On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)2]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)2]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein. Absorbance and fluorescence titrations, mass spectrometry together with melting and viscometry tests show significant differences in the binding features between silver and gold compounds. [Au(EIA)2]Cl covalently binds BSA. It is here evidenced that the selectivity is high: low affinity and external binding for all polynucleotides and G4s are found. Conversely, in the case of [Ag(EIA)2]Cl, the binding to BSA is weak and relies on electrostatic interactions. [Ag(EIA)2]Cl strongly/selectively interacts only with double strands by a mechanism where intercalation plays the major role, but groove binding is also operative. The absence of an interaction with triplexes indicates the major role played by the geometrical constraints to drive the binding mode

A focus on the biological targets for coinage metal-NHCs as potential anticancer complexes

Metal complexes of N-heterocyclic carbene (NHC) ligands are the object of increasing attention for therapeutic purposes. Among the different metal centres, interest on Au-based compounds started with the application as anti-arthritis drugs. On the other hand, Ag(I) antimicrobial properties have been known for a long time. For Au(I)/Au(III)-NHC and Ag(I)-NHC anti-tumour and anti-proliferative properties have been quite recently demonstrated. In addition to these and as for Group 11, copper is a much less investigated metal centre, but a few papers underline its pharmacological potential. This review wants to focus on the different biological targets for these metal-based compounds. It is divided into chapters which are respectively devoted on: i) mitochondria and thiol oxidoreductase systems; ii) other relevant enzymes; iii) nucleic acids. Examples of representative coinage NHCs for each of the targets are provided together with significant references on recent advances on the topic. Moreover, a final comment summarises the aspects enlightened by each chapter and provides some hints to better understand the metal-NHCs mechanistic behaviour based on structure-activity relationships

Different outcomes in the reactions of WCl6 with carboxylic acids

The reactions of WCl6 with a selection of carboxylic acids were investigated by using dichloromethane as reaction medium. The addition of pyridine-3-carboxylic acid (niacin) to WCl6 gave [C5H4NHC(O)Cl][WOCl5], 1, in 75% yield via selective Cl/O interchange. WCl6 reacted with RCO2H (R = CH3, CBr3, CHCl2) in 1:2 ratio resulting in the formation of HCl and the respective acyl chlorides, RC(O)Cl. WOCl4(kappa(1)-CH3CO2H), 2, was isolated from WCl6/CH3CO2H in 41% yield. The 1:2 reaction of WCl6 with CCl3CO2H proceeded with HCl release affording a mixture of WCl6(O2CCCl3), 3, and WCl4(O2CCCl3)(2), 4. Compound 3 was isolated from WCl6/CCl3CO2H (1:1 ratio) in 60% yield. All the metal products were characterized by analytical and spectroscopic techniques. The crystal structure of 1 was ascertained by X-ray diffractometry. DFT calculations were carried out in order to shed light into structural, mechanistic and thermodynamic features. (C) 2015 Elsevier Ltd. All rights reserved

Interaction of gold N-heterocyclic carbenes with nucleic acids

Metal complexes with N-heterocyclic carbenic ligands (NHCs) have found applications not only in catalysis but also as anticancer agents [1]. In particular, Gold-NHCs turned out to be particular promising. First of all, they are stable complexes whose synthesis is relatively simple. Moreover, their biological and targeting properties can be tuned by modifying substituents on the carbenic ligand. Preclinical studies showed antiproliferative properties both in vitro and in vivo andencouraging results on selectivity [2]. These compounds target mitochondria and proteins, among which of paramount importance is the selenoenzyme Thioredoxin reductase. However, more recent studies also consider their interaction with dsDNA or G-quadruplexes [3]. Indeed, on the one hand is now clear that most often one single target cannot exhaustively justify the biological action of a metallodrug; on the other hand, cancer is such a complex series of genetic diseases that a single target therapy may not be effective enough. Therefore, some of the latest approaches on anticancer metallodrug design include the synthesis of multitargeting platforms [4]. Within this frame, we synthesized and chemically characterized a Gold monocarbene with a planar aromatic moiety able to interact with dsDNA. Binding with natural DNA has been characterized by means of different spectroscopic methods. Moreover, inhibition of purified Thioredoxin reductase has been measured. Preliminary in vitro cytotoxicity experiments show moderate antiproliferative activity. In addition, single crystals of bis-(1-buthyl-3-methyl)imidazol-2-ylidene-gold hexafluorophosphate with the human telomere Tel-23 have been obtained. The adduct has been also characterized in solution by means of ESI-MS, circular dichroism and melting experiments. [1] L. Oehninger, R. Rubbiani, I. Ott, Dalton Trans 2013, 42, 3269- 3284. [2] Zou T., LumC.T., Lok C-N., Zhanga J-J., Che C-M., Chem. Soc. Rev., 2015, 44, 8786-8801. [3] F. Papi, C. Bazzicalupi, M. Ferraroni, L. Massai, B. Bertrand, P. Gratteri, D. Colangelo, L. Messori, Chem. Eur. J., 2017, 23, 13784- 13791. [4] T. Zou, C.N. Lok, P.K. Wan, Z.F. Zhang, S.K. Fung, C.M. Che, Curr. Op. Chem. Biol., 2018, 43, 30-36

124I Radiolabeling of a AuIII-NHC Complex for In Vivo Biodistribution Studies

AuIII complexes with N-heterocyclic carbene (NHC) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Reported herein is the synthesis of new AuIII-NHC complexes by direct oxidation with radioactive [124I]I2 as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET). While in vitro analyses provide direct evidence for the importance of AuIII-to-AuI reduction to achieve full anticancer activity, in vivo studies reveal that a fraction of the AuIII-NHC prodrug is not immediately reduced after administration but able to reach the major organs before metabolic activation

DNA interaction of a fluorescent, cytotoxic pyridinimino platinum(II) complex

New pyridinimino complexes of platinum(II) [PtCl2(N^N-R)] (N^N = 2-pyridylmethanimino, R = -(CH2)2O(CH2)2OH, -(CH)2O(CH2)2OCH2Pyr), Pyr = pyren-1-yl) have been prepared. They are characterized by a dioxygenated alkyl side chain and, in one case, by a fluorescent terminal 1-pyrenyl residue. The complexes were characterized by elemental analysis, IR, 1H–, 13C–and 195Pt NMR spectroscopies. For [PtCl2(N^N-(CH2)2O(CH2)2OH] the molecular structure was determined by single crystal X-ray diffraction. The complexes are soluble and stable in DMSO/H2O (80/20, v/v). The pyrenyl terminated compound was tested as antiproliferative agent against selected human cancer cell lines. Comparable cytotoxic effect was obtained on human ovarian carcinoma A-2780 and A-2780cis cells, thus suggesting a certain ability to circumvent cisplatin resistance. The interaction of this complex with DNA was investigated by linear flow dichroism and by spectrophotometric (absorbance and fluorescence) titrations. Both techniques enlightened the presence of a complex mode of interaction with DNA, involving both groove binding and intercalation