Cyclometalated Palladium(II) N‐Heterocyclic Carbene Complexes: Anticancer Agents for Potent In Vitro Cytotoxicity and In Vivo Tumor Growth Suppression

Fong, Tommy Tsz-Him; Lok, Chun‐Nam; Chung, Clive Yik‐Sham; Fung, Yi-Man Eva; Chow, Pui‐Keong; Wan, Pui-Ki; Che, Chi‐Ming

doi:10.1002/anie.201602814

Cited by 111 publications

(35 citation statements)

References 35 publications

(1 reference statement)

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“…The analysis of the data shows firstly that complex 3 b is much more cytotoxic toward cancer cells than 3 a . A similar marked influence of the N ‐heterocyclic carbene substituents on the antitumor activity has already been observed in the past by other authors and is mainly due to the influence of steric hindrance . Apparently, in these cases, the size and shape of the compounds play a determining role in their interaction with the involved bio‐target.…”

Section: Resultssupporting

confidence: 77%

Improved Synthesis, Anticancer Activity and Electrochemical Characterization of Unusual Zwitterionic Palladium Compounds with a Ten‐Term Coordinative Ring.

et al. 2019

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A new improved synthetic protocol for the preparation of uncommon zwitterionic palladium(II) complexes with a tenterm coordinative ring is reported. A suitable combination of reaction solvent and temperature allows to drastically reduce the reaction time and increase the yield. A detailed kinetic study, implemented by theoretical DFT calculations, clarifies and quantifies this solvent effect. The antiproliferative activity of the synthesized complexes was tested toward eight different cancer cell lines. The mesityl derivative showed potent and selective cytotoxicity toward several types of cancer cell lines, with IC 50 values lower than cisplatin. Additionaly, the anticancer activity against cisplatin-sensitive and cisplatin-resistant ovarian cancer cells suggested a different mechanism of action with respect to traditional platinum chemotherapeutics. Aiming to easily determine these promising metallo-drugs, a voltammetric study of their electrochemical fingerprint was carried out. For both compounds a suitable signal, ascribed to the reduction of the metallic center from palladium(II) to palladium (0), was identified and further investigated by Differential Pulse Voltammetry.

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Section: Resultssupporting

confidence: 77%

Improved Synthesis, Anticancer Activity and Electrochemical Characterization of Unusual Zwitterionic Palladium Compounds with a Ten‐Term Coordinative Ring.

et al. 2019

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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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“…The advantage of these multiple anticancer activities is that the risks of systemic toxicity caused by administration of more than one anticancer drug would be strongly decreased . Although for most of the cited examples the mechanism by which these drugs inhibit angiogenesis remains elusive, proteins such as growth factors, tubulin, or enzyme cathepsin B seem always to be involved. Even though proteins are considered as non‐traditional targets for metal complexes, some reviews highlight the importance of the metallodrug–protein interaction .…”

Section: Introductionmentioning

confidence: 99%

Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes

Zamora

Pérez

Rothemund

et al. 2017

Chemistry A European J

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A series of new organometallic Pt complexes of the type [Pt(C^N)Cl(DMSO)] (C^N=N,N-dimethyl-1-(2-aryl)methanamine-κ C2,N; aryl=phenyl 2 a, biphenyl 2 b, p-terphenyl 2 c, naphthyl 2 d, anthracenyl 2 e, or pyrenyl 2 f) have been synthesized to explore the influence of the aromaticity on their anticancer activity. The best performers, 2 b and d, are more active than cisplatin (CDDP) in epithelial ovarian carcinoma cells A2780, with 2 d having a higher selectivity factor than CDDP in all the tested cell lines. In addition, all the new compounds overcome the acquired resistance in A2780cisR cells and interestingly, show low micromolar IC values towards the triple negative breast cancer cell line MDA-MB-231 and the highly metastatic 518A2 melanoma cells. This study shows that the hydrophobicity, accumulation into cells, and metal levels on nuclear DNA for the complexes are consistent with their cytotoxicity. Complexes 2 b and d induce apoptosis in a caspase-independent manner and suppress the intracellular ROS generation without modifying the mitochondria membrane potential. In addition, 2 a-f effectively inhibit angiogenesis in the endothelial cell line EA.hy926 at sub-cytotoxic concentrations and 2 b and d show in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized SPF-eggs (SPF=specific-pathogen-free). Inhibition of tubulin polymerization and degeneration of cytoskeleton organization in 518A2 melanoma cells are presented as a preliminary mechanism of its antimetastatic activity.

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Cyclometalated Palladium(II) N‐Heterocyclic Carbene Complexes: Anticancer Agents for Potent In Vitro Cytotoxicity and In Vivo Tumor Growth Suppression

Cited by 111 publications

References 35 publications

Improved Synthesis, Anticancer Activity and Electrochemical Characterization of Unusual Zwitterionic Palladium Compounds with a Ten‐Term Coordinative Ring.

Improved Synthesis, Anticancer Activity and Electrochemical Characterization of Unusual Zwitterionic Palladium Compounds with a Ten‐Term Coordinative Ring.

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

Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes

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