxic to Cancer Cells

Tian, Zhou; Li, Juanjuan; Zhang, Shumiao; Xu, Zhishan; Yang, Yuliang; Kong, Deliang; Zhang, Hairong; Ge, Xingxing; Zhang, Junming; Zhe, Liu

doi:10.1021/acs.inorgchem.8b01944

Cited by 64 publications

(41 citation statements)

References 45 publications

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“…Organometallic transition metal‐based complexes exhibit a wide range of applications for the design of antitumor drugs due to their potential redox features, diverse structural types and varied ligand bonding modes . Organometallic complexes of the group VIIIB elements platinum, ruthenium, osmium, rhodium, palladium and iridium have received much attention as potential antitumor agents . Following the clinical success of platinum‐based antitumor drugs such as cisplatin, carboplatin and oxaliplatin, metal‐mediated antitumor drugs have attracted wide attention in chemotherapeutic research .…”

Section: Introductionmentioning

confidence: 99%

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Kong

Guo

Tian

et al. 2018

Applied Organom Chemis

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Fifteen organometallic Ir(III) half-sandwich complexes (1A-5C) having the general formula [(η 5 -Cp x )Ir(N^N)Cl]PF 6 (Cp x = Cp*, tetramethyl(phenyl) cyclopentadienyl (Cp xph ) or tetramethyl(biphenyl)cyclopentadienyl (Cp xbiph ); N^N = diamine) have been synthesized and characterized. The molecular structure of 1A was determined using single-crystal X-ray diffraction analysis.The hydrolysis of 1A-5C was monitored using UV-visible spectra. Complexes 3A-3C showed catalytic activity for the oxidation of NADH to NAD + , where 3C showed the highest turnover number of 29.9 within 450 min. Cytotoxicity examination by MTT assay was carried out against two human cancer cell lines (HeLa and A549) after 24 or 48 h drug treatment. The complexes showed high potency, where the most potent complex (3C; IC 50 = 3.4 μM) was six times more active than cisplatin against A549 cells after 24 h drug exposure. Cytotoxic potency towards A549 cells increased with phenyl substitution on Cp ring: Cp xbiph > Cp xph > Cp*. In addition, the biological studies showed that 3C caused cell apoptosis and cell cycle arrest at G 1 phase in A549 cancer cells.Moreover, 3C increased the level of reactive oxygen species markedly after 24 h, which may provide an important basis for killing cancer cells. Confocal laser scanning microscopy was used to track 3C in A549 cells. The cellular localization experiment showed that 3C targeted lysosomes and caused lysosomal damage.

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Section: Introductionmentioning

confidence: 99%

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Kong

Guo

Tian

et al. 2018

Applied Organom Chemis

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“…23 The lipophilicity of complexes Ir1 and Ir2, referred to as octanol-water partition coefficients (log P o/w ), was determined by using a classical shake-ask method. 31,32 Considering the hydrolysis of Ir1, 50 mM NaCl aqueous was adopted to suppress the aquation of Ir1. The log P o/w values for Ir1 and Ir2 were À1.06 and 1.39 (Fig.…”

Section: Partition Coefficients (Log P O/w ) and Cellular Uptakementioning

confidence: 99%

Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid

et al. 2020

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“…Metal complexes possessing O^O, O^N, and especially N^N‐chelating ligands have been extensively studied; however, complexes containing P^P‐chelating ligands are still in their infancy . Our previous work showed that half‐sandwich complexes bearing BINAP as P^P‐chelating ligand possess very promising anticancer properties; however, utilizing the self‐luminescence of the complexes in elucidating subcellular localization and further explanations of the mechanism of anticancer properties were not explored .…”

Section: Introductionmentioning

confidence: 99%

Organometallic ruthenium and iridium phosphorus complexes: Synthesis, cellular imaging, organelle targeting and anticancer applications

Tian

Zhang

et al. 2019

Applied Organom Chemis

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The use of metal complexes containing phosphorus ligands as anticancer agents has not been well studied. In this work, eight novel half‐sandwich IrIII and RuII compounds with P^P‐chelating ligands have been synthesized and fully characterized, and alongside two crystal structures were reported. All eight complexes displayed highly potent antiproliferative activity, up to nine times more potent than the clinical anticancer drug cisplatin towards A549 lung cancer cells. Complex Ir1, which has a simpler structure and highly potent antiproliferative activity, was selected to investigate in further mechanistic studies. No hydrolysis and nucleobase binding occurred for complex Ir1. In order to elucidate subcellular localization, the self‐luminescence of the complex Ir1 was utilized. Ir1 can specifically target lysosomes and facilitate excessive production of reactive oxygen species, resulting in lysosomal membrane permeabilization in A549 cells. Release of cathepsin B and changes in the mitochondria membrane potential also contributed to the observed cytotoxicity of Ir1, which demonstrated an anticancer action mechanism that was different from that of cisplatin. The favorable results from biological and chemical research demonstrated that these types of complexes hold significant theranostic potential.

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Lysosome-Targeted Chemotherapeutics: Half-Sandwich Ruthenium(II) Complexes That Are Selectively Toxic to Cancer Cells

Cited by 64 publications

References 45 publications

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid

Organometallic ruthenium and iridium phosphorus complexes: Synthesis, cellular imaging, organelle targeting and anticancer applications

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