Copper-containing coordination compounds attract wide attention due to the redox activity and biogenicity of copper ions, providing multiple pathways of biological activity. The pharmacological properties of metal complexes can be fine-tuned by varying the nature of the ligand and donor atoms. Copper-containing coordination compounds are effective antitumor agents, constituting a less expensive and safer alternative to classical platinum-containing chemotherapy, and are also effective as antimicrobial, antituberculosis, antimalarial, antifugal, and anti-inflammatory drugs. 64Cu-labeled coordination compounds are promising PET imaging agents for diagnosing malignant pathologies, including head and neck cancer, as well as the hallmark of Alzheimer’s disease amyloid-β (Aβ). In this review article, we summarize different strategies for possible use of coordination compounds in the treatment and diagnosis of various diseases, and also various studies of the mechanisms of antitumor and antimicrobial action.
We report herein the design, synthesis, and biological investigation of a series of novel Pt(IV) prodrugs with non-steroidal anti-inflammatory drugs naproxen, diclofenac, and flurbiprofen, as well as these with stearic acid in the axial position. Six Pt(IV) prodrugs 5–10 were designed, which showed superior antiproliferative activity compared to cisplatin as well as an ability to overcome tumor cell line resistance to cisplatin. By tuning the drug lipophilicity via variation of the axial ligands, the most potent Pt(IV) prodrug 7 was obtained, with an enhanced cellular accumulation of up to 153-fold that of cisplatin and nanomolar cytotoxicity both in 2D and 3D cell cultures. Pt2+ species were detected at different depths of MCF-7 spheroids after incubation with Pt(IV) prodrugs using a Pt-coated carbon nanoelectrode. Cisplatin accumulation in vivo in the murine mammary EMT6 tumor tissue of BALB/c mice after Pt(IV) prodrug injection was proved electrochemically as well. The drug tolerance study on BALB/c mice showed good tolerance of 7 in doses up to 8 mg/kg.
A chemo-anti-inflammatory strategy is of interest for the treatment of aggressive cancers. The platinum (IV) prodrug with non-steroidal anti-inflammatory drugs (NSAIDs) as axial ligands is designed to efficiently enter tumor cells due to high lipophilicity and release the cytotoxic metabolite and NSAID intracellularly, thereby reducing side effects and increasing the therapeutic efficacy of platinum chemotherapy. Over the last 7 years, a number of publications have been devoted to the design of such Pt(IV) prodrugs in combination with anti-inflammatory chemotherapy, with high therapeutic efficacy in vitro and In vivo. In this review, we summarize the studies devoted to the development of Pt(IV) prodrugs with NSAIDs as axial ligands, the study of the mechanism of their cytotoxic action and anti-inflammatory activity, the structure–activity ratio, and therapeutic efficacy.
A series of 73 ligands and 73 of their Cu+2 and Cu+1 copper complexes with different geometries, oxidation states of the metal, and redox activities were synthesized and characterized. The aim of the study was to establish the structure–activity relationship within a series of analogues with different substituents at the N(3) position, which govern the redox potentials of the Cu+2/Cu+1 redox couples, ROS generation ability, and intracellular accumulation. Possible cytotoxicity mechanisms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have been investigated. ROS formation in MCF-7 cells and three-dimensional (3D) spheroids was proven using the Pt-nanoelectrode. Drug accumulation and ROS formation at 40–60 μm spheroid depths were found to be the key factors for the drug efficacy in the 3D tumor model, governed by the Cu+2/Cu+1 redox potential. A nontoxic in vivo single-dose evaluation for two binuclear mixed-valence Cu+1/Cu+2 redox-active coordination compounds, 72k and 61k, was conducted.
We have synthesized and characterized a panel of new binuclear mixed valence Cu(I,II) complexes containing substituted 2-alkylthio-5-arylmethylene-4H-imidazolin-4-ones with unusual structure. These complexes are shown to be cytotoxic for various cell lines. We have found that these compounds did not intercalate DNA, inhibited number of polymerases (telomerase predominantly), accumulated in the cell nucleus, and caused DNA degradation. Preliminary studies revealed that lead compound inhibited human breast adenocarcinoma growth in mice model.
The biodistribution of chemotherapy compounds within tumor tissue is one of the main challenges in the development of antineoplastic drugs, and techniques for simple, inexpensive, sensitive, and selective detection of various analytes in tumors are of great importance. In this paper we propose the use of platinized carbon nanoelectrodes (PtNEs) for the electrochemical detection of platinum-based drugs in various biological models, including single cells and tumor spheroids in vitro and inside solid tumors in vivo. We have demonstrated the quantitative direct detection of Pt(II) in breast adenocarcinoma MCF-7 cells treated with cisplatin and a cisplatin-based DNP prodrug. To realize the potential of this technique in advanced tumor models, we measured Pt(II) in 3D tumor spheroids in vitro and in tumor-bearing mice in vivo. The concentration gradient of Pt(II) species correlated with the distance from the sample surface in MCF-7 tumor spheroids. We then performed the detection of Pt(II) species in tumor-bearing mice treated intravenously with cisplatin and DNP. We found that there was deeper penetration of DNP in comparison to cisplatin. This research demonstrates a minimally invasive, real-time electrochemical technique for the study of platinum-based drugs.
In recent research paper Dr. Suxing Jin et al. reported two multispecific platinum(IV) complexes DNP and NP with non‐steroidal anti-inflammatory drug naproxen (NPX) as axial ligand(s). Herein, we сlarify a...
A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 μM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 μM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 μM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 μM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.
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