Lucas Cunha Dias de Rezende

Radical CH Alkylation of BODIPY Dyes Using Potassium Trifluoroborates or Boronic Acids

A one-step synthetic procedure for the radical CH alkylation of BODIPY dyes has been developed. This new reaction generates alkyl radicals through the oxidation of boronic acids or potassium trifluoroborates and allows the synthesis of mono-, di-, tri-, and tetraalkylated fluorophores in a good to excellent yield for a broad range of organoboron compounds. Using this protocol, multiple bulky alkyl groups can be introduced onto the BODIPY core thus creating solid-state emissive BODIPY dyes.

Transcorneal iontophoresis of dendrimers: PAMAM corneal penetration and dexamethasone delivery

Iontophoresis of nanocarriers in the eye has been proposed to sustain drug delivery and maintain therapeutic concentrations. Fourth generation polyamidoamine (PAMAM) dendrimers are semi-rigid nanoparticles with surface groups that are easily modified. These dendrimers are known to modulate tight junctions, increase paracellular transport of small molecules and be translocated across epithelial barriers, exhibiting high uptake by different cell lines. The first aim of this study was to investigate the effect of iontophoresis on PAMAM penetration and distribution into the cornea. The second aim was to evaluate, ex vivo and in vivo, the effect of these dendrimers in dexamethasone (Dex) transcorneal iontophoresis. Anionic (PAMAM G3.5) and cationic (PAMAM G4) dendrimers were labeled with fluorescein isothiocyanate (FITC), and their distribution in the cornea was investigated using confocal microscopy after ex vivo anodal and cathodal iontophoresis for various application times. The particle size distribution and zeta potential of the dendrimers in an isosmotic solution were determined using dynamic light scattering and Nanoparticle Tracking Analysis (NTA), where the movement of small particles and the formation of large aggregates, from 5 to 100 nm, could be observed. Transcorneal iontophoresis increased the intensity and depth of PAMAM-FITC fluorescence in the cornea, suggesting improved transport of the dendrimers across the epithelium toward the stroma. PAMAM complexes with Dex were characterized by (13)C-NMR, (1)H-NMR and DOSY. PAMAM G3.5 and PAMAM G4 increased the aqueous solubility of Dex by 10.3 and 3.9-fold, respectively; however, the particle size distribution and zeta potential remained unchanged. PAMAM G3.5 decreased the Dex diffusion coefficient 48-fold compared with PAMAM G4. The ex vivo studies showed that iontophoresis increased the amount of Dex that penetrated into the cornea by 2.9, 5.6 and 3.0-fold for Dex, Dex-PAMAM G4 and Dex-PAMAM G3.5, respectively. In vivo experiments, however, revealed that iontophoresis of Dex-PAMAM-G3.5 increased Dex concentration in the aqueous humor by 6.6-fold, while iontophoresis of Dex-PAMAM G4 and Dex increased it 2.5 and 2-fold, respectively. Therefore, iontophoresis targeted PAMAM to the cornea but it is the sustained delivery of the Dex from PAMAM that prevents its rapid elimination from the aqueous humor. In conclusion, iontophoresis of PAMAM complexes represents a promising strategy for targeted and sustained topical drug delivery to the eye.

In vivo antimalarial activity of novel 2-hydroxy-3-anilino-1,4-naphthoquinones obtained by epoxide ring-opening reaction.

1,4-Naphthoquinone derivatives are known to have relevant activities against several parasites. Among the treatment options for malaria, atovaquone, a 1,4-naphthoquinone derivative, is widely applied in the treatment and prophylaxis of such disease. Based on the structure simplification of atovaquone, we designed and synthesized four novel naphthoquinoidal derivatives. The compounds were obtained by the underexplored epoxide-opening reaction of 1,4-naphthoquinone using aniline derivatives as nucleophiles. The antiplasmodial activity of the synthesized compounds was performed in vivo using Peters 4days suppression test. Significant parasitemia reduction and increased survival were observed for some of the compounds.

Novel fluorescent lapachone-based BODIPY: synthesis, computational and electrochemical aspects, and subcellular localisation of a potent antitumour hybrid quinone

For the first time, a fluorescent lapachone-based BODIPY was synthesised and characterised by NMR and mass spectrometry. Computational and electrochemical aspects, as well as cytotoxic activity and subcellular localisation, were studied. Confocal microscopy experiments indicated that the probe was a specific mitochondria-staining agent. These in-detail analyses were useful in understanding the cytotoxic effects and mechanism of action of this novel hybrid compound. This molecule constitutes a promising prototype owing to its potential biological activities and the new strategies aimed at mechanistic investigations in cells and in vivo, and opens up an interesting avenue of research.

Synthesis of two ‘heteroaromatic rings of the future’ for applications in medicinal chemistry

In a computational study, the 1H-pyrazolo[3,4-c]pyridin-5-ol and 2,6-naphthyridin-3-ol heterocycles were identified as unknown heteroaromatic ring systems of potential value for medicinal chemistry. Here we report robust and concise synthetic protocols that provide access to these two scaffolds on a multigram scale.

Effect of the substitution position (2, 3 or 8) on the spectroscopic and photophysical properties of BODIPY dyes with a phenyl, styryl or phenylethynyl group

A very active branch of organic chemistry is putting great effort into tailoring fluorescent dyes for a myriad of applications, from technological to bioanalytical and biomedical applications. Among the major families of fluorophores, those derived from 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY dyes) are undergoing a recent boost thanks to the simplicity and robustness of the chemistry involved. The BODIPY core can be modified with numerous side groups, the 8-position being a modification place with important effects on the spectroscopic and photophysical properties of the resulting dyes. Likewise, previous work has shown that the addition of groups attached at the 3- and 2-positions can result in dyes with very different properties. Herein, we generalize the effect of the substituent side groups by studying nine BODIPY dyes substituted with a phenyl, styryl or phenylethynyl moiety at the 2-, 3- or 8-position of the BODIPY scaffold. Within the class of phenyl- or phenylethynyl-substituted dyes, substitution at the 2-position always leads to dyes with the broadest bandwidths and the largest Stokes shifts. We investigate the solvent effect on the spectroscopic properties of the dyes, using four empirical solvent scales (dipolarity, polarizability, acidity and basicity: Catalan, J. Phys. Chem., 2009, 113, 5951). These analyses identify solvent dipolarity and polarizability as critical parameters accounting for the observed solvent-dependent shifts of the absorption and emission maxima. Finally, time-dependent density functional theory calculations provide insights into the structural and energetic issues concerning the spectroscopic properties of these fluorophores.

TFC049 Solid lipid nanoparticles: a study of passive and iontophoretic permeation mechanisms through skin.

Solid lipid nanoparticles (SLN) are drug delivery systems developed in the nineties to be an alternative to other colloidal systems like liposomes, emulsions and polymeric nanoparticles. Its use as a drug carrier for topical drug application has been vastly studied for the last years. SLN showed some promising characteristics for this use as the possibility of drug control release, small size, good stability and capacity of protection of the drug encapsulated, besides being less toxic than other drug delivery systems. Meanwhile, despite the large number of studies, there are almost no researches showing how SLN could act to improve drug penetration through the skin. In general, improved drug skin penetration is usually associated with increased hydration of stratum corneum (SC) caused by an adhesive layer (formed by SLN) occluding the skin surface. Furthermore, although intact particles are not normally considered to permeate the horny layer, some studies showed that the follicular pathway may be relevant to drug skin penetration. It is known that the follicular route is the main via of drug penetration when iontophoresis, a physical method that uses a weak electric current to increase skin drugs penetration, is applied. Therefore, iontophoresis of SLN may increase the penetration of intact SLN, increasing the encapsulated drug release inside the skin. SLN marked with hydrophilic and hydrophobic dyes at once may help to elucidate SLN skin penetration in the presence and absence of iontophoresis.

PNS039 Synthesis, spectroscopy and photophysical characterization of two meso-substituted tetramethyl borodipyrromethene (BODIPY) derivatives.

Fluorescence is a photophysical process that occurs in some compounds in excited electronic state, in which the return of the excited electron to lower energy orbitals is accompanied by luminescence emission. In the last decades, fluorescence-emitting compounds (fluorophores) have risen as an essential tool for academic and commercial researches; consequently, every year novel fluorescent compounds are synthesized and characterized. Borodipyrromethene (BODIPY) is a widely applied fluorescent scaffold, characterized by two pyrrolic units bridged by a sp2 carbon, and a BF2 unity complexed to the pyrrolic nitrogens. Herein we show the synthesis and characterization of two meso-substituted BODIPYs as a part of a new research project recently implemented in our group.