Iridium(I) Compounds as Prospective Anticancer Agents: Solution Chemistry, Antiproliferative Profiles and Protein Interactions for a Series of Iridium(I) N-Heterocyclic Carbene Complexes

Aseries of structurally related mono-and bis-NHC–iridium(I) (NHC:N-heterocyclic carbene) complexeshave been investigatedfor their suitability as potential anti-cancer drugs.Their spectral behaviour in aqueous buffersunder physiologic al-like conditions and their cytotoxicityagainstthe cancercell lines MCF-7 and HT-29are reported.Notably,almostall complexes exhibit significant cytotoxic ef-fects towards both cancer cell lines. In general,the cationicbis-carbene complex es show higherstabilityand greater an-ticanceractivity than their neutral mono-carbene analogueswith IC50valuesinthe high nanomolar range.Furthermore,to gain initialmechanistic insight, the interactions of theseiridium(I)–NHC complexes with two model proteins,namelylysozyme and cytochrome c, were exploredbyHR-ESI-MSanalyses. The different protein metalation patternsofthecomplexes can be roughlyclassified into two distinctgroups. Those interactions give us afirst idea about the pos-sible mechanism of action of this class of compounds. Over-all, our findings show that iridium(I)–NHC complexesrepre-sent very interesting candidates forfurther development asnew metal-based anticancer drugs

Drug repositioning: auranofin as a prospective antimicrobial agent for the treatment of severe staphylococcal infections

Auranofin, (AF), a gold(I) complex in clinical use for the therapy of rheumatoid arthritis, is reported here to produce remarkable bactericidal effects in vitro against Staphylococcus sp. Noticeably, a similar antimicrobial action and potency are also noticed toward a few methicillin-resistant Staphylococcus aureus strains but not toward Escherichia coli. The time and concentration dependencies of the antimicrobial actions of AF have been characterized through recording time kill curves, and a concentration dependent profile highlighted. Overall, the present results point out that auranofin might be quickly and successfully repurposed for the treatment of severe bacterial infections due to resistant Staphylococci

A case of extensive protein platination: the reaction of lysozyme with a Pt( )–terpyridine complex

The interaction between a Pt(ii)–terpyridine cytotoxic compound and the model protein lysozyme has been investigated by X-ray crystallography and electrospray mass spectrometry under different experimental conditions. The compound shows a high reactivity with the model protein

Cisplatin binding to angiogenin protein: new molecular pathways and targets for the drug's anticancer activity

Cisplatin (CisPt), a platinum-based chemotherapeutic widely used in the treatment of various cancers, has multiple mechanisms of action, including nuclear DNA (nDNA) and mitochondrial DNA (mDNA) damage and cytoskeletal perturbations affecting, in turn, the membrane transporter activity. CisPt binding to proteins and enzymes may modulate its biochemical mechanism of action and is associated with cancer cell resistance to the drug. In this work, we investigate the interaction between cisplatin and angiogenin (Ang), a protein strongly expressed in many types of cancer and a potent angiogenic factor. The adduct formed upon reaction of CisPt with Ang (Ang@CisPt) was characterized by X-ray crystallography to evidence the exact platination site and by UV-visible (UV-vis) absorption and circular dichroism (CD) spectroscopies to shed light on any possible change in the protein conformation. Furthermore, high-resolution electrospray ionization (ESI) mass spectrometry was utilized to evaluate the Ang : CisPt stoichiometry of the Ang@CisPt adduct. The effect of the Ang@CisPt adduct on a prostate cancer cell line (PC-3) was tested by colorimetric assays in terms of cell viability, at both levels of nuclear and mitochondrial damage, and reactive oxygen species (ROS) production. Cellular imaging by laser scanning confocal microscopy (LSM) was utilized to scrutinize the cytoskeleton actin reorganization and the lysosome and mitochondria organelle perturbation. These studies highlight the possibility of new molecular pathways and targets for CisPt activity

Interactions between Anticancertrans-Platinum Compounds and Proteins: Crystal Structures and ESI-MS Spectra of Two Protein Adducts of trans-(Dimethylamino)(methylamino)dichloridoplatinum(II)

The adducts formed between trans- (dimethylamino)(methylamino)dichloridoplatinum(II), [t-PtCl2(dma)(ma)], and two model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease, were independently characterized by X-ray crystallography and electrospray ionization mass spectrometry. In these adducts, the PtII center, upon chloride release, coordinates either to histidine or aspartic acid residues while both alkylamino ligands remain bound to the metal. Comparison with the cisplatin derivatives of the same proteins highlights for [t-PtCl2(dma)(ma)] a kind of biomolecular metalation remarkably different from that of cisplatin

Tyrosine kinase inhibitors (TKIs) for ovarian cancer treatment: from organic to inorganic chemotherapeutics towards selectivity-a perspective overview

Ovarian cancer (OC) is a lethal gynecologic cancer in industrialized countries. Treatments for OC include the surgical removal and chemotherapy. In the last decades, improvements have been made in the surgery technologies, drug combinations and administration protocols, and in diagnosis. However, mortality from OC is still high owing to recurrences and insurgence of drug resistance. Accordingly, it is urgent the development of novel agents capable to effectively target OC. In this respect, tyrosine kinase inhibitors (TKIs) may play an important role. Most of TKIs developed and tested so far are organic. However, owing to their chemical versatility, also metals can be exploited to design selective and potent TKIs. We provide a short and easy-to-read overview on the main organic TKIs with a summary of those that entered clinical trials. Additionally, we describe the potential of metal-based TKIs, focusing on this overlooked family of compounds that may significantly contribute towards the concept of precision-medicine

Chlorido and bromido oxaliplatin analogues as potential agents for CRC treatment: Solution behavior, protein binding and cytotoxicity evaluation

Despite the widespread use of platinum drugs in the treatment of colorectal cancer (CRC), due to the heavy side effects and to intrinsic or acquired Pt resistance, new and more efficient drugs are urgently needed. Starting from the encouraging results obtained for the complex PtI2(DACH), we summarise here our recent advances, reporting data on the synthesis and the chemical and biological features of two oxaliplatin analogues i.e. PtBr2(DACH) and PtCl2(DACH). The comparative approach of these studies reveals how these analogues possess interesting and differential pharmacological properties as well as some peculiar features that may be conveniently exploited to shed light in the mechanistic aspects involved in the pharmacological action of the parent drug oxaliplatin. Furthermore, these findings may inspire the design of more effective Pt-based anticancer drugs to be used in CRC treatment

Synthesis, characterization and DNA interactions of [Pt3(TPymT)Cl3], the trinuclear platinum(II) complex of the TPymT ligand

The triplatinum complex of the 2,4,6-Tris(2-pyrimidyl)-1,3,5-triazine ligand, Pt3TPymT hereafter, has been prepared and characterized for the first time. NMR studies point out that the three platinum(II) centers possess an identical coordination environment. The interactions of Pt3TPymT with DNA were explored in comparison to the free ligand. Specifically, fluorescence, mass spectrometry, viscometry and melting measurements were carried out. In contrast to expectations, the obtained data reveal that no intercalative binding takes place; we propose that binding of Pt3TPymT to DNA mainly occurs through external/groove binding

Description of a Non-Canonical AsPt Blue Species Originating from the Aerobic Oxidation of AP-1 in Aqueous Solution

The peculiar behavior of arsenoplatin-1, ([Pt(μ-NHC(CH3)O)2ClAs(OH)2], AP-1), in aqueous solution and the progressive appearance of a characteristic and intense blue color led us to carry out a more extensive investigation to determine the nature of this elusive chemical species, which we named “AsPt blue”. A multi-technique approach was therefore implemented to describe the processes involved in the formation of AsPt blue, and some characteristic features of this intriguing species were revealed