Novel dinuclear gold(i) complexes containing bis(diphenylphosphano)alkanes and (biphenyl-2-yl)(di-tert-butyl)phosphane: synthesis, structural characterization and anticancer activity

Four novel dinuclear phosphanegold(I) complexes containing bis(diphenylphosphano)alkanes and (biphenyl-2-yl)di-tert-butylphosphane (Bdbp), [Au2(Bdbp)2(Dppe)](PF6)2 (1), [Au2(Bdbp)2(Dppp)](PF6)2 (2), [Au2(Bdbp)2(Dppb)](PF6)2 (3) and [Au2(Bdbp)2(Dpma)](PF6)2 (4) (where Dppe = 1,2-bis(diphenylphosphano)ethane, Dppp = 1,3-bis(diphenylphosphano)propane, Dppb = 1,4-bis(diphenylphosphano)butane and Dpma = bis[2-(diphenylphosphano)methyl]amine), were synthesized and characterized by elemental analysis, FTIR and NMR spectroscopies. The structures of three of the complexes (1, 2 and 4) were determined by X-ray crystallography, which reveals that the complexes exist as dinuclear species, in which the gold(I) atom is linearly coordinated to the phosphorus (P2) and (P1) atoms. The in vitro cytotoxicity of the complexes was investigated against two established human cancer cell models, colorectal (HCT-116) and breast (MCF7) cancer cells. All four complexes showed excellent cytotoxicity against both cell models with significantly lower IC50 values than that of cisplatin. The mitochondrial membrane potential (ΔΨm) was also assessed to get a better understanding of the underlying molecular mechanism of toxicity. The exposure of the complexes for 24 hours resulted in mitochondrial depolarization (reduced mitochondrial health) thereby potentially triggering the release of cytochrome c and apoptotic cell death. Together, the findings of our studies demonstrate that the novel gold(I) complexes have superior anticancer activity compared to conventional cisplatin, which is potentially mediated through the disruption of ΔΨm and induction of apoptosis.No Full Tex

Possible incorporation of free N7-platinated guanines in DNA by DNA polymerases, relevance for the cisplatin mechanism of action

Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used anticancer drugs. The main cellular target of cisplatin is DNA, where the platinum atom is able to form covalent bonds with the N7 of purines. It is commonly accepted that there is a direct attack of cisplatin to DNA. But it should be noted that, inside cells, free purine bases, which can react with cisplatin, are also available. Free bases have many functional roles, not least the constitution of building blocks for the synthesis of new DNA and RNA molecules. For this reason, under physiological conditions, the erroneous insertion of platinated bases in the synthesized nucleic acids could compete with direct DNA/RNA platination. Moreover, due to the lower sterical hindrance offered by single nucleobases with respect to nucleic acids, platination is expected to be even easier for free purines with respect to DNA and RNA. We have recently shown, for the first time, that platinated DNA can be formed in vitro by Taq DNA polymerase promoted incorporation of platinated purines. Cytotoxicity tests with [Pt(dien)(N7-G)], dien = diethylenetriamine, G = 5’-dGTP, 5’-dGDP, 5’-GMP, 5’-dGMP, GUO, dGUO, complexes on HeLa cancer cells support this hypothesis being the relative cytotoxicity of [Pt(dien)(N7-G)] derivatives clearly related to their bioavailability. In vivo platination of free purines before their incorporation in nucleic acids opens therefore new perspectives in platinum based antitumour drugs, for both action mechanism better understanding and new molecular design

Noble metals strip peptides from class II MHC proteins

Class II major histocompatibility complex (MHC) proteins are essential for normal immune system function but also drive many autoimmune responses. They bind peptide antigens in endosomes and present them on the cell surface for recognition by CD4(+) T cells. A small molecule could potentially block an autoimmune response by disrupting MHC-peptide interactions, but this has proven difficult because peptides bind tightly and dissociate slowly from MHC proteins. Using a high-throughput screening assay we discovered a class of noble metal complexes that strip peptides from human class II MHC proteins by an allosteric mechanism. Biochemical experiments indicate the metal-bound MHC protein adopts a \u27peptide-empty\u27 conformation that resembles the transition state of peptide loading. Furthermore, these metal inhibitors block the ability of antigen-presenting cells to activate T cells. This previously unknown allosteric mechanism may help resolve how gold(I) drugs affect the progress of rheumatoid arthritis and may provide a basis for developing a new class of anti-autoimmune drugs