Riccardo Wanke

Cu(I) Complexes Bearing the New Sterically Demanding and Coordination Flexible Tris(3-phenyl-1-pyrazolyl)methanesulfonate Ligand and the Water-Soluble Phosphine 1,3,5-Triaza-7-phosphaadamantane or Related Ligands

The new sterically hindered scorpionate tris(3-phenylpyrazolyl)methanesulfonate (Tpms(Ph))(-) has been synthesized and its coordination behavior toward a Cu(I) center, in the presence of 1,3,5-triaza-7-phosphaadamantane (PTA), N-methyl-1,3,5-triaza-7-phosphaadamantane tetraphenylborate ((mPTA)[BPh4]) or hexamethylenetetramine (HMT) has been studied. The reaction between Li(Tpms(Ph)) (1) and [Cu(MeCN)4][PF6] yields [Cu(Tpms(Ph))(MeCN)] (2) which, upon further acetonitrile displacement on reaction with PTA, HMT, or (mPTA)[BPh4], gives the corresponding complexes [Cu(Tpms(Ph))(PTA)] (3), [Cu(Tpms(Ph))(HMT)] (4), and [Cu(Tpms(Ph))(mPTA)][PF6] (5). All the compounds have been characterized by (1)H, (31)P, (13)C, COSY or HMQC-NMR, IR, elemental analysis, and single crystal X-ray diffraction. In the complexes (3) and (5), which bear a phosphine ligand (i.e., PTA and mPTA, respectively), the new scorpionate ligand shows the typical N, N, N-coordination mode, whereas in (2) and (4), bearing a N-donor ligand (i.e., MeCN and HMT, respectively), it binds the metal via the N,N,O chelating mode, involving the sulfonate moiety.

Persistent Hydrogen‐Bonded and Non‐Hydrogen‐Bonded Phenoxyl Radicals

The production of stable phenoxyl radicals is undoubtedly a synthetic chemical challenge. Yet it is a useful way to gain information on the properties of the biological tyrosyl radicals. Recently, several persistent phenoxyl radicals have been reported, but only limited synthetic variations could be achieved. Herein, we show that the amide-o-substituted phenoxyl radical (i.e. with a salicylamide backbone) can be synthesised in a stable manner, thereby permitting easy synthetic modifications to be made through the amide bond. To study the effect of H-bonding on the properties of the phenolate/phenoxyl radical redox couple, simple H-bonded and non-H-bonded o,p-tBu-protected salicylamidate compounds have been prepared. Their redox properties were examined by cyclic voltammetry and showed a fully reversible one-electron oxidation process to the corresponding phenoxyl radical species. Remarkably, the redox potential appears to be correlated, at least partially, with H-bond strength, as relatively large differences (ca. 300 mV) in the redox potential between H-bonded and non-H-bonded phenolate salts are observed. The corresponding phenoxyl radicals produced electrochemically are persistent at room temperature for at least an hour; their UV/Vis and EPR characterisation is consistent with that of phenoxyl radicals, which makes them excellent models of biological tyrosyl radicals. The analyses of the experimental data coupled with theoretical calculations indicate that both the deviation from planarity of the amide function and intramolecular H-bonding influence the oxidation potential of the phenolate. The latter H-bonding effect appears to be predominantly exerted on the phenolate and not (or only a little) on the phenoxyl radical. Thus, in these systems the H-bonding energy involved in the phenoxyl radical appears to be relatively small.

Synthesis and Coordination Chemistry of a New N-4-Polydentate Class of Pyridyl-Functionalized Scorpionate Ligands: Complexes of Fe-II, Zn-II, V-IV, Pd-II and Use for Heterobimetallic Systems

The new potentially N(4)-multidentate pyridyl-functionalized scorpionates 4-((tris-2,2,2-(pyrazol-1-yl)ethoxy)methyl)pyridine (TpmPy, (1)) and 4-((tris-2,2,2-(3-phenylpyrazol-1-yl)ethoxy)methyl)pyridine (TpmPy(Ph), (2)) have been synthesized and their coordination behavior toward Fe(II), Ni(II), Zn(II), Cu(II), Pd(II), and V(III) centers has been studied. Reaction of (1) with Fe(BF(4))(2) x 6 H(2)O yields [Fe(TpmPy)(2)](BF(4))(2) (3), that, in the solid state, shows the sandwich structure with trihapto ligand coordination via the pyrazolyl arms, and is completely low spin (LS) until 400 K. Reactions of 2 equiv of (1) or (2) with Zn(II) or Ni(II) chlorides give the corresponding metal complexes with general formula [MCl(2)(TpmPy*)(2)] (M = Zn, Ni; TpmPy* = TpmPy, TpmPy(Ph)) (4-7) where the ligand is able to coordinate through either the pyrazolyl rings (in case of [Ni(TpmPy)(2)]Cl(2) (5)) or the pyridyl-side (for [ZnCl(2)(TpmPy)(2)] (4), [ZnCl(2)(TpmPy(Ph))(2)] (6) and [NiCl(2)(TpmPy(Ph))(2)] (7)). The reaction of (1) with VCl(3) gives [VOCl(2)(TpmPy)] (8) that shows the N(3)-pyrazolyl coordination-mode. Moreover, (1) and (2) react with cis-[PdCl(2)(CH(3)CN)(2)] to give the disubstituted complexes [PdCl(2)(TpmPy)(2)] (9) and [PdCl(2)(TpmPy(Ph))(2)] (10), respectively, bearing the scorpionate coordinated via the pyridyl group. Compounds (9) and (10) react with Fe(BF(4))(2) to give the heterobimetallic Pd/Fe systems [PdCl(2)(mu-TpmPy)(2)Fe](BF(4))(2) (11) and [PdCl(2)(mu-TpmPy(Ph))(2)Fe(2)(H(2)O)(6)](BF(4))(4) (13), respectively. Compound (11) can also be formed from reaction of (3) with cis-[PdCl(2)(CH(3)CN)(2)], while reaction of (3) with Cu(NO(3))(2) x 2.5 H(2)O generates [Fe(mu-TpmPy)(2)Cu(NO(3))(2)](BF(4))(2) (12), confirming the multidentate ability of the new chelating ligands. The X-ray diffraction analyses of compounds (1), (3), (4), (5), and (9) are also reported.

The role of competitive binding to human serum albumin on efavirenz-warfarin interaction: a nuclear magnetic resonance study

The potential for co-prescription of the anti-human immunodeficiency virus (anti-HIV) drug efavirenz (EFV) and the oral anticoagulant warfarin (WAR) is currently high as EFV is a drug of choice for HIV type 1 infection and because cardiovascular disease is increasing among HIV-infected individuals. However, clinical reports of EFV-WAR interaction, leading to WAR overdosing, call for elucidation of the mechanisms involved in this drug-drug interaction. Here we present the first report demonstrating competition of the two drugs for the same binding site of human serum albumin. Using ligand-based nuclear magnetic resonance experiments, this study proves that EFV has an effect on the concentration of free WAR. This previously unidentified EFV-WAR interaction represents a potential risk factor that should be taken into account when considering treatment options.

Chapter One – Insights into the Role of Bioactivation Mechanisms in the Toxic Events Elicited by Non-nucleoside Reverse Transcriptase Inhibitors

Abstract The indisputable benefits of combined antiretroviral therapies (cARTs) have lead to a dramatic change in the prognosis of human immunodeficiency virus (HIV) infection; a life-threatening disease a few decades ago is now perceived as a chronic illness in developed countries. However, as the eradication of HIV seems unlikely in the near future, chronic treatment with cART is unavoidable and increased concerns regarding the long-term adverse effects of these therapies are emerging. According to the World Health Organization, the most globally prescribed initial cART includes a non-nucleoside reverse transcriptase inhibitor (NNRTI). The currently approved NNRTIs are a class of chemically distinct compounds that share the possibility of undergoing biotransformation into electrophilic metabolites capable of reacting with biomacromolecules to afford covalent DNA and protein adducts that could be at the genesis of toxicity. Insights into the bioactivation mechanisms of the NNRTIs nevirapine, efavirenz, etravirine, and rilpivirine are presented in this review.

A novel di-compartmental bis-(2-hydroxyisophtalamide) macrocyclic ligand and its mononuclear Cu(II) and Ni(II) complexes

The synthesis and characterisation of the new di-compartmental bis-(2-hydroxyisophtalamide) macrocyclic pro-ligand, LH(6), which comprises two phenol-diamide units linked by ethylene bridges, is herein reported, together with its corresponding di-phenolate salt, [NBu(4)](2)[LH(4)]. The three macrocyclic compounds, [LH(4)(OMe)(2)] (protected ligand), LH(6) and [LH(4)][NBu(4)](2) were fully characterised including X-ray crystallography for [LH(4)(OMe)(2)] and [NBu(4)](2)[LH(4)]. The results of solid-state and solution studies have indicated that the macrocycle can adopt specific conformations, which are influenced by H-bonding interactions as well as the deviation of the amide carbonyl relative to the phenol plane. LH(6) reacts with M(II)(acetate)(2)·(H(2)O)(6) (M = Ni, Cu) in a 1 : 1 ratio in the presence of 4 eq of [NBu(4)](OH) in methanol to afford the dianionic [M(LH(2))](2-) complexes, (2-) and (2-), respectively. The X-ray crystallography, EPR, NMR and UV-vis spectroscopic data, combined with DFT calculations, indicate that (2-) and (2-) are unique unsymmetrical square planar mononuclear complexes that are intramolecularly H-bonded. Thus, one macrocyclic compartment contains a M(II)-N(2)O(2) centre resulting from the tetra-anionic di-phenolato di-amidato ligation; the other compartment possesses two protonated amide N-H groups that are H-bonded the coordinated phenolate O atoms. This represents a unique example in which a phenolate is both coordinated and intramolecularly H-bonded. This H-bonding appears unusually strong as revealed by N(H/D) exchange experiments; and may be responsible for the stability of the mononuclear complex, and the difficulty in isolating the corresponding dinuclear complex [M(2)(L)](2-).

Biomimetic oxidation of aromatic xenobiotics: synthesis of the phenolic metabolites from the anti-HIV drug efavirenz

We report the oxidation of the first line anti-HIV drug efavirenz (EFV), mediated by a bio-inspired nonheme Fe-complex. Depending upon the experimental conditions this system can be tuned either to yield the major EFV metabolite, 8-hydroxy-EFV, in enantiomerically pure form or to mimic cytochrome P450 (CYP) activity, yielding 8-hydroxy-EFV and 7-hydroxy-EFV, the two phenolic EFV metabolites reported to be formed in vivo. The successful oxidation of the anti-estrogen tamoxifen and the equine estrogen equilin into their CYP-mediated metabolites supports the general application of bio-inspired nonheme Fe-complexes in mirroring CYP activity.

INTEGRATION OF CELLULAR AND MOLECULAR ENDPOINTS TO ASSESS THE TOXICITY OF POLYCYCLIC AROMATIC HYDROCARBONS IN HEPG2 CELL LINE

Polycyclic aromatic hydrocarbons (PAHs) are persistent pollutants present in the environment with known mutagenic and carcinogenic properties. In the present study the effects of exposure to single or multiple doses of benzo[a]anthracene (BaA), pyrene (Pyr), and 3 halogenated derivatives of these compounds (1-chloropyrene, 1-bromopyrene [1-BrPyr], and 7-chlorobenzo[a]anthracene [7-ClBaA]) were evaluated in a liver-derived human cell line (HepG2). Cytotoxicity as assessed by the classic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red assays showed a mild toxic effect in response to single or multiple dose exposure for up to 72 h, except for multiple dose exposure to BaA and 7-ClBaA (1 μM/d for 4 d) and single exposure to 10 μM BaA. Furthermore, selective mitochondrial and lysosomal toxicity was observed for Pyr and BaA series, respectively. To understand the underlying molecular mechanisms responsible for this effect, reactive oxygen species production, mitochondrial membrane depolarization, lysosomal pH, DNA fragmentation, and early and late apoptosis mediators were evaluated after exposure to single doses of the compounds. All compounds were able to trigger oxidative stress after 24 h as measured by catalase activity, and a good correlation was found between mitochondrial membrane depolarization, lysosomal pH increase, and MTT and neutral red assays. Evaluation of cell death mediators showed that caspase-3/7, but not annexin-V, pathways were involved in toxicity triggered by the studied compounds. The integration of all results showed that 1-BrPyr and BaA have a higher toxicity potential. Environ Toxicol Chem 2017;36:3404-3414.

A Cross-genre Study of the (Ec)Static Perspective of Today’s Music

This article explores a particular perspective, shared across various contemporary musical currents, that focuses on sound itself as a complex entity. Through the analysis of certain fundamental musical elements and sonic characteristics, this study develops a new method for comparing different genres characterised by a similar approach to sound. Using the benefits of audio, spectra and score examinations, this strategy is applied to post-spectralist and minimalist compositions (e.g. G. F. Haas, B. Lang, R. Nova, G. Verrando), as well as glitch, electronic and basic-channel style pieces (Pan Sonic, R. Ikeda, Raime). Nine musical attributes are identified that help trace a new outlook on various currents in today’s music. The study’s contribution lies in its revealing of a shared musical perspective between different artistic practices, and in the establishment of new connections between pieces that belong to unrelated contexts.

Quinoid derivatives of the nevirapine metabolites 2-hydroxy- and 3-hydroxy-nevirapine: activation pathway to amino acid adducts

Nevirapine (NVP) is the non-nucleoside HIV-1 reverse transcriptase inhibitor most commonly used in developing countries, both as a component of combined antiretroviral therapy and to prevent mother-to-child transmission of the virus; however, severe hepatotoxicity and serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid derivatives prone to react with bionucleophiles and initiate toxic responses. We investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with bionucleophiles. Both metabolites yielded the same ring-contraction product upon oxidation with Fremys salt in aqueous medium. This is consistent with the formation of a 2,3-NVP-quinone intermediate, which upon stabilization by reduction was fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Additionally, we established that the oxidative activation of 2-hydroxy-NVP involved the transient formation of both the quinone and a quinone-imine, whereas 3-hydroxy-NVP was selectively converted into 2,3-NVP-quinone. The oxidations of 2-hydroxy-NVP and 3-hydroxy-NVP in the presence of the model amino acids ethyl valinate (to mimic the highly reactive N-terminal valine of hemoglobin) and N-acetylcysteine were also investigated. Ethyl valinate reacted with both 2,3-NVP-quinone and NVP-quinone-imine, yielding covalent adducts. By contrast, neither 2,3-NVP-quinone nor NVP-derived quinone-imine reacted with N-acetylcysteine. The product profile observed upon Fremys salt oxidation of 2-hydroxy-NVP in the presence of ethyl valinate was replicated with myeloperoxidase-mediated oxidation. Additionally, tyrosinase-mediated oxidations selectively yielded 2,3-NVP-quinone-derived products, while quinone-imine-derived products were obtained upon lactoperoxidase catalysis. These observations suggest that the metabolic conversion of phenolic NVP metabolites into quinoid electrophiles is biologically plausible. Moreover, the lack of reaction with sulfhydryl groups might hamper the in vivo detoxification of NVP-derived quinone and quinone-imine metabolites via glutathione conjugation. As a result, these metabolites could be available for reaction with nitrogen-based bionucleophiles (e.g., lysine residues of proteins) ultimately eliciting toxic events.