ABSTRACT
The synthesis of new cadiolide analogues was carried out using a one-pot multi component synthesis. The antibacterial activity of these molecules was evaluated on standard and antibiotic resistant bacterial strains chosen for their involvement in human health or in food-born poisoning. Four molecules have shown good activities with MICs of 2 µg/mL-1. The introduction of an indole group or the conversion of the lactone into lactam have highlighted two new families of molecules with promising antibacterial activity. In addition, most of these active molecules are devoid of cytotoxic activity against keratinocyte cells.
Subject(s)
4-Butyrolactone/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Epicocconone 1 is a natural chromophore isolated from the fungus Epicoccum nigrum that has shown applications in proteomics and fluorescent microscopy thanks to its unique pro-fluorescence properties. The modification of the skeleton of the natural product by replacing the triene side chain by a fluorenyl scaffold can noticeably increase the fluorophore's absorption coefficient. The synthesis of the analogues of the natural product has been made possible by the use of a palladium-catalyzed carbonylation reaction, allowing the construction of the ß-keto-dioxinone key intermediate. Two-photon absorption cross-section measurements of the fluorenyl epicocconone analogues show a structure dependency with values ranging from 60 to 280â GM and live cell imaging show intense staining of intracellular vesicle-like structures around the nucleus.
Subject(s)
Benzopyrans/chemistry , Fluorenes/chemistry , Fluorescent Dyes/chemistry , Furans/chemistry , Ketones/chemistry , Microscopy, Fluorescence, Multiphoton/methods , Animals , Benzopyrans/chemical synthesis , Catalysis , Fluorenes/chemical synthesis , Fluorescent Dyes/chemical synthesis , Furans/chemical synthesis , Ketones/chemical synthesis , Optical Imaging/methods , PC12 Cells , Palladium/chemistry , RatsABSTRACT
Over the last 20 years, the number of pathogenic multi-resistant microorganisms has grown steadily, which has stimulated the search for new strategies to combat antimicrobial resistance. Antimicrobial photodynamic therapy (aPDT), also called photodynamic inactivation, is emerging as a promising alternative to treatments based on conventional antibiotics. We have explored the effectiveness of methylene blue-loaded targeted mesoporous silica nanoparticles (MSNP) in the photodynamic inactivation of two Gram negative bacteria, namely Escherichia coli and Pseudomonas aeruginosa. For E. coli, nanoparticle association clearly reduced the dark toxicity of MB while preserving its photoinactivation activity. For P. aeruginosa, a remarkable difference was observed between amino- and mannose-decorated nanoparticles. The details of singlet oxygen production in the nanoparticles have been characterized, revealing the presence of two populations of this cytotoxic species. Strong quenching of singlet oxygen within the nanoparticles is observed.
Subject(s)
Anti-Infective Agents/administration & dosage , Nanoparticles/chemistry , Silicon Dioxide/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Escherichia coli/drug effects , Humans , Light , Mannose/chemistry , Methylene Blue , Nanoparticles/administration & dosage , Pseudomonas aeruginosa/drug effects , Silicon Dioxide/administration & dosage , Silicon Dioxide/chemical synthesisABSTRACT
The first quadrupolar 8-dimethylaminoquinoline-derived 6-(8-DMAQ-OAc)2 (1c) and 5-(8-DMAQ-OAc)2 (2c) photosensitive probes underwent photolysis under UV (365 nm) and NIR (730 nm two-photon (TP)) irradiation conditions, showing Qu = 9.3% and 6.6% quantum yields and δu = 0.07 GM and 0.40 GM uncaging cross-sections, respectively.
Subject(s)
Photons , Photosensitizing Agents/chemistry , Quinolines/chemistry , Molecular Structure , PhotolysisABSTRACT
Molecular systems that can be remotely controlled by light are gaining increasing importance in cell biology, physiology, and neurosciences because of the spatial and temporal precision that is achievable with laser microscopy. Two-photon excitation has significant advantages deep in biological tissues, but raises problems in the design of "smart" probes compatible with cell physiology. This Review discusses the chemical challenges in generating suitable two-photon probes.
Subject(s)
Absorptiometry, Photon/methods , Macrocyclic Compounds/chemistry , Photons , Cell Physiological Phenomena , Chelating Agents/chemistry , Nitrobenzenes/chemistry , Photochemical Processes , Photochemistry , Signal TransductionABSTRACT
A molecular engineering strategy based on rational variations of the bromine substitution pattern in two-photon absorbing singlet oxygen sensitizers allows studying the relations that exist between the positioning of an inter-system crossing promoter on the charge-transfer chromophore and its ability to generate singlet oxygen.
Subject(s)
Bromine/chemistry , Photosensitizing Agents/chemistry , Singlet Oxygen/chemistry , PhotonsABSTRACT
Numerous research efforts are investigating the possibility of using light interactions with metallic nanoparticles to improve the fluorescence properties of nearby molecules. Few investigations have considered the encapsulation of molecules in metallic nanocavities. In this paper, we present the optical properties of new hybrid nanoparticles consisting of gold nanoshells and fluorescent organic dyes in their liquid cores. Microspectroscopy on single nanoparticle demonstrates that the extinction spectra are in good agreement with Mie's theory. Finite difference time domain (FDTD) calculations reveal that excitation and emission radiations are efficiently transmitted through the thin gold nanoshells. Thus, they can be considered as transparent plasmonic nanocontainers for photoactive cores. In agreement with FDTD calculations, measurements show that fluorophores encapsulated in gold nanoshells keep their brightness, but they show fluorescence lifetimes 1 order of magnitude shorter. As a salient consequence, the photoresistance of encapsulated organic dyes is also improved by an order of magnitude. This unusual ultraviolet photoresistance results from the reduced probability of triplet-singlet conversion that eventually exposes dyes to singlet oxygen photodegradation.
Subject(s)
Nanotechnology/methods , Organic Chemicals/chemistry , Animals , Cattle , Fluorescence , Fluorescent Dyes/chemistry , Gold/chemistry , Light , Metal Nanoparticles/chemistry , Nanostructures/chemistry , Photobleaching , Rhodamines/chemistry , Serum Albumin, Bovine/chemistry , Surface Plasmon Resonance , Time Factors , Ultraviolet RaysABSTRACT
The synthesis and photophysical properties of two lipophilic quadrupolar chromophores featuring anthracenyl (1) or dibromobenzene (2) were described. These two chromophores combined significant two-photon absorption cross-sections with high fluorescence quantum yield for 1 and improved singlet oxygen generation efficiency for 2, in organic solvents. The use of Pluronic nanoparticles allowed a simple and straightforward introduction of these lipophilic chromophores into biological cell media. Their internal distribution in various cell lines was studied using fluorescence microscopy and flow-cytometry following a successful staining that was achieved upon 2 h of incubation. Finally, multiphoton excitation microscopy and photodynamic therapy capability of the chromophores were demonstrated by cell exposure to a 820 nm fs laser and cell death upon one photon resonant irradiation at 436 ± 10 nm, respectively.
Subject(s)
Alkynes/chemistry , Aniline Compounds/chemistry , Anthracenes/chemistry , Bromobenzenes/chemistry , Photosensitizing Agents/chemistry , Polymers/chemistry , Alkynes/pharmacology , Alkynes/therapeutic use , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Animals , Anthracenes/pharmacology , Anthracenes/therapeutic use , Apoptosis , Bromobenzenes/pharmacology , Bromobenzenes/therapeutic use , Cell Line, Tumor , Fluorescent Dyes/chemistry , Hydrophobic and Hydrophilic Interactions , Microscopy, Fluorescence , Nanoparticles/chemistry , Neoplasms/drug therapy , Photochemotherapy , Photons , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Poloxamer/chemistry , Quantum Theory , Rats , Singlet Oxygen/metabolismABSTRACT
We report the preparation of gold nanoclusters (AuNCs) as a delivery vehicle for the clinically approved photodynamic and chemotherapeutic agents Protoporphyrin IX (PpIX) and doxorubicin (DOX), respectively, and their effect on tumor cells. DOX was attached to the gold nanoclusters through a singlet oxygen-cleavable linker and was therefore released after PpIX irradiation with red light, contributing, synergistically with singlet oxygen, to induce cell death. The doubly functionalized AuNCs proved more effective than a combination of individually functionalized AuNCs. Unlike free DOX, the photoactive nanosystem was non-toxic in the absence of light, which paves the way to introduce a spatiotemporal control of the anticancer therapy and could contribute to reducing the undesirable side effects of DOX.
ABSTRACT
Indazole derivatives are currently drawing more and more attention in medicinal chemistry as kinase inhibitors. 1H-indazole-3-carboxaldehydes are key intermediates to access to a variety of polyfunctionalized 3-substituted indazoles. We report here a general access to this motif, based on the nitrosation of indoles in a slightly acidic environment. These very mild conditions allow the conversion of both electron-rich and electron-deficient indoles into 1H-indazole-3-carboxaldehydes.
ABSTRACT
Reaction of porphycene isothiocyanates with primary and secondary amines leads to the formation of thiazolo[4,5-c]porphycenes, with a substantial shift in the absorption and fluorescence spectra. The conjugates show fluorescence in the near-infrared and are capable of photosensitizing the production of the cytotoxic species singlet oxygen.
Subject(s)
Click Chemistry , Nanoparticles/chemistry , Porphyrins/chemistry , Proteins/chemistry , Theranostic Nanomedicine , Thiazoles/chemistry , Amines/chemistry , Fluorescence , Infrared Rays , Isothiocyanates/chemistry , Molecular Structure , Porphyrins/chemical synthesis , Quantum Theory , Singlet Oxygen/chemistry , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Thiazoles/chemical synthesisABSTRACT
High two-photon photolysis cross sections and water solubility of probes are important to avoid toxicity in biomedical applications of photolysis. Systematic variation of the position of a carboxyl electron-withdrawing group (EWG) on photolysis of 8-dimethylaminoquinoline protecting groups identified the C5-substituted isomer as a privileged dipole. The 5-benzoyl-8-DMAQ substitution yields a caging group with an enhanced two-photon uncaging cross section (δu = 2.0 GM) and good water solubility (c ≤ 50 mM, pH 7.4).
Subject(s)
Aminoquinolines/chemistry , Photolysis , Photons , Molecular Structure , SolubilityABSTRACT
A chromophore featuring a diyne bridge that connects two dibromobenzene moieties shows a much improved two-photon singlet oxygen generation ability in the biological transparency window compared to a related and relevant literature benchmark, as a result of a distorted ground state.
Subject(s)
Bromobenzenes/chemistry , Photons , Photosensitizing Agents/chemistry , Singlet Oxygen/chemistry , AbsorptionABSTRACT
The systematic SAR study of a "caging" group showed a strong influence of the position of the donor dimethylamino group on the efficiency of photolysis of the DMAQ (2-hydroxymethylene-(N,N-dimethylamino)quinoline) caged acetate under one-photon near-UV or two-photon near-IR excitation. Photorelease of l-glutamate by the most efficient 8-DMAQ derivative strongly and efficiently activated glutamate receptors, generating large, fast rising responses similar to those elicited by glutamate photoreleased from the widely used MNI-caged glutamate.