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A new green-to-blue TTA system based on an asymmetric BODIPY and a perylene derived emitter was characterised by spectroscopic techniques. This couple has provided efficient photocatalytic activity in three different coupling reactions.

A novel dual functional and visual rhodamine ethylenediamine bis(triazolyl silsesquioxane) (RBS) chemosensor was successfully synthesized using “click” chemistry. The results have unambiguously demonstrated that RBS can act in fluorescent and colorimetric sensing of Cu2+ and Zn2+ by their respective coordination with triazole structures and, more importantly, it has also been found that triazole-amide of RBS could turn on chelation-enhanced fluorescence (CHEF) of Cu2+. Remarkably, the addition of Cu2+ triggered an enhanced fluorescent emission by 63.3-fold (ϕF = 0.41), while Zn2+ enhanced it 48.3-fold (ϕF = 0.29) relative to the original RBS (ϕF = 0.006) in acetonitrile (MeCN) solvent. The fluorescent limit of detection for Cu2+ and Zn2+ is similar and fall within 3.0 nM, while under colorimetric sensing the responses were 2.14 × 10–8 and 4.0 × 10–8 mol L−1, respectively. Moreover, the effective sensing profile of RBS and extended applications of RBS–Cu2+ and RBS–Zn2+ for fingerprinting detection and imaging were observed with adequate sensitivity, stability and legibility under the dual visual responses. Graphical abstract

An effective approachfor the direct thiolation of five-membered heteroarenes involving visible-light-absorbing EDA complexes is reported. The reaction takes place from an EDA complex between an alkylamine and the heteroarene halide. Selective photolysis to the EDA complex has allowed to generate the heteroarene radical that is suitably trapped by disulfide derivatives, providing a potent synthetic versatility.

[EN] Heteroarene boronate esters constitute valuable intermediates in modern organic synthesis. As building blocks, they can be further applied to the synthesis of new materials, since they can be easily transformed into any other functional group. Efforts toward novel and efficient strategies for their preparation are clearly desirable. Here, we have achieved the borylation of commercially available heteroarene halides under very mild conditions in an easy-to-use gel nanoreactor. Its use of visible light as the energy source at room temperature in photocatalyst-free and aerobic conditions makes this protocol very attractive. The gel network provides an adequate stabilizing microenvironment to support wide substrate scope, including furan, thiophene, selenophene, and pyrrole boronate esters., Financial support from the Generalitat Valenciana (CIDEGENT/2018/044) and the Spanish Ministry of Science and Innovation (PID2019-105391GB-C21, PID2019-105391GBC22, BEAGAL18/00166, and BES-2017-080215) is gratefully acknowledged. We thank the Electron Microscopy Service from the UPV and Prof. Julia Perez-Prieto for spectroscopy facilities. D.D.D. also thanks NANOtec, INTech, Cabildo de Tenerife, and ULL for laboratory facilities.

[EN] Four new dyes that derive from borylated arylisoquinolines were prepared, containing a third aryl residue (naphthyl, 4-methoxynaphthyl, pyrenyl or anthryl) that is linked via an additional stereogenic axis. The triaryl cores were synthesized by Suzuki couplings and then transformed into boronic acid esters by employing an Ir(I)-catalyzed reaction. The chromophores show dual emission behavior, where the long-wavelength emission band can reach maxima close to 600 nm in polar solvents. The fluorescence quantum yields of the dyes are generally in the range of 0.2¿0.4, reaching in some cases values as high as 0.5¿0.6. Laserflash photolysis provided evidence for the existence of excited triplet states. The dyes form fluoroboronate complexes with fluoride anions, leading to the observation of the quenching of the long-wavelength emission band and ratiometric response by the build-up of a hypsochromically shifted emission signal., Funding by the Spanish Ministry of Economy, Industry, and Competitiveness (CTQ2014-54729-C2-1-P for U.P., CTQ2013-48164-C2-1-P and CTQ2013-48164-C2-2-P for A.R., Ramon y Cajal contracts RYC-2013-12585 for A.R. and RYC-2015-17737 for I.V.), the Spanish Ministry of Science, Innovation, and Universities (CTQ2017-89832-P for U.P., CTQ2016-78875-P for M.C.J., and CTQ2017-89416-R for I.V.), the European Research and Development Fund, and the Andalusian Government (2012/FQM-2140 for U.P., 2009/FQM-4537 and 2012/FQM-1078 for A.R) is gratefully acknowledged.

The palladium-catalysed cross-coupling reaction between alkenes and aryl halides (the Mizoroki–Heck reaction) is a powerful methodology to construct new carbon–carbon bonds. However, the success of this reaction is in part hampered by an extremely marked regioselectivity on the double bond, which dictates that electron-poor alkenes react exclusively on the β-carbon. Here, we show that ligand-free, few-atom palladium clusters in solution catalyse the α-selective intramolecular Mizoroki–Heck coupling of iodoaryl cinnamates, and mechanistic studies support the formation of a sterically encumbered cinnamate–palladium cluster intermediate. Following this rationale, the α-selective intermolecular coupling of aryl iodides with styrenes is also achieved with palladium clusters encapsulated within fine-tuned and sterically restricted zeolite cavities to produce 1,1-bisarylethylenes, which are further engaged with aryl halides by a metal-free photoredox-catalysed coupling. These ligand-free methodologies significantly expand the chemical space of the Mizoroki–Heck coupling. [Figure not available: see fulltext.], This work was supported by MINECO (Spain, projects CTQ 2017-86735-P, PID2019-105391GB-C22 and MAT2017-82288-C2-1-P, Severo Ochoa programme SEV-2016-0683 and the Juan de la Cierva programme). F.G.-P. and R.G. thank ITQ for the concession of a contract. J.O.-M. acknowledges the Juan de la Cierva programme for the concession of a contract, and R.P.-R. and J.C.-S. thank the Plan GenT programme (CIDEGENT/2018/044) funded by Generalitat Valenciana. HR STEM measurements were performed at DME-UCA in Cadiz University, with financial support from FEDER/MINECO (PID2019-110018GA-I00 and PID2019-107578GA-I00). We acknowledge ALBA Synchrotron for allocating beamtime and CLÆSS beamline staff for their technical support during our experiment.

[EN] The largely demand in continued security issues makes necessary the development of novel materials with outstanding properties to improve the current detection techniques. In this context, latent fingerprint (LF) by fluorescent labeled materials (FLM) is one of the most attractive personnel identification methodologies. Here, two FLM based on polyhedral oligomeric silsesquioxane (POSS) nanohybrids labeled with dansyl chromophores have been synthesized and fully characterized. Their photophysical properties have confirmed that these materials clearly possess the prime qualifications as suitable LF sensing platforms. In fact, they adequately detect LFs on glassy surface with excellence legibility., Financial support by the Alexander von Humboldt Foundation (Georg Forster Research Fellowship to E.O. Dare), Generalitat Valenciana (CIDEGENT/2018/044) and Universitat Regensburg is gratefully acknowledged. Laboratory assistance from MSc A. Abramov and Dr. B. Maiti (Universitat Regensburg) is deeply acknowledged. D.D.D. thanks the DFG for the Heisenberg Professorship Award and the Spanish Ministry of Science, Innovation and Universities for the Senior Beatriz Galindo Award (Distinguished Researcher; BEAGAL18/00166). D.D.D. thanks NANOtec, INTech, Cabildo de Tenerife and ULL for laboratory facilities.

[EN] The covalent binding of beta-lactams to proteins upon photochemical activation has been demonstrated by using an integrated approach that combines photochemical, proteomic and computational studies, selecting human serum albumin (HSA) as a target protein and ezetimibe (1) as a probe. The results have revealed a novel protein haptenation pathway for this family of drugs that is an alternative to the known nucleophilic ring opening of beta-lactams by the free amino group of lysine residues. Thus, photochemical ring splitting of the beta-lactam ring, following a formal retro-Staudinger reaction, gives a highly reactive ketene intermediate that is trapped by the neighbouring lysine residues, leading to an amide adduct. For the investigated 1/HSA system, covalent modification of residues Lys414 and Lys525, which are located in sub-domains IIIA and IIIB, respectively, occurs. The observed photobinding may constitute the key step in the sequence of events leading to photoallergy. Docking and molecular dynamics simulation studies provide an insight into the molecular basis of the selectivity of 1 for these HSA sub-domains and the covalent modification mechanism. Computational studies also reveal positive cooperative binding of sub-domain IIIB that explains the experimentally observed modification of Lys414, which is located in a barely accessible pocket (sub-domain IIIA)., Financial support from Ministerio de Economia, Industria y Competitividad (CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2013-42899-R, SAF2016-75638-R), Instituto de Salud Carlos III (RD12/0013/0009 and RD16/0006/0030), Generalitat Valenciana (PROMETEOII/2013/005), Xunta de Galicia (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and European Union (European Regional Development Fund -ERDF) is gratefully acknowledged. E.L. thanks the Xunta de Galicia for a postdoctoral fellowship. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER.

The recent demand for fluorescent‐labeled materials (FLMs) in forensic security concepts such as latent fingerprints (LFs) that encode information for anti‐counterfeiting and encryption of confidential data makes necessary the development of building new and innovative materials. Here, novel FLMs based on polyhedral oligomeric silsesquioxanes (POSS) functionalized with fluorophores via “click” reactions have been successfully synthesized and fully characterized. A comprehensive study of their photophysical properties has displayed large Stokes's shift together with good photostability in all cases, fulfilling the fundamental requisites for any legible LF detection on various surfaces. The excellent performance of the hetero‐bifunctional FLM in the visualization of LF is emphasized by their legibility, selectivity, sensitivity and temporal photostability. In this study, development mechanisms have been proposed and the overall concept constitute a novel approach for vis‐à‐vis forensic investigations to trace an individual's identity., A series of fluorescent‐labeled nanohybrids based on polyhedral oligomeric silsesquioxanes (POSS) linked to appropriate fluorophores via “click” chemistry can be used to visualize latent fingerprints on several surfaces, providing reasonable legibility patterns that satisfy the requirements for fingerprinting identification in forensic technology.

[EN] Boron-containing thiophenes are important entities in organic/medicinal chemistry as well as in material science. In this Letter, a novel, straightforward, and fast procedure for their production employing visible light as an energy source at room temperature and ambient pressure is reported. All substrates are commercially available, and the process does not require the use of any external photocatalyst., Financial support from the Generalitat Valenciana (CIDE-GENT/2018/044) and the Spanish Government (CTQ2016-78875-P, CTQ2017-87372-P, and BES-2017-080215) is gratefully acknowledged.

[EN] Currently, evolution of chemical transformations by visible light irradiation is highly desirable from cost, safety, availability, and environmental friendliness points of view. Besides, activation of less reactive substrates under very mild conditions becomes one of the most challenging tasks in organic synthesis. However, the insufficient energy provided by one photon of visible light for their activation definitely makes necessary the development of new protocols together with the design of new photocatalytic systems to overcome this limitation. In this context, the implementation of biphotonic processes has been found to be a solution for these drawbacks. This new mechanistic paradigm which combines light upconversion processes with energy/electron transfers holds great potential for high energy demanding bond activations, expanding the accessible reactivity window. Here, we wish to highlight the recent applications of biphotonic processes in organic synthesis., Financial support from the Generalitat Valenciana (CIDEGENT/2018/044) and the Spanish Government (CTQ2016-78875-P, BES-2017-080215 and BEAGAL18/00166) is gratefully acknowledged.

[EN] Transient absorption spectroscopy in combination with in silico methods has been employed to study the interactions between human serum albumin (HSA) and the anti-psychotic agent chlorpromazine (CPZ) as well as its two demethylated metabolites (MCPZ and DCPZ). Thus, solutions containing CPZ, MCPZ or DCPZ and HSA (molar ligand:protein ratios between 1:0 and 1:3) were submitted to laser flash photolysis and the Delta A(max) value at lambda = 470 nm, corresponding to the triplet excited state, was monitored. In all cases, the protein-bound ligand exhibited higher Delta Amax values measured after the laser pulse and were also considerably longer-lived than the non-complexed forms. This is in agreement with an enhanced hydrophilicity of the metabolites, due to the replacement of methyl groups with H that led to a lower extent of protein binding. For the three compounds, laser flash photolysis displacement experiments using warfarin or ibuprofen indicated Sudlow site I as the main binding site. Docking and molecular dynamics simulation studies revealed that the binding mode of the two demethylated ligands with HSA would be remarkable different from CPZ, specially for DCPZ, which appears to come from the different ability of their terminal ammonium groups to stablish hydrogen bonding interactions with the negatively charged residues within the protein pocket (Glu153, Glu292) as well as to allocate the methyl groups in an apolar environment. DCPZ would be rotated 180 degrees in relation to CPZ locating the aromatic ring away from the Sudlow site I of HSA. (C) 2019 Elsevier B.V. All rights reserved., Financial support from Ministerio de Economia, Industria y Competitividad (CTQ2016-78875-P, SAF2016-75638-R, BES-2011-043706), Generalitat Valenciana (Prometeo 2017/075), Xunta de Galicia [Centro Singular de Investigacion de Galicia accreditation 2016-2019 (ED431G/09, ED431B 2018/04) and post-doctoral fellowship to E. L.] and European Union (European Regional Development Fund-ERDF) is gratefully acknowledged. I. A. holds a "Miguel Servet" contract (CP1116/00052) funded by the Carlos III Health Institute. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for computational facilities.

[EN] In this work, a molecular hydrogel made of gelator (S)-4-((3-methyl-1-(nonylamino)-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SVN) has been employed as soft container to modify the photochemical and photophysical behavior of the antipsychotic drug cyamemazine (CMZ). The interaction of CMZ with the gel network has been evidenced by fluorescence spectroscopy through a hypsochromic shift of the emission band (from lambda(max) = 521 nm in solution to lambda(max) = 511 nm in the gel) and an increase of the fluorescence lifetime (5.6 ns in PBS vs. 7.2 ns in the gel). In the laser flash photolysis experiments on CMZ/SVN systems, the CMZ triplet excited state ((3)CMZ*), monitored at lambda = 320 nm, has been more efficiently generated and became much longer-lived than in solution (2.7 mu s vs. 0.7 mu s); besides, photochemical ionization leading to the radical cation CMZ(+center dot) was disfavored. In the steady-state experiments, photooxidation of CMZ to afford the N,S-dioxide derivative CMZ-SONO has been retarded in the gel, which provides a more lipophilic and constrained microenvironment. Both the photophysical properties and the photoreactivity are in agreement with CMZ located in a less polar domain when entrapped in the supramolecular gel, as result of the interaction of the drug with the fibers of the supramolecular SVN gel., Financial support from the Spanish Government (CTQ2016-78875-P and CTQ2015-71004-R), the Generalitat Valenciana (PROMETEO/2017/075) and the European Union is gratefully acknowledged.

[EN] Triflusal is a platelet antiaggregant employed for the treatment and prevention of thromboembolic diseases. After administration, it is biotransformed into its active metabolite, the 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). We present here an investigation on HTB photobinding to human serum albumin (HSA), the most abundant protein in plasma, using an approach that combines fluorescence, MS/MS, and peptide fingerprint analysis as well as theoretical calculations (docking and molecular dynamics simulation studies). The proteomic analysis of HTB/HSA photolysates shows that HTB addition takes place at the epsilon-amino groups of the Lys137, Lys199, Lys205, Lys351, Lys432, Lys525, Lys541 and Lys545 residues and involves replacement of the trifluoromethyl moiety of HTB with a new amide function. Only Lys199 is located in an internal pocket of the protein, and the remaining modified residues are placed in the external part. Docking and molecular dynamic simulation studies reveal that HTB supramolecular binding to HSA occurs in the "V-cleft" region and that the process is assisted by the presence of Glu/Asp residues in the neighborhood of the external Lys, in agreement with the experimentally observed modifications. In principle, photobinding can occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects., We gratefully acknowledge financial support from the Spanish Government (CTQ2016-78875-P, SAF2016-75638-R, BES-2014-069404, and RETICS network ARADyAL RD16/0006/0030), the Generalitat Valenciana (PROMETEO/2017/075 and CIDEGENT/2018/044), the Xunta de Galicia [Centro Singular de Investigacion de Galicia accreditation 2016-2019 (ED431G/09), ED431B 2018/04 and post-doctoral fellowship to EL], and the European Union (European Regional Development Fund-ERDF). The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB3 and is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.

[EN] The non-steroidal anti-inflammatory drug (S)-carprofen (CPF) has been used as a photoactive probe to investigate the possible existence of a common recognition center in serum albumins (SAs) of different species. The methodology involves irradiation of the CPF/SA complexes, coupled with gel filtration chromatography or proteomic analysis of the photolysates, docking and molecular dynamics simulations. Photolysis of CPF/SA complexes at = 320 nm, and gel filtration chromatography, revealed that the protein fraction still contained the drug fluorophore, in agreement with covalent attachment of the photogenerated radical intermediate CBZ to SAs. After trypsin digestion and ESI-MS/MS, the incorporation of CBZ was detected at several positions in the different albumins. Remarkably, modifications at the IB/IIIA interface were observed in all cases (Tyr452 in HSA, RbSA and RtSA and Tyr451 in BSA, PSA and SSA). The molecular basis of this common recognition, studied by docking and molecular dynamics simulation studies on the corresponding non-covalent complexes, corroborated the experimentally observed covalent modifications. Our computational studies also revealed that the previously reported displacement of CPF by (S)-ibuprofen, a site II specific drug, would be due to an allosteric effect in site II, rather than a direct molecular displacement, as expected., Financial support from the Spanish Ministry of Economy and Competiveness (CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404), Generalitat Valenciana (PROMETEO2017/075), Conselleria de Cultura, Educacion e Ordenacion Universitaria (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and the European Regional Development Fund (ERDF) is acknowledged. This work was also supported by Instituto de Salud Carlos III (ISCIII) co-funded by Fondo Europeo de Desarrollo Regional FEDER for the Thematic Networks and Co-operative Research Centres: ARADyAL (RD16/0006/0030). EL thanks the Xunta de Galicia for his postdoctoral fellowship. We are also grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+I 2013-2016, funded by ISCIII and FEDER.

[EN] Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues., Financial support from the Spanish Ministry of Economy and Competiveness [CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404 (predoctoral fellowship to O.M.-M.)], the Generalitat Valenciana (PROMETEO/2017/075), the Community of Madrid (2016-T1/AMB-1275), the Xunta de Galicia (Centro Singular de Investigacion de Galicia accreditation 2016-2019, ED431G/09 and postdoctoral fellowship to E.L.), and the European Union (European Regional Development Fund, ERDF) is gratefully acknowledged. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.

[EN] Through-bond triplet exciplex formation in donor-acceptor systems linked through a rigid bile acid scaffold has been demonstrated on the basis of kinetic evidence upon population of the triplet acceptors (naphthalene, or biphenyl) by through-bond triplet-triplet energy transfer from benzophenone., Financial support from the Spanish Government (Grants SEV-2012-0267, CTQ2012-38754-C03-03, CTQ2013-47872-C2-1-P and JCI-2011-09926), EU (PCIG12GA-2012-334257), Generalitat Valenciana (Prometeo Program), and Technical University of Valencia (VLC/Campus, ASIC-UPV for computational facilities and Predoctoral FPI fellowship for P. Miro) is gratefully acknowledged.

[EN] Diclofenac (DCF) can cause adverse reactions such as gastrointestinal, renal and cardiovascular disorders; therefore, topical administration may be an attractive alternative to the management of local pain in order to avoid these side effects. However, previous studies have shown that DCF, in combination with sunlight, displays capability to induce photosensitivity disorders. In humans, DCF is biotransformed into hydroxylated metabolites at positions 4¿ and 5 (4¿OH-DCF and 5OH-DCF), and this chemical change produces non negligible alterations of the drug chromophore, resulting in a significant modification of its light-absorbing properties. In the present work, 5OH-DCF exhibited higher photo(geno)toxic potential than the parent drug, as shown by several in vitro assays (3T3 NRU phototoxicity, DNA ssb gel electrophoresis and COMET), whereas 4¿OH-DCF did not display significant photo(geno)toxicity. This could be associated, at least partially with their more efficient UV-light absorption by 5OH-DCF metabolite and with a higher photoreactivity. Interestingly, most of the cellular DNA damage photosensitized by DCF and 5OH-DCF was repaired by the cells after several hours, although this effect was not complete in the case of 5OH-DCF., This work was supported by the Carlos III Institute of Health (Grants: RD16/0006/0030, PI16/01877), by the MINECO (Grants: CTQ2013-47872, CTQ2016-78875), and by the Generalitat Valenciana (Prometeo 2017/075).

[EN] Binding of the inmunodrepresive agent mycophenolate mofetil (MMP) and its pharmacologically active metabolite mycophenolic acid (MPA) to human serum albumin (HSA) and ¿1-acid glycoprotein (HAAG) has been investigated by an integrated approach involving selective excitation of the drug fluorophore, following their UV-A triggered fluorescence and docking studies. The formation of the protein/ligand complexes was evidenced by a dramatic enhancement of the fluorescence intensity and a hypsochromic shift of the emission band. In HSA, competitive studies using oleic acid as site I probe revealed site I as the main binding site of the ligands. Binding constants revealed that the affinity of the active metabolite by HSA is four-fold higher than its proactive form. Moreover, the affinity of MMP by HSA is three-fold higher than by HAAG. Docking studies revealed significant molecular binding differences in the binding of MMP and MPA to sub-domain IIA of HSA (site 1). For MPA, the aromatic moiety would be in close contact to Trp214 with the flexible chain pointing to the other end of the sub-domain; on the contrary, for MMP, the carboxylate group of the chain would be fixed nearby Trp214 through electrostatic interactions with residues Arg218 and Arg222., Financial support from the Spanish Ministry of Economy and Competiveness (CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2016-75638-R), the Xunta de Galicia (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09), the European Union (European Regional Development Fund-ERDF) and the Generalitat Valenciana (PROMETEO/2017/075) is gratefully acknowledged

[EN] Singlet oxygen photosensitization (studied by time-resolved near-infrared emission spectroscopy) and in vitro phototoxicity (by means of the 3T3 neutral red uptake assay) have been investigated for the prodrugs fenofibrate (FFB), mycophenolate mofetil (MMP), and trifusal (TFS) as well as for their active metabolites fenofibric acid (FFA), mycophenolic acid (MPA), and 2-hydroxy-4-(trifluoromethyl) benzoic acid (HTB). The results show that FFB and its active metabolite FFA generate O-1(2) with a quantum yield in the range 0.30 to 0.40 and show a photo-irritation factor (PIF) higher than 40. By contrast, MMP/MPA and TFS/HTB are not photoactive in the used assays. These results correlate well with the previously reported in vivo phototoxicity in treated patients., This work has been supported by grants CTQ-2013-47872C2-1-P, CTQ2016-78875-P, CTQ2013-48767-C3-1-R, CTQ2016-78454-C2-1-R, CTQ2015-71896-REDT, FIS PI16/01877, and BES-2014-069404 ( predoctoral fellowship to O. M.- M.) from MINECO. R. B.- O. thanks the European Social Funds and the SUR del DEC de la Generalitat de Catalunya for a predoctoral fellowship (2017 FI_B2 00140).

[EN] The properties of singlet and triplet excited states are strongly medium-dependent. Hence, these species constitute valuable tools as reporters to probe compartmentalised microenvironments, including drug@protein supramolecular systems. In the present review, the attention is focused on the photophysical properties of the probe drugs (rather than those of the protein chromophores) using transport proteins (serum albumins and 1-acid glycoproteins) as hosts. Specifically, fluorescence measurements allow investigating the structural and dynamic properties of biomolecules or their complexes. Thus, the emission quantum yields and the decay kinetics of the drug singlet excited states provide key information to determine important parameters such as the stoichiometry of the complex, the binding constant, the relative degrees of occupancy of the different compartments, etc. Application of the FRET concept allows determining donor-acceptor interchromophoric distances. In addition, anisotropy measurements can be related to the orientation of the drug within the binding sites, where the degrees of freedom for conformational relaxation are restricted. Transient absorption spectroscopy is also a potentially powerful tool to investigate the binding of drugs to proteins, where formation of encapsulated triplet excited states is favoured over other possible processes leading to ionic species (i. e. radical ions), and their photophysical properties are markedly sensitive to the microenvironment experienced within the protein binding sites. Even under aerobic conditions, the triplet lifetimes of protein-complexed drugs are remarkably long, which provides a broad dynamic range for identification of distinct triplet populations or for chiral discrimination. Specific applications of the laser flash photolysis technique include the determination of drug distribution among the bulk solution and the protein binding sites, competition of two types of proteins to bind a 3 drug, occurrence of drug-drug interactions within protein binding sites, enzymatic-like activity of the protein or determination of enantiomeric compositions. The use of proteins as supramolecular hosts modifies the photoreactivity of encapsulated substrates by providing protection against oxygen or other external reagents, by imposing conformational restrictions in the binding pockets, or by influencing the stereochemical outcome. In this review, a selected group of examples is presented including decarboxylation, dehalogenation, nucleophilic addition, dimerisation, oxidation, Norrish type II reaction, photo-Fries rearrangement and 6 electrocyclisation, Financial support from the Spanish Government (CTQ2010-14882, JCI-2011-09926, RyC-2007-00476), from the EU (PCIG12-GA-2012-334257), from the Universitat Politènica de València (SP20120757) and from the Consellería de Educació, Cultura i Esport (PROMETEOII/2013/005, GV/2013/051) is gratefully acknowledged.

[EN] A multidisciplinary strategy to obtain structural information on the intraprotein region is described here. As probe ligands, (S)- and (R)-CPFMe (the methyl esters of the chiral drug carprofen) have been selected, while bovine 1-acid glycoprotein (BAAG) has been chosen as biological host. The procedure involves separate irradiation of the BAAG/(S)-CPFMe and BAAG/(R)-CPFMe complexes, coupled with fluorescence, laser flash photolysis, proteomic analysis, docking and molecular dynamic simulations. Thus, irradiation of the BAAG/CPFMe complexes at  = 320 nm, was followed by fluorescence spectroscopy. The intensity of the emission band obtained after irradiation indicated photodehalogenation, whereas its structureless shape suggested covalent binding of the resulting radical CBZMe● to the biopolymer. After gel filtration chromatography, the spectra still displayed emission, in agreement with covalent attachment of CBZMe● to BAAG. Stereodifferentiation was observed in this process. After trypsin digestion and ESI-MS/MS, incorporation of CBZMe was detected at Phe68. Docking and molecular dynamics simulation studies, which were carried out using a homology model of BAAG, reveal that the closer proximity of the aromatic moiety of the (S)- enantiomer to the phenyl group of Phe68 would be responsible for the experimentally observed more effective chemical modification of the protein. The proposed tridimensional structure of BAAG covalently modified by the two enantiomers is also provided. In principle, this approach can be extended to a variety of protein/ligand complexes., Financial support from the Spanish Ministry of Economy and Competitiveness (CTQ2013-47872-C2-1-P, SAF2013-42899-R, BES-2011-043706), Generalitat Valenciana (PROMETEOII/2013/005), Instituto de Salud Carlos III (RD12/0013/0009), Xunta de Galicia (GRC2013-041), the Conselleria de Cultura, Educacion e Ordenacion Universitaria (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and the European Regional Development Fund (ERDF) is gratefully acknowledged. E. L. thanks the Xunta de Galicia for a postdoctoral fellowship. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER

[EN] Most optical processes occurring in nature are based on the well-known selection rules for opticaltransitions between electronic levels of atoms, molecules, and solids. Since in most situations themagnetic component of light has a negligible contribution, the dipolar electric approximation isgenerally assumed. However, this traditional understanding is challenged by nanostructured materials,which interact strongly with light and produce very large enhancements of the magnetic field in theirsurroundings. Here we report on the magnetic response of different metallic nanostructures and theirinfluence on the spectroscopy of molecular oxygen, a paradigmatic example of dipole-forbidden optical transitions in photochemistry, A. M. acknowledge support from U. S. National Science Foundation (Grant ECCS-1710697). The authors acknowledge the financial support from the following projects: CTQ2014-61671-EXP, MAT2015-69669-P, and PrometeoII/2017/026. We would also like to acknowledge the UNM Center for Advanced Research Computing (CARC) for the computational resources used in this work.

Chlorpromazine (CPZ) is an anti-psychotic drug widely used to treat disorders such as schizophrenia or manic-depression. Unfortunately, CPZ exhibits undesirable side effects such as phototoxic and photoallergic reactions in humans. In general, the influence of drug metabolism on this type of reactions has not been previously considered in photosafety testing. Thus, the present work aims to investigate the possible photo(geno)toxic potential of drug metabolites, using CPZ as an established reference compound. In this case, the metabolites selected for the study are demethylchlorpromazine (DMCPZ), didemethylchlorpromazine (DDMCPZ) and chlorpromazine sulfoxide (CPZSO). The demethylated CPZ metabolites DMCPZ and DDMCPZ maintain identical chromophore to the parent drug. In this work, it has been found that the nature of the aminoalkyl side chain modulates the hydrophobicity and the photochemical properties (for instance, the excited state lifetimes), but it does not change the photoreactivity pattern, which is characterized by reductive photodehalogenation, triggered by homolytic carbon-chlorine bond cleavage with formation of highly reactive aryl radical intermediates. Accordingly, these metabolites are phototoxic to cells, as revealed by the 3T3 NRU assay; their photo-irritation factors are even higher than that of CPZ. The same trend is observed in photogenotoxicity studies, both with isolated and with cellular DNA, where DMCPZ and DDMCPZ are more active than CPZ itself. In summary, side-chain demethylation of CPZ, as a consequence of Phase I biotransformation, does not result a photodetoxification. Instead, it leads to metabolites that exhibit in an even enhanced photo(geno)toxicity., This work was supported by the MINECO (Grant: CTQ2013-47872), by Carlos III Institute of Health (Grants: RD12/0013/0009 and CP11/00154) and by the Generalitat Valenciana (Prometeo II/2013/005).

Oxidative electron transfer cycloreversion of trans,trans-2-cyclopropyl-4-methyl-3-phenyloxetane, using triphenylthiapyrylium perchlorate as a photosensitizer, leads to distonic 1,4-radical cations; subsequent cleavage gives rise to fragmentation products (pathway a), whereas nucleophilic trapping by acetonitrile affords a ring expanded oxazine (pathway b)., Financial support by the MICINN (Grants CTQ-2010-14882, CTQ-2009-13699 and JCI-2010-06204), from CSIC (JAEDOC 101-2011) and from Generalitat Valenciana (Grant No.GV/2012/041-20120205) is gratefully acknowledged.

This research was financed by the Netherlands Organisation for Scientific Research NWO-CW (contract number ECHO 700.55.014) and by the Spanish Government MINECO (project CTQ2010-14882). VLV's stay at LaserLaB Amsterdam was supported by the EU Laserlab Europe program (contract number 2008-1-228334; project lcvu001484).

[EN] The feasibility of an electron transfer imino-Diels Alder reaction betweenN-benzylideneaniline and arylalkenes in the presence of a pyrylium salt as a photosensitizer has been demonstrated by a combination of product studies, laser flash photolysis (LFP), and DFT theoretical calculations. A stepwise mechanism involving two intermediates and two transition states is proposed., Financial support from the MICINN (Grants CTQ2010-14882, CTQ2009-13699, CTQ2009-11027, and JCI-2010-06204) and from the UPV (Grant No. 20100994 and MCI Program) is gratefully acknowledged. Dedicated to Prof. Dr. Jaime Primo (Universidad Politecnica de Valencia) on the occasion of his 60th birthday.

A new methodology based on transient absorption spectroscopy has been developed to assess the distribution of a drug between two transport proteins that are present in blood. The results show that serum albumins are the major carriers for (S)- and (R)-flurbiprofen (FBP); conversely, for the corresponding FBP methyl esters (FBPMe), the process is species-dependent, with bovine alpha-1-acid glycoprotein competing favorably with bovine serum albumin when both proteins are present in the same medium. Thus, transient absorption spectroscopy constitutes a new methodology for rapid and reliable assessment of drug distribution between serum albumins and alpha-1-acid glycoproteins that can be applied in situ and does not require any previous workup or separation of the analytes. The concept can, in principle, be extended to the investigation of drug distribution between several compartments available in biological systems.

In the present work, a systematic fluorescence study on supramolecular systems using two serum albumins (HSA or BSA) as hosts and the nonsteroidal antiinflammatory drugs carprofen (CPF) or naproxen (NPX) as guests has been undertaken. In parallel, model dyads containing Tyr or Trp covalently linked to CPF or NPX have also been investigated. In HSA/(S)-CPF and BSA/(S)-CPF ( λ exc = 266 nm), at 1:1 M ratio, an important degree (more than 40%) of singlet–singlet energy transfer (SSET) was observed to take place. The distance ( r ) calculated for energy transfer from the SAs to (S)-CPF through a FRET mechanism was found to be ca. 21 A. In the case of HSA/(S)-NPX and BSA/(S)-NPX, energy transfer occurred to a lower extent (ca. 7%), and r was determined as ca. 24 A. In order to investigate the possible excited state interactions between bound ligands and the relevant amino acids present in the protein binding sites, four pairs of model dyads were designed and synthesised, namely ( S , S )-TyrCPF, ( S , R )-TyrCPF, ( S , S )-TrpCPF, ( S , R )-TrpCPF, ( S , S )-TyrNPX, ( S , R )-TyrNPX, ( S , S )-TrpNPX and ( S , R )-TrpNPX. A complete SSET was observed from Tyr or Trp to CPF, since no contribution from the amino acids was present in the emission of the dyads. Likewise, a very efficient Tyr or Trp to NPX energy transfer was observed. Remarkably, in ( S , S )-TrpNPX and ( S , R )-TrpNPX a configuration-dependent reduction in the emission intensity was observed, revealing a strong and stereoselective intramolecular quenching. This effect can be attributed to exciplex formation and is dynamic in nature, as the fluorescence lifetimes were much shorter in ( S , R )- and ( S , S )-TrpNPX (1.5 and 3.1 ns, respectively) than in (S)-NPX (11 ns).

A common tool for investigating the specific distribution of a ligand between different protein microenvironments is the use of displacement probes, which force the ligand to move from one to another site or from the protein to the bulk aqueous solution. Open problems associated with this methodology are the possibility of two different molecules sharing the same site and the potential appearance of allosteric effects. A possible approach to address these issues could be based on the use of two different singlet excited states, together with the corresponding triplets, acting as reporters. As a first step towards the development of this concept, we have synthesized two model diastereomeric dyads containing covalently linked flurbiprofen (FBP) and carprofen (CPF) moieties and studied their photophysical and photochemical behaviour, looking for spectroscopically detectable excited state interactions between the two chromophores. The main deactivation processes that take place upon excitation of dyads ( R , R )-FBP–CPF and ( S , R )-FBP–CPF are the following: initial excitation at 266 nm leads to the first singlet excited states of both subunits. Singlet–singlet energy transfer (SSET) from 1 FBP* to CPF is thermodynamically allowed and indeed it appears to take place very efficiently. Radiative deactivation of 1 CPF* is followed by intersystem crossing (ISC) and triplet–triplet energy transfer (TTET) from 3 CPF* to FBP, which is also downhill in energy. The final step corresponds to deactivation of 3 FBP* to the ground state. In connection with the possibility of making use of the photophysical properties of FBP and CPF to investigate drug–drug interactions in protein binding studies, the most clear-cut conclusions are the following: (a) if the two drugs are within the same protein molecule (irrespective of the site) the only detectable emission will likely correspond to CPF, as its excited singlet is lower in energy, and SSET via the Forster mechanism is feasible, and (b) the transient triplet–triplet absorptions corresponding to the two chromophores are in principle detectable by laser flash photolysis; however, if the two drugs share the same binding site of a protein only the FBP triplet will be observed, as TTET occurs via the Dexter mechanism, which can only operate at very short distances.

Cycloreversion of cis- and trans-1,2,3-triphenylazetidine (c-2 and t-2) is achieved by electron transfer to (tris(4-bromophenyl)aminium radical cation (5 (*+)). Stepwise C-N and C-C bond cleavage of azetidine radical cations leads to cis- and trans-stilbene, together with N-benzylideneaniline, as final products. Mechanistic evidence is provided by quenching studies, using laser flash photolysis to generate 5 (*+) from its neutral precursor.

[EN] The photoreactivity of diastereomeric dyads containing (S)- or (R)-flurbiprofen (FBP) and (S)-Tyr, either directly linked (1) or separated by a cyclic spacer (3) has been investigated. The main feature is a remarkable intramolecular quenching of FBP fluorescence, especially in 1. The process is clearly configuration dependent, being more efficient for the (R,S)- diastereomer in 1 and for the (S,S)-analogue in 3. Noteworthy, exciplex emission is detected in the 380-500 nm region in the case of 3. Fluorescence decay kinetics from the femtosecond to the nanosecond time-domains provides evidence for the dynamic nature of the quenching. In agreement with the steady-state and time-resolved observations, molecular modelling points to a more favourable geometric arrangement of the two interacting chromophores in 1 than in 3., Financial support from the Spanish Government (CTQ2013-47872-C2-1-P), EU (PCIG12GA-2012-334257, LASERLAB-EUROPE grant agreement no. 284464, EU FP7, and MSCA- 657465) and Generalitat Valenciana (PROMETEOII/2013/005) is gratefully acknowledged.

[EN] The photoreactivity of fenofibric acid (FA) in the presence of human and bovine serum albumins (HSA and BSA, respectively) has been investigated by steady-state irradiation, fluorescence, and laser flash photolysis (LFP). Spectroscopic measurements allowed for the determination of a 1:1 stoichiometry for the FA/SA complexes and pointed to a moderate binding of FA to the proteins; by contrast, the FA photoproducts were complexed more efficiently with SAs. Covalent photobinding to the protein, which is directly related to the photoallergic properties of the drug, was detected after long irradiation times and was found to be significantly higher in the case of BSA. Intermolecular FA-amino acid and FA-albumin irradiations resulted in the formation of photoproducts arising from coupling between both moieties, as indicated by mass spectrometric analysis. Mechanistic studies using model drug-amino acid linked systems indicated that the key photochemical step involved in photoallergy is formal hydrogen atom transfer from an amino acid residue to the excited benzophenone chromophore of FA or (more likely) its photoproducts. This results in the formation of caged radical pairs followed by C-C coupling to give covalent photoaducts., Financial support from the Spanish Government (CTQ2013-47872-C2-1-P, JCI-2011-09926, and Miguel Servet CP11/00154), EU (PCIG12GA-2012-334257) and Generalitat Valenciana (PROMETEOII/2013/005) is gratefully acknowledged.

Naproxen [(+)-(S)- or (−)-(R)-2-(6-methoxynaphthalen-2-yl)propanoic acid, NPX] is a photoactive naphthalene derivative, widely prescribed as nonsteroidal anti-inflammatory drug. A variety of NPX-derived dyads have been synthesized, and their photobehavior has been investigated. In addition to the NPX unit, these dyads contain different types of photo- and/or electroactive moieties, such as naphthalenes (NAP), diaryl ketones (KPF), tertiary amines (PYR), oxetanes (OXT) or thymidine (THY). The excited state intramolecular interactions occurring in the dyads have been examined by both steady-state and time-resolved techniques. As a general observation, dynamic quenching of the NPX singlet-excited state is observed, as indicated by the reduced lifetimes in comparison to the isolated NPX chromophore. This is the result of energy transfer (NPX–NAP, NPX–KPF), electron transfer (NPX–PYR, NPX–OXT), excimer (NPX–NPX) or exciplex (NPX–NAP, NPX–KPF) formation, radiationless decay (NPX–THY), and/or chemical reaction (NPX–OXT, NPX–THY). Thus, the discussed dyads constitute interesting case studies for the photophysical behavior of naproxen in various mechanistic scenarios. For the dyads synthesized as diastereomeric pairs, a significant stereodifferentiation in the photophysical/photochemical properties is observed. Due to the delicate balance between the competing excited state deactivation pathways and the multiple signaling possibilities, these dyads can also be used as probes for the study of specific microenvironments of biological interest.

Photolysis of 3-halo-2,3-dihydrobenzopyran-4-ones 1a,b and 2a,b in acetonitrile and hexane led to dehalogenated dihydrobenzopyran-4-ones 3a,b and benzopyran-4-ones 4a,b. Their formation is accounted for in terms of primary cleavage of the carbon halogen bond to give α-carbonyl radicals (I) and/or cations (II). Intermediates II, precursors of 4, can be generated either directly by heterolysis or by initial homolysis followed by electron transfer. The ionic routes are more favored in acetonitrile than in hexane. The involvement of radical and ionic pathways in the photochemistry of 3-halo-2,3-dihydrobenzopyran-4-ones is supported by detection of Br2 -. in the laser flash photolysis experiments performed on 2a.

[EN] Three stereoisomeric salts of naproxen (NPX) with arginine (Arg), namely (S)-NPX/(S)-Arg, (R)-NPX/(S)-Arg and (S)NPX/(R)-Arg, have been prepared, and their fluorescence spectra recorded in solution and in the solid state. While the emission properties in solution did not show significant differences with lambda(max) = 355 nm, tau(F) (MeOH) ca. 11.5 ns and tau(F) (H2O) ca. 9 ns (as NPX/Na), the (R)-NPX/(S)-Arg and (S)-NPX/(R)-Arg solid salts displayed red-shifted fluorescence spectra With maxima at 375 mn and tau(F) = 1.1 ns. By contrast, the behaviour of solid (S)-NPX/(S)-Arg was similar to that of NPX/Na With; ax = 355 nm and tau(F) ca. 5.5 ns. These results are explained based on the X-ray crystal structures and attributed to formation of NPX excimers emitting at longer wavelengths. Accordingly, such excimer emission was also observed in the fluorescence spectrum of a model NPX dyad in solution., The UPV (PI 2003-0522 and predoctoral fellowship to I.V.), the MYCT (Grant CTQ2004-03811) the Generalitat Valenciana (Grupos03/082 and GV04B-468) are gratefully acknowledged for financial support. We also thank our colleague Dr. M. L. Marin for providing a gift of (2-methoxynaphthalen-6-yl)acetic acid and Dr. A. Llamas (Unidade de Raios X de la Universidade de Santiago de Compostela) for the X-ray measurements.

The photophysical properties of S-flurbiprofen [S-2-fluoro-alpha-methyl-4-biphenylacetic acid], a nonsteroidal anti-inflammatory drug, have been examined using steady-state and time-resolved spectroscopic techniques. The energy of its first singlet excited state is 99 kcal mol(-1). The fluorescence quantum yields and lifetimes (at 300 nm) have been determined in acetonitrile, methanol, hexane and PBS; they are in the range 0.15phi(F)0.33 and 0.7tau(F)2.0 ns. The intersystem crossing quantum yields are between 0.45 and 0.71; the lambda(max) of the T-T absorption is 360 nm, and the triplets live from 15 to 106 micros. Steady state photolysis in aqueous medium leads to S-2-hydroxy-alpha-methyl-4-biphenylacetic acid via photonucleophilic aromatic substitution, in addition to the photodecarboxylation products observed in organic solvents.

The properties of singlet and triplet excited states are strongly medium-dependent. Hence, these species constitute valuable tools as reporters to probe compartmentalised microenvironments, including drug@protein supramolecular systems. In the present review, the attention is focused on the photophysical properties of the probe drugs (rather than those of the protein chromophores) using transport proteins (serum albumins and α1-acid glycoproteins) as hosts. Specifically, fluorescence measurements allow investigation of the structural and dynamic properties of biomolecules or their complexes. Thus, the emission quantum yields and the decay kinetics of the drug singlet excited states provide key information to determine important parameters such as the stoichiometry of the complex, the binding constant, the relative degrees of occupancy of the different compartments, etc. Application of the FRET concept allows determination of donor–acceptor interchromophoric distances. In addition, anisotropy measurements can be related to the orientation of the drug within the binding sites, where the degrees of freedom for conformational relaxation are restricted. Transient absorption spectroscopy is also a potentially powerful tool to investigate the binding of drugs to proteins, where formation of encapsulated triplet excited states is favoured over other possible processes leading to ionic species (i.e. radical ions), and their photophysical properties are markedly sensitive to the microenvironment experienced within the protein binding sites. Even under aerobic conditions, the triplet lifetimes of protein-complexed drugs are remarkably long, which provides a broad dynamic range for identification of distinct triplet populations or for chiral discrimination. Specific applications of the laser flash photolysis technique include the determination of drug distribution among the bulk solution and the protein binding sites, competition of two types of proteins to bind a drug, occurrence of drug–drug interactions within protein binding sites, enzymatic-like activity of the protein or determination of enantiomeric compositions. The use of proteins as supramolecular hosts modifies the photoreactivity of encapsulated substrates by providing protection against oxygen or other external reagents, by imposing conformational restrictions in the binding pockets, or by influencing the stereochemical outcome. In this review, a selected group of examples is presented including decarboxylation, dehalogenation, nucleophilic addition, dimerisation, oxidation, Norrish type II reaction, photo-Fries rearrangement and 6π electrocyclisation.

ConspectusDiscovered more than eight decades ago, the Diels–Alder (DA) cycloaddition (CA) remains one of the most versatile tools in synthetic organic chemistry. Hetero-DA processes are powerful methods for the synthesis of densely functionalized six-membered heterocycles, ubiquitous substructures found in natural products and bioactive compounds. These reactions frequently employ azadienes and oxadienes, but only a few groups have reported DA processes with thiadienes. The electron transfer (ET) version of the DA reaction, though less investigated, has emerged as a subject of increasing interest.In the last two decades, researchers have paid closer attention to radical ionic hetero-cycloreversions, mainly in connection with their possible involvement in the repair of pyrimidine(6–4)pyrimidone photolesions in DNA by photolyases. In biological systems, these reactions likely occur through a reductive photosensitization mechanism. In addition, photooxidation can lead to cycloreversion (CR) reactions, and re...

[EN] Discovered more than eight decades ago, the Diels-Alder (DA) cycloaddition (CA) remains one of the most versatile tools in synthetic organic chemistry. Hetero-DA processes are powerful methods for the synthesis of densely functionalized six-membered heterocycles, ubiquitous substructures found in natural products and bioactive compounds. These reactions frequently employ azadienes and oxadienes, but only a few groups have reported DA processes with thiadienes. The electron transfer (ET) version of the DA reaction, though less investigated, has emerged as a subject of increasing interest. In the last two decades, researchers have paid closer attention to radical ionic hetero-cycloreversions, mainly in connection with their possible involvement in the repair of pyrimidine(6-4)pyrimidone photolesions in DNA by photolyases. In biological systems, these reactions likely occur through a reductive photosensitization mechanism. In addition, photooxidation can lead to cycloreversion (CR) reactions, and researchers can exploit this strategy for DNA repair therapies. In this Account, we discuss electron-transfer (ET) mediated hetero-CR reactions. We focus on the oxidative and reductive ET splitting of oxetanes, azetidines, and thietanes. Photoinduced electron transfer facilitates the splitting of a variety of four-membered heterocycles. In this context, researchers have commonly examined oxetanes, both experimentally and theoretically. Although a few studies have reported the cycloreversion of azetidines and thietanes carried out under electron transfer conditions, the number of examples remains limited. In general, the cleavage of the ionized four-membered rings appears to occur via a nonconcerted two-step mechanism. The trapping of the intermediate 1,4-radical ions and transient absorption spectroscopy data support this hypothesis, and it explains the observed loss of stereochemistry in the products. In the initial step, either C-C or C-X bond breaking may occur, and the preferred route depends on the substitution pattern of the ring, the type of heteroatom, and various experimental conditions. To better accommodate spin and charge, C-X cleavage happens more frequently, especially in the radical anionic version of the reaction. The addition or withdrawal of a single electron provides a new complementary synthetic strategy to activate hetero-cycloreversions. Despite its potential, this strategy remains largely unexplored. However, it offers a useful method to achieve C=X/olefin metathesis or, upon ring expansion, to construct six-membered heterocyclic rings., Financial support from the Spanish Government (Grants CTQ2010-14882, SEV2012-0267, and JCI-2010-06204) and the Generalitat Valenciana (Prometeo II/2013/005) is gratefully acknowledged.