A series of 6 substitutionally inert and luminescent iridium(iii) antitumor agents of the type [Ir(CN)(NN)][PF] containing a benzimidazole NN ligand with an ester group as a handle for further functionalization has been prepared. They exhibit IC values in the high nanomolar range in some ovarian and breast cancer cell lines (approximately 100× more cytotoxic than cisplatin (CDDP) in MDA-MB-231) and are located in the actin cortex predominantly as shown by confocal luminescence microscopy. This discovery could open the door to a new large family of drug bioconjugates with diverse and simultaneous functions.
The substitution inert platinum agent [Pt(1S,2Sdiaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] 2+ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.
To design an anticancer drug capable of inhibiting not only the proliferation of the differentiated tumor cells but also reducing the tumorigenic capability of cancer stem cells (CSCs), the new PtIV prodrugs with axial cinnamate ligands were synthesized. We demonstrate their superior antiproliferative activity in monolayer and 3D spheroid antiproliferative activity tests using panel of cancer cell lines. An outstanding activity was found against rhabdomyosarcoma cells, one of the most problematic and poorly treatable pediatric tumors. The results also suggest that the released PtII compound inhibits antiproliferative activity of cancer cells by DNA‐damage mediated mechanism; the released cinnamic acid can trigger processes leading to differentiation, making the CSCs more sensitive to killing by the platinum part of the complex. PtIV complex with axial cinnamate ligands is the first PtIV prodrug capable of overcoming CSCs resistance and induce death in both CSCs and bulk cancer.
A remarkable array of mechanistic and pharmacological behaviours is discoveredviaclick derivatisation of asymmetric, optically pure helicate-like compounds.
Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)]Cl (2) and [Au(ACRTU) (PPh)]PF (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.
NAMI-A is a ruthenium-based drug endowed with the unique property of selectively targeting solid tumour metastases. Although two clinical studies had already been completed, limited information exists on the behavior of NAMI-A after injection into the bloodstream. PK data in humans informs us of a rather low free drug concentration, of a relatively high half-life time of elimination and of a linear relationship between the administered dose and the corresponding AUC for up to toxic doses. In the present study, we examined the chemical kinetics of albumin binding with or without the presence of reducing agents, and we evaluated how these chemical aspects might influence the in vivo PK and the in vitro ability of NAMI-A to inhibit cell migration, which is a bona fide, rapid and easy way to suggest anti-metastatic properties. The experimental data support the binding of NAMI-A to serum albumin. The reaction is facilitated when the drug is in its reduced form and, in agreement with already reported data, the adduct formed with albumin maintains the biological activity of the ruthenium drug. The formation of the adduct is favored by low ratios of NAMI-A : HSA and by the reduction of the drug with ascorbic acid. The difference in in vivo PK and the faster binding to albumin of the reduced NAMI-A seem to suggest that the drug is not rapidly reduced immediately upon injection, even at low doses. Most probably, cell and protein binding prevail over the reduction of the drug. This observation supports the thesis that the reduction of the drug before injection must be considered relevant for the pharmacological activity of NAMI-A against tumour metastases.
One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.
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