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Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated the compound well, especially compared to cisplatin. DNA interaction studies support a mode of action related to intercalation. [ABSTRACT FROM AUTHOR]

Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6‐p‐cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono‐ or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4‐membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays. [ABSTRACT FROM AUTHOR]

The clinical use of many potent anticancer agents is limited by their non-selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox-active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the Co III center. Investigations revealed long-term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the Co III prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated the compound well, especially compared to cisplatin. DNA interaction studies support a mode of action related to intercalation.

Investigations on incorporating an N -flanking anthracenyl moiety to [Rh(Cp*)(NHC)Cl 2 ] complexes surprisingly led to the formation of an intramolecular C-C bond between the Cp* and anthracenyl moieties, with additional auxiliary interactions between the metal and the anthracenyl ring system. In silico modeling supports a reaction mechanism whereby Rh(η 4 -tetramethylfulvene) intermediates undergo metallocycloaddition and the abstraction of a chlorido ligand, affording unique cationic complexes that feature Rh centers coordinated by a nonadentate ligand with exclusively carbon donor atoms. Some Rh-C interactions were extremely weak but nevertheless exhibited covalent bonding character. These weak Rh-C interactions were readily displaced by stronger electron donors, and the nonadentate ligand reverted to the heptadentate coordination mode observed in the intermediate. As far as we are aware, this study provides the first conclusive evidence of complexes bearing a single nonadentate κ 9 -coordinating ligand that features only carbon donors bound to a metal center.

Ruthenium-based complexes have attracted attention as promising anticancer candidates due to their lower general toxicity than the widely used platinum drugs. The complex [Ru II (η 6 -p-cymene)(8-oxyquinolinato)Cl] 1 has shown significant cytotoxic activity in cancer cells, independent of the cellular uptake. In an attempt to rationalize this finding, we investigated the fate of 1 in cells as well as developed an analysis method for 1 and its derivatives based on molecular mass spectrometry. The methods were applied for the analysis of cell medium and HCT116 human colorectal cancer cell lysate samples. The amount of Ru detected in cell lysate after treatment with 1 by ICP-MS was virtually time-independent, while the Ru content in the cell pellet increased significantly over the course of 24 h. The compound was still detectable by LC-ESI-TOF-MS after 24 h in cell lysate as its [1- Cl] + ion that may be formed directly from 1 or after a chlorido-aqua ligand exchange reaction facilitated in the cytosol.

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.

Organometallic compounds based on bioactive ligand systems have shown promising antiproliferative properties. The use of 8-hydroxyquinoline and its derivatives as bioactive ligands resulted in organometallic complexes with potent anticancer activity, but they lack aqueous solubility for further development. We report here the preparation of a series of M II/III (cym/Cp*)Cl complexes (η 6 -p-cymene (cym): M = Ru, Os; η 5 -pentamethylcyclopentadienyl (Cp*): M = Rh, Ir) with hydroxyquinoline-derived co-ligands and in a subsequent step the substitution of the chlorido ligands for amphiphilic 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (PTA). Solubility studies indicated that the introduced PTA ligand significantly improved the aqueous solubility of all complexes. The complexes were shown to be stable in aqueous and DMSO solution over a period of at least 3 d. As would be expected for such modification of complexes, the higher solubility resulted in significantly decreased cytotoxicity in cancer cells. The antiproliferative activity was still more pronounced than that of RAPTA-C [Ru(cym)(PTA)Cl] which, however, has been demonstrated to have antimetastatic and antiangiogenic properties in vivo., (Copyright © 2019 Elsevier Inc. All rights reserved.)