Chemical strategies to modify amyloidogenic peptides using iridium(III) complexes: coordination and photo-induced oxidation

Amyloidogenic peptides are considered central pathological contributors towards neurodegeneration as observed in neurodegenerative disorders [e.g., amyloid-?? (A??) peptides in Alzheimer's disease (AD)]; however, their roles in the pathologies of such diseases have not been fully elucidated since they are challenging targets to be studied due to their heterogeneous nature and intrinsically disordered structure. Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration. Herein, we report effective chemical strategies for modification of A?? peptides (i.e., coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(III) complex in a photo-dependent manner. Such peptide variations can be achieved by our rationally designed Ir(III) complexes (Ir-Me, Ir-H, Ir-F, and Ir-F2) leading to significantly modulating the aggregation pathways of two main A?? isoforms, A??40 and A??42, as well as the production of toxic A?? species. Overall, we demonstrate chemical tactics for modification of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and photophysical properties of transition metal complexes

The interaction of metal compounds with protein targets: new tools in medicinal chemistry and chemical biology

In cells and organisms, metal complexes can be specifically designed to interact with biomolecules and accordingly alter important biological processes. These interactions have been widely explored for targeting specific biological functions and diseases. In fact, several studies have demonstrated that inorganic chemistry offers significant diversity and versatility for the preparation of highly potent protein modulators (e.g. inhibitors). Moreover, both coordination and organometallic complexes featuring favourable chemico-physical properties (e.g. luminescence) have proven to be well suited to image proteins and peptides in living cells by various methods. An inherent advantage of metal complexes is the accessibility of multiple oxidation states, and overall charge and geometries, which makes them attractive from the point of view of chemical design. However, these properties can become a disadvantage if not controlled and fine-tuned in the biological application. In this review, we generally discuss the use of metal compounds, targeting proteins and/or peptides, in medicinal chemistry and chemical biology, and then focus on representative recent examples and applications. Furthermore, we highlight future challenges and attractive perspectives in the field, which may stimulate research and define new frontiers in bioinorganic chemistry

The reactions of alpha-amino acids and alpha-amino acid esters with high valent transition metal halides: synthesis of coordination complexes, activation processes and stabilization of alpha-ammonium acylchloride cations

Titanium tetrachloride smoothly reacted with a selection of alpha-amino acids (aaH) in affording yellow to orange solid coordination compounds, 1a-d, in 70-78% yields. The salts [NHEt3][TiCl4(aa)], 2a- b, were obtained from TiCl4/aaH/NEt3 (aa = L- phenylalanine, N, N- dimethylphenylalanine), in 60-65% yields. The complex, 3, was isolated from the reaction of L- proline with NbCl5/(NHPr2)-Pr-i, performed in CH2Cl2 at room temperature. The X-ray structure of 3 features a bridging (E)-1,2-bis(3,4-dihydro-2H-pyrrol-5-yl) ethene- 1,2- diolate ligand, resulting from the unprecedented C-C coupling between two proline units. Unusually stable alpha-ammonium acyl chlorides were prepared by the reactions of PCl5/MCln (MCln = NbCl5, WCl6) with L- proline, N, N- dimethylphenylalanine, sarcosine and Lmethionine. MX5 (M - Nb, Ta; X - F, Cl) reacted with L-eucine methylester and L- proline ethylester to give ionic coordination compounds, [MX4L2][ MX6] ( M = Nb, L = Me2CHCH2CH( NH2) CO2Me, X = F, 9; Cl, 11a; M = Nb, X = Cl, L = HNCH2CH3CH3CHCO2Et, 11c; Ta, 11d), in moderate to good yields. [NbCl5( Me2CHCH2CHNH3CO2Me)][ NbCl6], 12, was isolated as a co-product of the reaction of NbCl5 with L- leucine isopropylester, and crystallographically characterized. The reaction of NbCl5 with L- serine isopropylester afforded NbCl3 (OCH2CHNHCO2 Pr-i), 13, in 66% yield. The activation of the ester O-R bond was observed in the reactions of L- leucine methyl ester with NbF5 and L- proline ethyl ester with MBr5 (M = Nb, Ta), these reactions proceeding with the release of EtF and EtBr, respectively. All the metal products were characterized by analytical and spectroscopic methods, while DFT calculations were carried out in order to provide insight into the structural and mechanistic aspects