BASHY Dyes Are Highly Efficient Lipid Droplet-Targeting Photosensitizers that Induce Ferroptosis through Lipid Peroxidation.

Ferroptosis is an iron-dependent lipid-peroxidation-driven mechanism of cell death and a promising therapeutic target to eradicate cancer cells. In this study, we discovered that boronic acid-derived salicylidenehydrazone (BASHY) dyes are highly efficient singlet-oxygen photosensitizers (PSs; ΦΔ up to 0.8) that induce ferroptosis triggered by photodynamic therapy. The best-performing BASHY dye displayed a high phototoxicity against the human glioblastoma multiform U87 cell line, with an IC50 value in the low nanomolar range (4.40 nM) and a remarkable phototoxicity index (PI > 22,700). Importantly, BASHY dyes were shown to accumulate in lipid droplets (LDs) and this intracellular partition was found to be essential for the enhanced phototoxicity and the induction of ferroptosis through lipid peroxidation. The safety and phototoxicity of this platform were validated using an in vivo zebrafish model (Danio rerio).

Engineering the BASHY Dye Platform toward Architectures with Responsive Fluorescence.

A set of nine boronic-acid-derived salicylidenehydrazone (BASHY) complexes has been synthesized in good to very good chemical yields in a versatile three-component reaction. In an extension to previous reports on this dye platform, the focus was put on the electronic modification of the "vertical" positions of the salicylidenehydrazone backbone. This enabled the observation of fluorescence quenching by photoinduced electron transfer (PeT), which can be reverted by the addition of acid in organic solvent (OFF-ON fluorescence switching). The resulting emission is observed in the green-to-orange spectral region (maxima at 520-590 nm). In contrast, under physiological pH conditions in water, the PeT process is inherently decativated, thereby enabling the observation of fluorescence in the red-to-NIR region (maxima at 650-680 nm) with appreciable quantum yields and lifetimes. The latter characteristic supported the application of the dyes in fluorescence lifetime imaging (FLIM) of live A549 cells.

Metal-Mediated Organocatalysis in Water: Serendipitous Discovery of Aldol Reaction Catalyzed by the [Ru(bpy)2(nornicotine)2]2+ Complex.

The [Ru(bpy)2(Nor)2]2+ complex (Nor = nornicotine) is an efficient catalyst for the aldol reaction of acetone with activated benzaldehydes in a buffered aqueous solution. The metal plays the role of an activator for the nornicotine organocatalyst ligands. The resulting catalytic activity is potentiated by a factor of about 4.5 as compared to free nornicotine. Similar rate enhancements can be achieved by using Zn(II) cations as the activator. The observations are rationalized with the reduced basicity of the pyrrolidine N in nornicotine due to the enhanced electron withdrawal of the metal-complexed pyridyl moiety.

Visible Light-Gated Organocatalysis Using a RuII -Photocage.

The light-gated organocatalysis via the release of 4-N,N-dimethylaminopyridine (DMAP) by irradiation of the [Ru(bpy)2 (DMAP)2 ]2+ complex with visible light was investigated. As model reaction the acetylation of benzyl alcohols with acetic anhydride was chosen. The pre-catalyst releases one DMAP molecule on irradiation at wavelengths longer than 455 nm. The photochemical process was characterized by steady-state irradiation and ultrafast transient absorption spectroscopy. The latter enabled the observation of the 3 MLCT state and the spectral features of the penta-coordinated intermediate [Ru(bpy)2 (DMAP)]2+ . The released DMAP catalyzes the acetylation of a wide range of benzyl alcohols with chemical yields of up to 99 %. Control experiments revealed unequivocally that it is the released DMAP which takes the role of the catalyst.

Cyanine-Like Boronic Acid-Derived Salicylidenehydrazone Complexes (Cy-BASHY) for Bioimaging Applications.

Boronic acid-derived salicylidenehydrazone complex (BASHY) dyes with a polymethine backbone were designed to yield efficient red-emitting and two-photon absorbing fluorophores that can be used as markers for astrocytes. The dyes are chemically stable in aqueous solution and do not undergo photodecomposition. Their photophysical properties can be electronically fine-tuned and thereby adapted to potentially different imaging situations and requirements.

Binding of Flavylium Ions to Sulfonatocalix[4]arene and Implication in the Photorelease of Biologically Relevant Guests in Water.

The formation of host-guest complexes between seven flavylium cations and water-soluble p-sulfonatocalix[4]arene (SC4) was investigated by UV/vis absorption, fluorescence, and NMR spectroscopies. The results show the cationic guests form complexes with affinities in the submillimolar range. A representative chalcone/flavylium photoswitch was investigated in more detail regarding its pH- and light-triggered interconversion between the two forms. The dramatic affinity differentiation of the SC4 binding of the two switchable species (40 M-1 for the trans-chalcone versus 3.5 × 104 M-1 for the flavylium cation) enables the pH-gated photocontrol of the complexation process. These responsive properties were explored to demonstrate the competitive and selective release of biologically relevant guests from their supramolecular complexes with p-sulfonatocalix[4]arene (SC4), following the principle of AND logic. The guest release can be reverted by the thermally activated reaction of the flavylium ion back to the trans-chalcone.

Photocaged Competitor Guests: A General Approach Toward Light-Activated Cargo Release From Cucurbiturils.

A general approach toward the light-induced guest release from cucurbit[7]uril by means of a photoactivatable competitor was devised. An o-nitrobenzyl-caged competitor is photolyzed to generate a competitive guest that can displace cargo from the host macrocycle solely based on considerations of chemical equilibrium. With this method the release of terpene guests from inclusion complexes with cucurbit[7]uril was demonstrated. The binding of the herein investigated terpenes, all being lead fragrant components in essential oils, has been characterized for the first time. They feature binding constants of up to 108  L mol-1 and a high differential binding selectivity (spanning four orders of magnitude for the binding constants for the particular set of terpenes). By fine-tuning the photoactivatable competitor guest, selective and also sequential release of the terpenes was achieved.

Electronic and Functional Scope of Boronic Acid Derived Salicylidenehydrazone (BASHY) Complexes as Fluorescent Dyes.

A series of boronic acid derived salicylidenehydrazone (BASHY) complexes was prepared and photophysically characterized. The dye platform can be modified by (a) electronic tuning along the cyanine-type axis via modification of the donor-acceptor pair and (b) functional tuning via the boronic acid residue. On the one hand, approach (a) allows the control of photophysical parameters such as Stokes shift, emission color, and two-photon-absorption (2PA) cross section. The resulting dyes show emission light-up behavior in nonpolar media and are characterized by high fluorescence quantum yields (ca. 0.5-0.7) and brightness (ca. 35000-40000 M-1 cm-1). Moreover, the 2PA cross sections reach values in the order of 200-300 GM. On the other hand, the variation of the dye structure through the boronic acid derived moiety (approach (b)) enables the functionalization of the BASHY platform for a broad spectrum of potential applications, ranging from biorelevant contexts to optoelectronic materials. Importantly, this functionalization is generally electronically orthogonal with respect to the dye's photophysical properties, which are only determined by the electronic structure of the cyanine-type backbone (approach (a)). Rare exceptions to this generalization are the presence of redox-active residues (such a triphenylamine or pyrene). Finally, the advantageous photophysics is complemented by a significant photostability.

Universal access to megastigmanes through controlled cyclisation towards highly substituted cyclohexenes.

We report the selective formation of cyclohexenes with a tetrasubstituted double bond, the structural key element of megastigmanes. For this purpose the ZrCl4-mediated epoxide ring opening of epoxy-geranylacetone was employed. This approach provides a universal entry to the preparation of the members of the megastigmane family, which was exemplified in the asymmetric synthesis of tectoionol B.

Phytotoxic and Nematicidal Components of Lavandula luisieri.

Several preparations were obtained from the aerial parts of predomesticated Lavandula luisieri, including the essential oil and ethanolic, hexane, and ethyl acetate extractives. Additionally, pilot plant vapor pressure extraction was carried out at a pressure range of 0.5-1.0 bar to give a vapor pressure oil and an aqueous residue. A chemical study of the hexane extract led to the isolation of six necrodane derivatives (1, 2, and 4-7), with four of these (1, 2, 5, and 7) being new, as well as camphor, a cadinane sesquiterpene (9), tormentic acid, and ursolic acid. The EtOAc and EtOH extracts contained a mixture of phenolic compounds with rosmarinic acid being the major component. Workup of the aqueous residue resulted in the isolation of the necrodane 3 and (1R*,2S*,4R*)-p-menth-5-ene-1,2,8-triol (8), both new natural compounds. The structures of the new compounds were established based on their spectroscopic data. The phytotoxic and nematicidal activities of these compounds were evaluated.

Homocoupling versus reduction of radicals: an experimental and theoretical study of Ti(III)-mediated deoxygenation of activated alcohols.

A detailed experimental and theoretical study corroborates that the reductive deoxygenation of activated (allylic or benzylic) alcohols with excess Ti(III) proceeds via an allyl(benzyl)-radical and allyl(benzyl)-Ti, which is protonated, regioselectively in the case of allylic derivatives. The H atom of the newly formed C-H bond in the product originates from the -OH group of the starting material. The deoxygenation of lithium alkoxides or alcohols by using 1.0 mol of Ti(III) leads to the corresponding dimerization products in good yields. An excellent agreement with the experimental data was obtained by using a reaction kinetics simulator to discriminate between competing reactions.

A simple assay for quality binders to cucurbiturils.

A new approach towards the rapid identification of quality binders to cucurbiturils--those that combine high affinity with high selectivity for a particular homologue--was developed. The assay exploits macrocycle-specific optical fingerprints (colorimetric or fluorimetric) of carefully selected indicators dyes. The screening of a guest library revealed known (e.g., adamantane derivatives) and new (e.g., terpenes) quality binders. The predictive power of the assay was underpinned by the modeling of the involved thermodynamic equilibria.

Easy access to a cyclic key intermediate for the synthesis of trisporic acids and related compounds.

The synthesis of a cyclohexane skeleton possessing different oxygenated functional groups at C-3, C-8 and C-9, and a D1,6-double bond has been accomplished in 10 steps with an overall 17% yield. This compound is a key intermediate for access to a wide range of compounds of the bioactive trisporoid family. The synthetic sequence consists of the preparation of a properly functionalized epoxygeraniol derivative, and its subsequent stereoselective cyclization mediated by Ti(III). This last step implies a domino process that starts with a homolytic epoxide opening followed by a radical cyclization and regioselective elimination. This concerted process gives access to the cyclohexane moiety with stereochemical control of five of its six carbon atoms.

Azaborahelicene fluorophores derived from four-coordinate N,C-boron chelates: synthesis, photophysical and chiroptical properties.

A series of six azaborahelicenes with varying electron-donor substitution at the 4-position of the aryl residue (i.e., naphthyl) or with variable π-extension of the aryl residue (thianthrenyl, anthryl, pyrenyl) was prepared with an efficient and flexible synthetic protocol. These different types of functionalization afforded notably pronounced intramolecular charge-transfer (ICT) character for the dyes with the strongest electron donor substitution (NMe2) or easiest to oxidize aryl residues, as evidenced by photophysical investigations. These effects also impact the corresponding chiroptical properties of the separated M- and P-enantiomers, which notably display circularly polarized luminescence (CPL) with dissymmetry factors in the order of magnitude of 10-4 to 10-3. Theoretical calculations confirm the optical spectroscopy data and are in agreement with the proposed involvement of ICT processes.

First total synthesis of (+)-apotrisporin E and (+)-apotrientriols A-B: a cyclization approach to apocarotenoids.

The first total synthesis of the natural apocarotenoids (+)-apotrisporin E (1) and (+)-apotrientriols A and B (2-3) has been accomplished. The structure, relative stereochemistry and the assignation of the absolute configuration have been confirmed. This is a fast and easy access to this family of natural products whose key steps are a diastereoselective cyclization and a HWE olefination to attach the dienic side chain. This work also opens the door to the synthesis of other apocarotenoids such as trisporols and trisporic acids.

Isocyanate-functionalized chitin and chitosan as gelling agents of castor oil.

The main objective of this work was the incorporation of reactive isocyanate groups into chitin and chitosan in order to effectively use the products as reactive thickening agents in castor oil. The resulting gel-like dispersions could be potentially used as biodegradable lubricating greases. Three different NCO-functionalized polymers were obtained: two of them by promoting the reaction of chitosan with 1,6-hexamethylene diisocyanate (HMDI), and the other by using chitin instead of chitosan. These polymers were characterized through 1H-NMR, FTIR and thermogravimetric analysis (TGA). Thermal and rheological behaviours of the oleogels prepared by dispersing these polymers in castor oil were studied by means of TGA and small-amplitude oscillatory shear (SAOS) measurements. The evolution and values of the linear viscoelasticity functions with frequency for -NCO-functionalized chitosan- and chitin-based oleogels are quite similar to those found for standard lubricating greases. In relation to long-term stability of these oleogels, no phase separation was observed and the values of viscoelastic functions increase significantly during the first seven days of ageing, and then remain almost constant. TGA analysis showed that the degradation temperature of the resulting oleogels is higher than that found for traditional lubricating greases.

Photofunctional Scope of Fluorescent Dithienylethene Conjugates with Aza-Heteroaromatic Cations.

A series of dithienylethene (DTE) photoswitches with aza-heteroaromatic cationic moieties is synthesized. The switches are characterized regarding their photochemical and photophysical properties in acetonitrile and in water. The efficiency of the switching and the photostationary state composition depend on the degree of π-conjugation of the heteroaromatic systems. Thus, DTEs with acridinium-derived moieties have very low quantum yields for the ring-closing process, which is in contrast to switches with pyridinium and quinolinium moieties. All switches emit fluorescence in their open forms. The involved electronic transitions are traced back to an integrative picture including the DTE core and the cationic arms. The emission can be fine-tuned by the π-conjugation of the heteroaromatic cations, reaching the red spectral region for DTEs with acridinium moieties. On ring-closing of the DTEs the fluorescence is not observable anymore. Theoretical calculations point to rather low-lying energy levels of the highly conjugated ring-closed DTEs, which would originate near-infrared emission (> 1200 nm). The latter is predicted to be very weak due to the concurrent non-radiative deactivation, according to the energy-gap law. In essence, an ON-OFF fluorescence switching as the result of the electrocyclic ring-closing reaction is observed.

Total synthesis of (+)-seco-C-oleanane via stepwise controlled radical cascade cyclization.

An asymmetric concise total synthesis of the (+)-seco-C-oleanane 1 was accomplished. The successful route to this natural product involves as the key step a stepwise regio- and stereocontrolled catalytic radical polyene cascade cyclization from preoleanatetraene oxide (16), a process mediated by Cp(2)TiCl. The use of this single-electron-transfer complex permits mild cyclization conditions without using unnecessary prefunctionalizations and stops the process at the bicyclic level. Theoretical data revealed high activation energy for the third ring closure, which would account for the control of the cyclization. This process also led to natural (-)-achilleol B, camelliol A, and (+)-seco-ß-amyrin as minor compounds.

A minor dihydropyran apocarotenoid from mated cultures of Blakeslea trispora.

The heterocyclic C15 apocarotenoid 1 was isolated from mated cultures of the strains F986 (+) and F921 (−) of Blakeslea trispora. This new compound formed during sexual interaction is a minor constituent of the culture media and its structure was elucidated by spectroscopic data, including 2D-NMR. A plausible biosynthetic pathway involving a double degradation of β-carotene, followed by several oxidations of the resulting monocyclofarnesane C15 fragment is proposed.

Communic acids: occurrence, properties and use as chirons for the synthesis of bioactive compounds.

Communic acids are diterpenes with labdane skeletons found in many plant species, mainly conifers, predominating in the genus Juniperus (fam. Cupresaceae). In this review we briefly describe their distribution and different biological activities (anti- bacterial, antitumoral, hypolipidemic, relaxing smooth muscle, etc.). This paper also includes a detailed explanation of their use as chiral building blocks for the synthesis of bioactive natural products. Among other uses, communic acids have proven useful as chirons for the synthesis of quassinoids (formal), abietane antioxidants, ambrox and other perfume fixatives, podolactone herbicides, etc., featuring shorter and more efficient processes.