Synthesis and structural characterization of benzyl-functionalized N-heterocyclic carbene platinum complexes: Dramatic substituent effect on anti-cancer activity

Dahm, Georges; Bouché, Mathilde; Bailly, Corinne; Karmazin, Lydia; Bellemin‐Laponnaz, Stéphane

doi:10.1016/j.jorganchem.2019.120908

Cited by 7 publications

(4 citation statements)

References 35 publications

(7 reference statements)

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“…The NHC-Pt-I 2 complex was synthesized according to our previous protocol [ 16 , 21 , 31 ]. The same procedure was used and modified for the synthesis of the NHC-Pt-Br 2 complex, NaI being replaced by NaBr.…”

Section: Methodsmentioning

confidence: 99%

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma

Charignon

Bouché

Clave-Darcissac

et al. 2020

IJMS

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We describe here the evaluation of the cytotoxic efficacy of two platinum (II) complexes bearing an N-heterocyclic carbene (NHC) ligand, a pyridine ligand and bromide or iodide ligands on a panel of human metastatic cutaneous melanoma cell lines representing different genetic subsets including BRAF-inhibitor-resistant cell lines, namely A375, SK-MEL-28, MeWo, HMCB, A375-R, SK-MEL-5-R and 501MEL-R. Cisplatin and dacarbazine were also studied for comparison purposes. Remarkably, the iodine-labelled Pt-NHC complex strongly inhibited proliferation of all tested melanoma cells after 1-h exposure, likely due to its rapid uptake by melanoma cells. The mechanism of this inhibitory activity involves the formation of DNA double-strand breaks and apoptosis. Considering the intrinsic chemoresistance of metastatic melanoma cells of current systemic treatments, these findings are promising and could give research opportunities in the future to improve the prognosis of patients suffering from unresectable metastatic melanoma that are not eligible or that do not respond to the most effective drugs available to date, namely BRAF inhibitors and the anti-PD-1 monoclonal antibody (mAb).

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Section: Methodsmentioning

confidence: 99%

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma

Charignon

Bouché

Clave-Darcissac

et al. 2020

IJMS

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“…These complexes usually display IC 50 values in the micromolar range against various cancer cell lines, even against cisplatin‐resistant cell lines . Screening of the substituents on the carbene even allowed to identify complexes having biological activities with IC 50 below 0.01 µ m …”

Section: Platinum Nhc Complexes Exhibit Anticancer Activitiesmentioning

confidence: 99%

“…[21] Screening of the substituents on the carbene even allowed to identify complexes having biological activities with IC 50 below 0.01 μM. [22] Figure 3. Selected chemical structures of Pt(II) NHC complexes with anticancer activities.…”

Section: Platinum Nhc Complexes Exhibit Anticancer Activitiesmentioning

confidence: 99%

N‐Heterocyclic Carbene Platinum Complexes: A Big Step Forward for Effective Antitumor Compounds

Bellemin‐Laponnaz

2019

Eur J Inorg Chem

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The discovery of cisplatin is an important milestone in the history of successful anticancer drugs. This is also a notable example of the translational scientific achievement that remains a driving force in multidisciplinary research. The clinical success of cisplatin has led chemists to vary the ligands around the platinum metal to improve cisplatin's effectiveness while reducing its side effects. While there have been more failures than successes, key developments in the elucidation of mechanisms of the tumor-resistance properties have been accomplished. N-Heterocyclic carbene as ligand for organometallic [a]

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“…N -Heterocyclic carbene (NHC) ligands form stable metal complexes with a wide variety of metal centers. − These metal complexes have been investigated for their biological properties; , for example, Ag I (NHC) complexes are potent antibacterial and antimicrobial agents, − while Au I (NHC) compounds have been considered for anticancer drug design. − Furthermore, Pd, Ag, Rh, − Ir, ,− Pt, − and Ru-, − ,,,,− and Os(arene) − , complexes with NHC ligands (such as 1a – 4a shown in Figure ) have been investigated, with some of them being potent antiproliferative agents in vitro. The mode of action of these complexes, in particular, of the Au complexes, has been suggested to be related to the inhibition of thioredoxin reductase (TrxR), ,− a protein that is commonly overexpressed in cancer cells. − There is also evidence that Ru-, Os(arene)(NHC), and Rh I (NHC) complexes may inhibit TrxR. ,,, However, the correlation between TrxR inhibition and antiproliferative potency is limited, and other targets are likely to be more important for this compound class. , …”

Section: Introductionmentioning

confidence: 99%

Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl₂Complexes

et al. 2020

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Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N-heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of Rh III -and Ir III (Cp*)(NHC)Cl 2 (Cp* = η 5 -pentamethylcyclopentadienyl) compounds and comparison of their properties to the Ru II -and Os II (cym) analogues (cym = η 6 -p-cymene). Like the Ru II -and Os II (cym) complexes, the Rh III -and Ir III (Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC 50 ) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC 50 values of ∼1 μM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl 2 complexes may be a scaffold for the development of TrxR inhibitors.

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Synthesis and structural characterization of benzyl-functionalized N-heterocyclic carbene platinum complexes: Dramatic substituent effect on anti-cancer activity

Cited by 7 publications

References 35 publications

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma

N‐Heterocyclic Carbene Platinum Complexes: A Big Step Forward for Effective Antitumor Compounds

Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl₂Complexes

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Synthesis and structural characterization of benzyl-functionalized N-heterocyclic carbene platinum complexes: Dramatic substituent effect on anti-cancer activity

Cited by 7 publications

References 35 publications

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma

N‐Heterocyclic Carbene Platinum Complexes: A Big Step Forward for Effective Antitumor Compounds

Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl2Complexes

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Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl₂Complexes