5-Aminolevulinic acid derivatives in photomedicine: Characteristics, application and perspectives

The introduction of lipophilic derivatives of the naturally occurring heme precursor 5-aminolevulinic acid (5-ALA) into photomedicine has led to a true revival of this research area. 5-ALA-mediated photodynamic therapy (PDT) and fluorescence photodetection (FD) of neoplastic disease is probably one of the most selective cancer treatments currently known in oncology. To date, this method has been assessed experimentally for the treatment of various medical indications. However, the limited local bioavailability of 5-ALA has widely prevented its use in daily clinical practice. Although researchers were already aware of this drawback early during the development of 5-ALA-mediated PDT, only recently have well-established concepts in pharmaceutical science been adapted to investigate ways to overcome this drawback. Recently, two derivatives of 5-ALA, methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), gained marketing authorization from the regulatory offices in Europe and Australia. MAL is marketed under the trade name Metvix for the treatment of actinic keratosis and difficult-to-treat basal cell carcinoma. HAL has recently been launched under the trade name Hexvix to improve the detection of superficial bladder cancer in Europe. This review will first present the fundamental concepts underlying the use of 5-ALA derivatives in PDT and FD from a chemical, biochemical and pharmaceutical point of view. Experimental evidences from preclinical data on the improvements and limits observed with 5-ALA derivatives will then be introduced. The state-of-the-art from clinical studies with 5-ALA esters will be discussed, with special emphasis placed on the process that led to the development of MAL in dermatology and to HAL in urology. Finally, we will discuss promising medical fields in which use of 5-ALA derivatives might potentially lead to further use of this methodology in photomedicine.     

Tuning the Chemistry of Organonitrogen Compounds for Promoting All‐Organic Anionic Rechargeable Batteries

The ever‐increasing demand for rechargeable batteries induces significant pressure on the worldwide metal supply, depleting resources and increasing costs and environmental concerns. In this context, developing the chemistry of anion‐inserting electrode organic materials could promote the fabrication of molecular (metal‐free) rechargeable batteries. However, few examples have been reported because little effort has been made to develop such anionic‐ion batteries. Here we show the design of two anionic host electrode materials based on the N‐substituted salts of azaaromatics (zwitterions). A combination of NMR, EDS, FTIR spectroscopies coupled with thermal analyses and single‐crystal XRD allowed a thorough structural and chemical characterization of the compounds. Thanks to a reversible electrochemical activity located at an average potential of 2.2 V vs. Li⁺/Li, the coupling with dilithium 2,5‐(dianilino)terephthalate (Li₂DAnT) as the positive electrode enabled the fabrication of the first all‐organic anionic rechargeable batteries based on crystallized host electrode materials capable of delivering a specific capacity of ≈27 mAh/g_electrodes with a stable cycling over dozens of cycles (≈24 Wh/kg_electrodes).     

Carbonylation of C−N Bonds in Tertiary Amines Catalyzed by Low‐Valent Iron Catalysts

The first iron catalysts able to promote the formal insertion of CO into the C?N bond of amines are reported. Using low‐valent iron complexes, including K₂[Fe(CO)₄], amides are formed from aromatic and aliphatic amines, in the presence of an iodoalkane promoter. Inorganic Lewis acids, such as AlCl₃ and Nd(OTf)₃, have a positive influence on the catalytic activity of the iron salts, enabling the carbonylation at a low pressure of CO (6 to 8 bars).     

Real-time method for the identification and quantification of hydrocarbon pyrolysis products: Part II. Application to transient pyrolysis and validation by numerical simulation

A real-time quantification infra red method has been developed with a gas cell to determine the composition of hydrocarbon pyrolysis products. The aim is to chemically characterise the fuel decomposition in case of regenerative cooling. The method can be extended to a large variety of applications. A transient analysis of the method behaviour is conducted to estimate its capacity to be applied to unsteady conditions (one measure per second), which can be encountered in cooling activity and unsteady processes. A numerical tool called RESPIRE (French acronym for Supersonic Combustion Ramjet Cooling with Endothermic Fuel, Transient Reactor Programming) is used to help in understanding the complex phenomena involved in such a chemical reactor. The validation of transient behaviour with respect to the computations shows negligible time delay (lower than few seconds with gasification rate higher than 60 wt.%) due to residence time in the experimental setup. The quantification accuracy is confirmed to be around 2 mol%. The agreement obtained on gas cell measurements is found to be correct over 10-20 wt.% of gasification rate and very satisfactory over 60 wt.% but this depends on the species. An extension of the method has been developed with a dedicated online cell to be specifically applied to supercritical and multiphase flows. The quantification of the gas phase in the pyrolysis mixture in case of biphasic flow is proposed and validated with an uncertainty around 3 wt.%. The coke formation is monitored as a function of time and its quantification is even tested with 50% of uncertainty after a numerical calibration with respect to simulation.     

Identification and functional characterization of a novel α-conotoxin (EIIA) from Conus ermineus

Nicotinic acetylcholine receptors (nAChRs) are one of the most important families in the ligand-gated ion channel superfamily due to their involvement in primordial brain functions and in several neurodegenerative pathologies. The discovery of new ligands which can bind with high affinity and selectivity to nAChR subtypes is of prime interest in order to study these receptors and to potentially discover new drugs for treating various pathologies. Predatory cone snails of the genus Conus hunt their prey using venoms containing a large number of small, highly structured peptides called conotoxins. Conotoxins are classified in different structural families and target a large panel of receptors and ion channels. Interestingly, nAChRs represent the only subgroup for which Conus has developed seven distinct families of conotoxins. Conus venoms have thus received much attention as they could represent a potential source of selective ligands of nAChR subtypes. We describe the mass spectrometric-based approaches which led to the discovery of a novel α-conotoxin targeting muscular nAChR from the venom of Conus ermineus. The presence of several posttranslational modifications complicated the N-terminal sequencing. To discriminate between the different possible sequences, analogs with variable N-terminus were synthesized and fragmented by MS/MS. Understanding the fragmentation pathways in the low m/z range appeared crucial to determine the right sequence. The biological activity of this novel α-conotoxin (α-EIIA) that belongs to the unusual α4/4 subfamily was determined by binding experiments. The results revealed not only its selectivity for the muscular nAChR, but also a clear discrimination between the two binding sites described for this receptor.     

Decatungstate (W10O)/Silane: A New and Promising Radical Source Under Soft Light Irradiation

The use of decatungstate in combination with silanes to generate silyl radicals under green fluorescence bulb irradiation as well as sunlight exposure is described. The mechanisms are investigated by ESR and laser flash photolysis experiments. The high potential of this reaction is evidenced here when using a decatungstate/silane/diphenyl iodonium salt combination as an initiating system for the ring opening photopolymerization of epoxides.

     

Post-Assembly Photomasking of Potassium Acyltrifluoroborates (KATs) for Two-Photon 3D Patterning of PEG-Hydrogels

Chemical ligation reactions of functional groups that can be masked with two-photon labile protecting groups provide a powerful technology for the three-dimensional patterning of molecules – including proteins – onto hydrogel scaffolds. In order to utilize readily prepared hydrogels constructed by the potassium acyltrifluoroborate (KAT)-hydroxylamine amide formation ligation for two-photon patterning, we have developed a unique post-polymerization protecting group strategy through the reaction of KATs and dithiols in water and deprotection by two-photon excitation. After precise 3D spatially confined light irradiation, the unprotected KATs undergo ligations with hydroxylamine-functionalized superfolder GFP and sulforhodamine B for the composition of three-dimensional patterns.     

Annelated Pyridines as Highly Nucleophilic and Lewis Basic Catalysts for Acylation Reactions

New heterocyclic derivatives of 9‐azajulolidine have been synthesized and characterized with respect to their nucleophilicity and Lewis basicity. The Lewis basicity of these bases as quantified through their theoretically calculated methyl‐cation affinities correlate well with the experimentally measured reaction rates for addition to benzhydryl cations. All newly synthesized pyridines show exceptional catalytic activities in benchmark acylation reactions, which correlate only poorly with Lewis basicity or nucleophilicity parameters. A combination of Lewis basicity with charge and geometric parameters in the framework of a three‐component quantitative structure–activity relationship (QSAR) model is, however, highly predictive.     

Diastereo‐ and Enantioselective Synthesis of Organometallic Bis(helicene)s by a Combination of C?H Activation and Dynamic Isomerization

Homochiral and heterochiral cis‐bis‐cycloplatinated‐[6]helicene derivatives 1 b^{1, 2} , as representative examples of platina[6]helicenes that share a common platinum center, have been prepared. A diastereo‐ and enantioselective synthesis, which combines CH activation and dynamic isomerization from heterochiral structure 1 b² into homochiral structure 1 b¹ , is also described. Overall, this isomerization process results in the transfer of chiral information from one helicene moiety to the other one. The chiroptical properties of homochiral (P)‐ and (M)‐ 1 b¹ were greatly modified upon oxidation into their corresponding (P)‐ and (M)‐diiodo‐Pt^IV complexes ( 5 ). The changes were also analyzed by performing theoretical calculations. C? H activation in the synthesis of organometallic helicenes is further demonstrated by the preparation of cis‐bis‐cycloplatinated‐[8]helicene 1 c .