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.

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.

Photooxidation Responsive Elastin-Like Polypeptide Conjugates for Photodynamic Therapy Application.

Stimuli-responsive recombinant elastin-like polypeptides (ELPs) are artificial protein polymers derived from the hydrophobic domain of tropoelastin that have attracted significant interest for drug delivery and tissue engineering applications. In the present study, we have conjugated a photosensitizer (PS) to a hydrophobic methionine-containing ELP scaffold, which upon reaction with singlet oxygen (1O2) is transformed into a hydrophilic sulfoxide derivative facilitating the disassembly of photosensitizer-delivery particles during the photodynamic therapy (PDT) process. A peripherally substituted carboxy-Zn(II)-phthalocyanine derivative (TT1) bearing a carboxyl group directly linked to the Pc-ring, and presenting an absorption maximum around 680 nm, was selected as PS which simultaneously acted as a photooxidation catalyst. A TT1-ELP[M1V3-40] conjugate was prepared from ELP[M1V3-40] modified with an alkyne group at the N-terminal chain end, and from TT1-amide-C3-azide by copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. This innovative model photooxidation sensitive PS delivery technology offers promising attributes in terms of temperature-controlled particle formation and oxidation-triggered release, narrow molar mass distribution, reproducibility, scalability, non-immunogenicity, biocompatibility, and biodegradability for pharmaceutical applications in an effort to improve the clinical effectiveness of PDT treatments.

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.

Optical Supramolecular Sensing of Creatinine.

Calix[4]pyrrole phosphonate-cavitands were used as receptors for the design of supramolecular sensors for creatinine and its lipophilic derivative hexylcreatinine. The sensing principle is based on indicator displacement assays of an inherently fluorescent guest dye or a black-hole quencher from the receptor's cavity by means of competition with the creatinine analytes. The systems were thermodynamically and kinetically characterized regarding their 1:1 binding properties by means of nuclear magnetic resonance spectroscopy (1H and 31P NMR), isothermal titration calorimetry, and optical spectroscopies (UV/vis absorption and fluorescence). For the use of the black-hole indicator dye, the calix[4]pyrrole was modified with a dansyl chromophore as a signaling unit that engages in Förster resonance energy transfer with the indicator dye. The 1:1 binding constants of the indicator dyes are in the range of 107 M-1, while hexylcreatinine showed values around (2-4) × 105 M-1. The competitive displacement of the indicators by hexylcreatinine produced supramolecular fluorescence turn-on sensors that work at micromolar analyte concentrations that are compatible with those observed for healthy as well as sick patients. The limit of detection for one of the systems reached submicromolar ranges (110 nM).

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.

Occurrence and Chemical Synthesis of Apocarotenoids from Mucorales: A Review.

Apocarotenoids are metabolites originated by degradation of carotenes through the loss of carbon atoms placed at the side chain of their structure as consequence of oxydative reactions. We present here the first review of apocarotenoids in the fungi mucorales Phycomyces blakesleeanus, Blakeslea trispora and Mucor mucedo. This review is divided into two parts: the first one presents their structures and sources, whereas the second part is dedicated to their chemical synthesis.

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.

Hydrogels containing porphyrin-loaded nanoparticles for topical photodynamic applications.

5,10,15,20-tetrakis(1-methylpyridinium-4-yl)-porphyrin tetra-iodide (TMPyP), a potent water-soluble photosensitizer (PS) used in antimicrobial applications, was encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TMPyP-PLGA) for topical delivery purposes. Nanoparticles resulted in a mean particle size around 130nm, narrow polydispersity index (PdI), spherical morphology and association efficiency up to 93%. Free TMPyP and TMPyP-PLGA nanoparticles were incorporated into Carbopol(®) hydrogels, resulting in controlled TMPyP release of about 60% and 20% after 4.5h, respectively. Critical properties such as appearance, clarity, viscosity and pH were maintained over time, as hydrogels were stable during 6 months at 4°C, 25°C/60% RH and 40°C/75% RH. For photodynamic applications, the photoproduction of singlet oxygen from these hydrogels was quite efficient being both formulations very photostable after 20min. No TMPyP permeation through pig ear skin was observed after 24h, and histological assays did not show relevant damages in surrounding tissues. All these excellent characteristics make them promising platforms for photodynamic applications through topical clinical use.

Use of Photosensitizers in Semisolid Formulations for Microbial Photodynamic Inactivation.

Semisolid formulations, such as gels, creams and ointments, have recently contributed to the progression of photodynamic therapy (PDT) and microbial photodynamic inactivation (PDI) in clinical applications. The most important challenges facing this field are the physicochemical properties of photosensitizers (PSs), optimal drug release profiles, and the photosensitivity of surrounding tissues. By further integration of nanotechnology with semisolid formulations, very promising pharmaceuticals have been generated against several dermatological diseases (PDT) and (antibiotic-resistant) pathogenic microorganisms (PDI). This review focuses on the different PSs and their associated semisolid formulations currently found in both the market and clinical trials that are used in PDT/PDI. Special emphasis is placed on the advantages that the semisolid formulations bring to drug delivery in PDI. Lastly, some potential considerations for improvement in this field are also discussed.

Synthesis of Stilbene Derivatives: A Comparative Study of their Antioxidant Activities.

A series of structurally simple compounds belonging to thestilbene family were synthesized by means of a Ti(III)-mediated methodology that allows access, in an efficient manner, to derivatives of dihydrostilbene, E-stilbene, and stilbene oxide, with high yields. The antioxidant activity of these compounds has been evaluated by means of two electrochemical assays, which provide complementary information, showing that the majority of these stilbene analogs exhibit significant antioxidant activity dependent on the electronic structure and functionalization of the molecule in each case.

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.

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.

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.

Apocarotenoids in the sexual interaction of Phycomyces blakesleeanus.

A simple genetic test allowed us to carry out the first systematic study of the apocarotenoids in the Mucorales. We have identified 13 apocarotenoids in the culture media of the fungus Phycomyces blakesleeanus (Mucoromycota, Mucorales). Three of these compounds were novel apocarotenoids: (2S,8R,E)-8,14-epoxycyclofarnesa-4,6,9-triene-2,11-diol (6), (2S,6E,8E)-cyclofarnesa-4,6,8-triene-2,10,11-triol (7), and its 6Z isomer (8). Four of the remaining compounds have been reported previously from this fungus and six from other Mucorales. All of them belong to three families, the 18-carbon trisporoids, the 15-carbon cyclofarnesoids, and the 7-carbon methylhexanoids, derived from the three fragments that result when ß-carotene is cleaved at its 11',12' and 12,13 double bonds. The apocarotenoids were more varied and more abundant in mated cultures of strains of opposite sex than in single cultures. The presence of acetate in the medium blocked the production of many apocarotenoids while having little effect on the concentrations of the remaining ones.

Protecting-group-free synthesis of chokols.

As a result of a combined theoretical and experimental study, we describe a two-step protocol for the preparation of an optically pure, multifunctional, cyclopentanic core shared by a number of natural products. This process is based on a hitherto unreported Ti(III)-mediated diastereoselective cyclization in which the hydroxy-directed template effect played by the Ti(III) species was found to be crucial for the stereoselective outcome of the reaction. The viability of this concept was confirmed with the first protecting-group free synthesis of three enantiopure chokols, namely, chokols K, E, and B.