Proton Domino Reactions at an Imidazole Relay Control the Oxidation of a TyrZ-His190 Artificial Mimic of Photosystem II.

A close mimic of P680 and the TyrosineZ-Histidine190 pair in photosystem II (PS II) has been synthesized using a ruthenium chromophore and imidazole-phenol ligands. The intramolecular oxidation of the ligands by the photoproduced Ru(III) species is characterized by a small driving force, very similar to PS II where the complexity of kinetics was attributed to the reversibility of electron transfer steps. Laser flash photolysis revealed biphasic kinetics for ligand oxidation. The fast phase (τ<50 ns) corresponds to partial oxidation of the imidazole-phenol ligand, proton transfer within the hydrogen bond, and formation of a neutral phenoxyl radical. The slow phase (5-9 µs) corresponds to full oxidation of the ligand which is kinetically controlled by deprotonation of the distant 1-nitrogen of the imidazolium. These results show that imidazole with its two protonatable sites plays a special role as a proton relay in a 'proton domino' reaction.

Second Coordination Sphere Effect Shifts CO2 to CO Reduction by Iron Porphyrin from Fe0 to FeI.

Iron porphyrins are among the most studied molecular catalysts for carbon dioxide (CO2 ) reduction and their reactivity is constantly being enhanced through the implementation of chemical functionalities in the second coordination sphere inspired by the active sites of enzymes. In this study, we were intrigued to observe that a multipoint hydrogen bonding scheme provided by embarked urea groups could also shift the redox activation step of CO2 from the well-admitted Fe(0) to the Fe(I) state. Using EPR, resonance Raman, IR and UV-Visible spectroscopies, we underpinned a two-electron activation step of CO2 starting from the Fe(I) oxidation state to form, after protonation, an Fe(III)-COOH species. The addition of another electron and a proton to the latter species converged to the cleavage of a C-O bond with the loss of water molecule resulting in an Fe(II)-CO species. DFT analyses of these postulated intermediates are in good agreement with our collected spectroscopic data, allowing us to propose an alternative pathway in the catalytic CO2 reduction with iron porphyrin catalyst. Such a remarkable shift opens new lines of research in the design of molecular catalysts to reach low overpotentials in performing multi-electronic CO2 reduction catalysis.

Time-Resolved Mechanistic Depiction of Photoinduced CO2 Reduction Catalysis on a Urea-Modified Iron Porphyrin.

The development of functional artificial photosynthetic devices relies on the understanding of mechanistic aspects involved in specialized photocatalysts. Modified iron porphyrins have long been explored as efficient catalysts for the light-induced reduction of carbon dioxide (CO2) towards solar fuels. In spite of the advancements in homogeneous catalysis, the development of the next generation of catalysts requires a complete understanding of the fundamental photoinduced processes taking place prior to and after activation of the substrate by the catalyst. In this work, we employ a state-of-the-art nanosecond optical transient absorption spectroscopic setup with a double excitation capability to induce charge accumulation and trigger the reduction of CO2 to carbon monoxide (CO). Our biomimetic system is composed of a urea-modified iron(III) tetraphenylporphyrin (UrFeIII) catalyst, the prototypical [Ru(bpy)3]2+ (bpy=2,2'-bipyridine) used as a photosensitizer, and sodium ascorbate as an electron donor. Under inert atmosphere, we show that two electrons can be successively accumulated on the catalyst as the fates of the photogenerated UrFeII and UrFeI reduced species are tracked. In the presence of CO2, the catalytic cycle is kick-started providing further evidence on CO2 activation by the UrFe catalyst in its formal FeI oxidation state.

Proton-controlled Action of an Imidazole as Electron Relay in a Photoredox Triad.

Electron relays play a crucial role for efficient light-induced activation by a photo-redox moiety of catalysts for multi-electronic transformations. Their insertion between the two units reduces detrimental energy transfer quenching while establishing at the same time unidirectional electron flow. This rectifying function allows charge accumulation necessary for catalysis. Mapping these events in photophysical studies is an important step towards the development of efficient molecular photocatalysts. Three modular complexes comprised of a Ru-chromophore, an imidazole electron relay function, and a terpyridine unit as coordination site for a metal ion were synthesized and the light-induced electron transfer events studied by laser flash photolysis. In all cases, formation of an imidazole radical by internal electron transfer to the oxidized chromophore was observed. The effect of added base evidenced that the reaction sequence depends strongly on the possibility for deprotonation of the imidazole function in a proton-coupled electron transfer process. In the complex with MnII present as a proxy for a catalytic site, a strongly accelerated decay of the imidazole radical together with a decreased rate of back electron transfer from the external electron acceptor to the oxidized complex was observed. This transient formation of an imidazolyl radical is clear evidence for the function of the imidazole group as an electron relay. The implication of the imidazole proton and the external base for the kinetics and energetics of the electron trafficking is discussed.

Dissection of Light-Induced Charge Accumulation at a Highly Active Iron Porphyrin: Insights in the Photocatalytic CO2 Reduction.

Iron porphyrins are among the best molecular catalysts for the electrocatalytic CO2 reduction reaction. Powering these catalysts with the help of photosensitizers comes along with a couple of unsolved challenges that need to be addressed with much vigor. We have designed an iron porphyrin catalyst decorated with urea functions (UrFe) acting as a multipoint hydrogen bonding scaffold towards the CO2 substrate. We found a spectacular photocatalytic activity reaching unreported TONs and TOFs as high as 7270 and 3720 h-1 , respectively. While the Fe0 redox state has been widely accepted as the catalytically active species, we show here that the FeI species is already involved in the CO2 activation, which represents the rate-determining step in the photocatalytic cycle. The urea functions help to dock the CO2 upon photocatalysis. DFT calculations bring support to our experimental findings that constitute a new paradigm in the catalytic reduction of CO2 .

Singlet fission in naturally-organized carotenoid molecules.

We have investigated the photophysics of aggregated lutein/violaxanthin in daffodil chromoplasts. We reveal the presence of three carotenoid aggregate species, the main one composed of a mixture of lutein/violaxanthin absorbing at 481 nm, and two secondary populations of aggregated carotenoids absorbing circa 500 and 402 nm. The major population exhibits an efficient singlet fission process, generating µs-lived triplet states on an ultrafast timescale. The structural organization of aggregated lutein/violaxanthin in daffodil chromoplasts produces well-defined electronic levels that permit the energetic pathways to be disentangled unequivocally, allowing us to propose a consistent mechanism for singlet fission in carotenoid aggregates. Transient absorption measurements on this system reveal for the first time an entangled triplet signature for carotenoid aggregates, and its evolution into dissociated triplet states. A clear picture of the carotenoid singlet fission pathway is obtained, which is usually blurred due to the intrinsic disorder of carotenoid aggregates.

Phthalocyanine as a Bioinspired Model for Chlorophyll f-Containing Photosystem†II Drives Photosynthesis into the Far-Red Region.

The textbook explanation that P680 pigments are the red limit to drive oxygenic photosynthesis must be reconsidered by the recent discovery that chlorophyll f (Chlf)-containing Photosystem II (PSII) absorbing at 727 nm can drive water oxidation. Two different families of unsymmetrically substituted Zn phthalocyanines (Pc) absorbing in the 700-800 nm spectral window and containing a fused imidazole-phenyl substituent or a fused imidazole-hydroxyphenyl group have been synthetized and characterized as a bioinspired model of the Chlf/TyrosineZ /Histidine190 cofactors of PSII. Transient absorption studies in the presence of an electron acceptor and irradiating in the far-red region evidenced an intramolecular electron transfer process. Visible and FT-IR signatures indicate the formation of a hydrogen-bonded phenoxyl radical in ZnPc II-OH. This study sets the foundation for the utilization of a broader spectral window for multi-electronic catalytic processes with one of the most robust and efficient dyes.

Spectroscopic Characterisation of a Bio-Inspired Ni-Based Proton Reduction Catalyst Bearing a Pentadentate N2 S3 Ligand with Improved Photocatalytic Activity.

Inspired by the sulfur-rich environment found in active hydrogenase enzymes, a Ni-based proton reduction catalyst with pentadentate N2 S3 ligand was synthesised. When coupled with [Ru(bpy)3 ]2+ (bpy=2,2'-bipyridine) as photosensitiser and ascorbate as electron donor in a 1:1 mixture of dimethylacetamide and aqueous ascorbic acid/ascorbate buffer, the catalyst showed improved photocatalytic activity compared with a homologous counterpart bearing a tetradentate N2 S2 ligand. The mechanistic pathway of photoinduced hydrogen evolution was comprehensively analysed through optical transient absorption and time-resolved X-ray absorption spectroscopy, which revealed important electronic and structural changes in the catalytic system during photoirradiation. The NiII catalyst undergoes a photoinduced metal-centred reduction to form a NiI intermediate with distorted square-bipyramidal geometry. Further kinetic analyses revealed differences in charge-separation dynamics between the pentadentate and tetradentate forms.

Final results of a prospective study of scalp cooling in preventing chemotherapy-induced alopecia.

Aim: Alopecia is a distressing effect of cancer treatments. Our study examined efficacy and safety of scalp cooling to prevent chemotherapy-induced alopecia. Materials & methods: Early breast cancer patients candidate to anthracycline and/or taxane were eligible. Dean's alopecia scale was used to classify alopecia. Results: From February 2016 to November 2018, 127 women were enrolled; 55 (43.3%) received epirubicin/cyclophosphamide (4 EC 3 weeks) followed by paclitaxel (12 P weeks); 50 (39.4%) received 4 EC 3 weeks; 20 (15.7%) received 12 P weeks/trastuzumab and 2 docetaxel/cyclophosphamide (4 TC 3 weeks). The success rate was 71.7% (G0 21.3%, G1 31.5%, G2 18.9%). Frequent side effects were: coldness, headache, scalp pain and head heaviness. Conclusion: In our study, scalp cooling can prevent alopecia thus supporting the wider use in early breast cancer.

Second-Sphere Biomimetic Multipoint Hydrogen-Bonding Patterns to Boost CO2 Reduction of Iron Porphyrins.

Inspired by nature's orchestra of chemical subtleties to activate and reduce CO2 , we have developed a family of iron porphyrin derivatives in to which we have introduced urea groups functioning as multipoint hydrogen-bonding pillars on the periphery of the porphyrinic ring. This structure closely resembles the hydrogen-bond stabilization scheme of the carbon dioxide (CO2 ) adduct in the carbon monoxide dehydrogenase (CODH). We found that such changes to the second coordination sphere significantly lowered the overpotential for CO2 reduction in this family of molecular catalysts and importantly increased the CO2 binding rate while maintaining high turnover frequency (TOF) and selectivity. Entrapped water molecules within the molecular clefts were found to be the source of protons for the CO2 reduction.

Water Molecules Gating a Photoinduced One-Electron Two-Protons Transfer in a Tyrosine/Histidine (Tyr/His) Model of Photosystem†II.

We investigate a biomimetic model of a TyrZ /His190 pair, a hydrogen-bonded phenol/imidazole covalently attached to a porphyrin sensitizer. Laser flash photolysis in the presence of an external electron acceptor reveals the need for water molecules to unlock the light-induced oxidation of the phenol through an intramolecular pathway. Kinetics monitoring encompasses two fast phases with distinct spectral properties. The first phase is related to a one-electron transfer from the phenol to the porphyrin radical cation coupled with a domino two-proton transfer leading to the ejection of a proton from the imidazole-phenol pair. The second phase concerns conveying the released proton to the porphyrin N4 coordinating cavity. Our study provides an unprecedented example of a light-induced electron-transfer process in a TyrZ /His190 model of photosystem II, evidencing the movement of both the phenol and imidazole protons along an isoenergetic pathway.

Electron transfer activity of a de novo designed copper center in a three-helix bundle fold.

In this work, we characterized the intermolecular electron transfer (ET) properties of a de novo designed metallopeptide using laser-flash photolysis. α3D-CH3 is three helix bundle peptide that was designed to contain a copper ET site that is found in the ß-barrel fold of native cupredoxins. The ET activity of Cuα3D-CH3 was determined using five different photosensitizers. By exhibiting a complete depletion of the photo-oxidant and the successive formation of a Cu(II) species at 400 nm, the transient and generated spectra demonstrated an ET transfer reaction between the photo-oxidant and Cu(I)α3D-CH3. This observation illustrated our success in integrating an ET center within a de novo designed scaffold. From the kinetic traces at 400 nm, first-order and bimolecular rate constants of 10(5) s(-1) and 10(8) M(-1) s(-1) were derived. Moreover, a Marcus equation analysis on the rate versus driving force study produced a reorganization energy of 1.1 eV, demonstrating that the helical fold of α3D requires further structural optimization to efficiently perform ET. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson.

Secondary-Rim γ-Cyclodextrin Functionalization to Conjugate with C60 : Improved Efficacy as a Photosensitizer.

DIBAL-H-mediated demethylation provides a novel method to access secondary-rim functionalized γ-cyclodextrin. 2A ,3B -Dihydroxyl-per-O-methylated-γ-cyclodextrin has been obtained, whose conjugation with C60 allows access to the most water-soluble C60 conjugate described so far. The water solubility of 0.12 m (550 mg mL-1 ) is 150 times higher than that of the native γ-CD/C60 complex. Its singlet oxygen (1 O2 ) quantum yield is 0.39, an increase of one to two orders of magnitude compared to that of α(ß)CD-C60 conjugates.

Time-Resolved Interception of Multiple-Charge Accumulation in a Sensitizer-Acceptor Dyad.

Biomimetic models that contain elements of photosynthesis are fundamental in the development of synthetic systems that can use sunlight to produce fuel. The critical task consists of running several rounds of light-induced charge separation, which is required to accumulate enough redox equivalents at the catalytic sites for the target chemistry to occur. Long-lived first charge-separated state and distinct electronic signatures for the sequential charge accumulated species are essential features to be able to track these events on a spectroscopic ground. Herein, we use a double-excitation nanosecond pump-pump-probe experiment to interrogate two successive rounds of photo-induced electron transfer on a molecular dyad containing a naphthalene diimide (NDI) linked to a [Ru(bpy)3 ]2+ (bpy=bipyridine) chromophore by using a reversible electron donor. We report an unprecedented long-lived two-electron charge accumulation (t=200 µs).

Synergistic "ping-pong" energy transfer for efficient light activation in a chromophore-catalyst dyad.

The synthesis of a porphyrin-Ru(II) polypyridine complex where the porphyrin acts as a photoactive unit and the Ru(II) polypyridine as a catalytic precursor is described. Comparatively, the free base porphyrin was found to outperform the ruthenium based chromophore in the yield of light induced electron transfer. Mechanistic insights indicate the occurrence of a ping-pong energy transfer from the (1)LC excited state of the porphyrin chromophore to the (3)MCLT state of the catalyst and back to the (3)LC excited state of the porphyrin unit. The latter, triplet-triplet energy transfer back to the chromophore, efficiently competes with fast radiationless deactivation of the excited state at the catalyst site. The energy thus recovered by the chromophore allows improved yield of formation of the oxidized form of the chromophore and concomitantly of the oxidation of the catalytic unit by intramolecular charge transfer. The presented results are among the rare examples where a porphyrin chromophore is successfully used to drive an oxidative activation process where reductive processes prevail in the literature.

Carbon dioxide reduction via light activation of a ruthenium-Ni(cyclam) complex.

In this paper we report the synthesis of a chromophore-catalyst assembly designed for the photoreduction of carbon dioxide. The chromophore unit is made up of a ruthenium trisbipyridyl-like unit covalently attached to a nickel cyclam (cyclam = 1,4,8,11-tetraazacyclotetradecane) via a triazole ring. The intramolecular electron transfer activation of the catalyst unit by visible light was studied by nanosecond flash photolysis and EPR spectroscopy. In aqueous solutions (pH = 6.5), activation of the Ru(II)-Ni(II) modular assembly with 450 nm visible light in the presence of a sacrificial electron donor accomplishes the reduction of CO2 into CO and H2 in a ratio of 2.7 to 1.

BMI variation increases recurrence risk in women with early-stage breast cancer.

AIMS: The prognostic role of BMI variation during and/or after treatments for early-stage breast cancer is still unknown. PATIENTS & METHODS: The χ(2) test was conducted to explore the correlation between breast cancer recurrence and BMI changes in 520 early-stage breast cancer patients. Cox proportional hazard models were used to analyze the association of BMI changes, baseline BMI, known prognostic factors and recurrences. RESULTS: BMI gain was significant determinant of recurrences (p = 0.0008). In multivariate analyses, BMI variation more than 5.71% was associated with higher rates of recurrences, as well as age less than 55 years, stage disease and molecular subtype. CONCLUSION: Women who experience BMI gain after breast cancer may be at increased risk of poor outcomes.

Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.

BACKGROUND: Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. METHODS: Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). CONCLUSIONS: First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Click chemistry on a ruthenium polypyridine complex. An efficient and versatile synthetic route for the synthesis of photoactive modular assemblies.

In this Communication, we present the synthesis and use of [Ru(bpy)(2)(bpy-CCH)](2+), a versatile synthon for the construction of more sophisticated dyads by means of click chemistry. The resulting chromophore-acceptor or -donor complexes have been studied by flash photolysis and are shown to undergo efficient electron transfer to/from the chromophore. Additionally, the photophysical and chemical properties of the original chromophore remain intact, making it a very useful component for the preparation of visible-light-active dyads.

Tracking light-induced electron transfer toward O2 in a hybrid photoredox-laccase system.

Photobiocatalysis uses light to perform specific chemical transformations in a selective and efficient way. The intention is to couple a photoredox cycle with an enzyme performing multielectronic catalytic activities. Laccase, a robust multicopper oxidase, can be envisioned to use dioxygen as a clean electron sink when coupled to an oxidation photocatalyst. Here, we provide a detailed study of the coupling of a [Ru(bpy)3]2+ photosensitizer to laccase. We demonstrate that efficient laccase reduction requires an electron relay like methyl viologen. In the presence of dioxygen, electrons transiently stored in superoxide ions are scavenged by laccase to form water instead of H2O2. The net result is the photo accumulation of highly oxidizing [Ru(bpy)3]3+. This study provides ground for the use of laccase in tandem with a light-driven oxidative process and O2 as one-electron transfer relay and as four-electron substrate to be a sustainable final electron acceptor in a photocatalytic process.