Publications

Abstract The disinfection-induced and photo-induced degradation of the UV filter 3-methylbutyl-(2E)-3-(4-methoxyphenyl)-acrylate (IMC) is investigated. High performance liquid chromatography was used to follow the degradation reactions, determine kinetic features and also the influence of external variables on degradation [pH; temperature; chlorine concentration; dissolved organic matter (DOM) concentration]. Liquid chromatography preceded by solid-phase extraction, was used for the determination of by-products. IMC was found to rapidly and substantially degrade in aqueous solution, when in exposure to active chlorine, displaying a pseudo second-order degradation rate constant of 0.042 +/- 0.001 L mol(-1) s(-1), and a half-life period of 23.8 +/- 0.6 s. Contact with aqueous active chlorine proved to yield merely the dichlorinated form of IMC, as the prominent disinfection by-product. The assessment of influence of external variables on degradation, was insured by a Box-Behnken experimental design formulation approach, with factorial analysis. In this regard, data shows that temperature plays a decisive factor in the reaction rate, without DOM in solution, leading to decreasing degradation rates as the temperature increases. With DOM in solution, pH and DOM proved to be the most influential variables on IMC degradation. Regarding the photo-degradation study, results have shown that IMC remained quite stable in aqueous solution when exposed to artificial solar radiation, with a rate constant of 0.00073 +/- 0.00002 min(-1) and a half-life period of 938.5 +/- 31.1 min. This work addresses yet another filter that has never been studied, and hopes to provide clarification on its environmental fate and behaviour when in the aqueous environmental compartments.

Abstract Blood-brain barrier is a tightly packed layer of endothelial cells surrounding the brain that acts as the main obstacle for drugs enter the central nervous system (CNS), due to its unique features, as tight junctions and drug efflux systems. Therefore, since the incidence of CNS disorders is increasing worldwide, medical therapeutics need to be improved. Consequently, aiming to surpass blood-brain barrier and overcome CNS disabilities, silencing P-glycoprotein as a drug efflux transporter at brain endothelial cells through siRNA is considered a promising approach. For siRNA enzymatic protection and efficient delivery to its target, two different nanoparticles platforms, solid lipid (SLN) and poly-lactic-co-glycolic (PLGA) nanoparticles were used in this study. Polymeric PLGA nanoparticles were around 115 nm in size and had 50 % of siRNA association efficiency, while SLN presented 150 nm and association efficiency close to 52 %. Their surface was functionalized with a peptide-binding transferrin receptor, in a site-oriented manner confirmed by NMR, and their targeting ability against human brain endothelial cells was successfully demonstrated by fluorescence microscopy and flow cytometry. The interaction of modified nanoparticles with brain endothelial cells increased 3-fold compared to non-modified lipid nanoparticles, and 4-fold compared to non-modified PLGA nanoparticles, respectively. These nanosystems, which were also demonstrated to be safe for human brain endothelial cells, without significant cytotoxicity, bring a new hopeful breath to the future of brain diseases therapies.

Abstract Cancer is the major cause of morbidity and mortality worldwide. Hydroxycinnamic acids (HCAs) are naturally occurring compounds and their alkyl esters may possess enhanced biological activities. We evaluated C4, C14, C16, and C18 alkyl esters of p-coumaric, ferulic, sinapic, and caffeic acids (19 compounds) for their cytotoxic activity against four human cancer cells and also examined their effect on cell cycle alteration and apoptosis induction. The tetradecyl (1c) and hexadecyl (1d) esters of p-coumaric acid and tetradecyl ester of caffeic acid (4c), but not the parental HCAs, were selectively effective against MOLT-4 (human lymphoblastic leukemia) cells with IC50 values of 0.123 +/- 0.012, 0.301 +/- 0.069 and 1.0 +/- 0.1 mu M, respectively. Compounds 1c, 1d, and 4c significantly increased apoptotic cells in sub-G1 phase and activated the caspase-3 enzyme in MOLT-4 cells. Compound 1c was 15.4 and 23.6 times more potent than doxorubicin and cisplatin, respectively, against the drug resistant MES-SA-DX5 uterine sarcoma cells. These p-coumarate esters were several times less effective against NIH/3T3 fibroblast cells. Docking studies showed that 1c may cause cytotoxicity by interaction with carbonic anhydrase IX. In conclusion, long chain alkyl esters of p-coumaric acid are promising scaffolds for selective apoptosis induction in cancer cells.

Abstract Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp(2) oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.

Abstract Monoamine oxidase (MAO) is an enzyme responsible for metabolism of monoamine neurotransmitters which play an important role in brain development and function. This enzyme exists in two isoforms, and it has been demonstrated that MAO-B activity, but not MAO-A activity, increases with aging. MAO inhibitors show clinical value because besides the monoamine level regulation they reduce the formation of byproducts of the MAO catalytic cycle, which are toxic to the brain. A series of 2-phenylbenzofuran derivatives was designed, synthesized and evaluated against hMAO-A and hMAO-B enzymes. A bromine substituent was introduced in the 2-phenyl ring, whereas position 5 or 7 of the benzofuran moiety was substituted with a methyl group. Most of the tested compounds inhibited preferentially MAO-B in a reversible manner, with IC50 values in the low micro or nanomolar range. The 2-( 2'-bromophenyl)-5-methylbenzofuran ( 5) was the most active compound identified (IC50 = 0.20 mu M). In addition, none of the studied compounds showed cytotoxic activity against the human neuroblastoma cell line SH-SY5Y. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationship for this type of compounds.

Abstract Chromone derivatives have been extensively studied recently because of to their promising biological activities. The new title chromone-thiazole hybrid presented here, C14H10N2O3S, is a candidate as a selective ligand for adenosine receptors. The compound has been synthesized and characterized by the usual spectroscopic means (NMR and EM/IE) and its structure elucidated by X-ray crystallography, which revealed the presence of packing polymorphism. The two polymorphs (one with space group P2(1)/n and one with P2(1)/c) show slightly different conformations and the major change induced by crystallization regards the intramolecular contacts defining the supramolecular structure. Those differences been highlighted by Hirshfeld surface analysis mapped over d(norm) and ESP.

Abstract The herbicide terbuthylazine (TBA) is widely used for preemergence or postemergence control of many grass and broadleaf weeds and has, besides other issues, a poor aqueous solubility profile that results in reduced bioavailability. Cyclodextrins and modified cyclodextrins were considered, among other substances, appropriate agents for improving pesticide water solubility. Therefore, the inclusion complex formation of terbuthylazine with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was studied to attain its aqueous solubility enhancement. Their characterization was accomplished with different analytical techniques, namely, by UV-Vis, DSC, FTIR, and 1 HNMR. From the analysis of the complexation performance of the herbicide it was concluded that the interaction of terbuthylazine with CDs leads to the formation of inclusion complexes with a stoichiometry of 1 : 1. The association constants of the TBA/beta-CD and TBA/HP-beta-CD complexes were determined by UV. The mean values obtained for the stability constants are 460.4 +/- 26.5 and 532.1 +/- 27.6 to TBA/beta-CD and TBA/HP-beta-CD, respectively. H-1 NMR data corroborate the formation of the TBA/beta-CD and TBA/HP-beta-CD complexes synthesized by the kneading method. A formulation incorporating TBA cyclodextrin complexes might lead to an improvement in terbuthylazine bioavailability. The development of TBA-CD formulations may be interesting since it would enable, through their inclusion into the hydrophobic cavity of CDs, enhancement of solubility, bioavailability, and stability of the herbicide.

Abstract Coumarins represent an important family of naturally occurring and/or synthetic oxygen- containing heterocycles, bearing a characteristic benzopyrone framework. These compounds are widely distributed both in human diet and therapeutics. Among other characteristics, several coumarin derivatives proved to have an interesting antioxidant profile. In the current review, an overview of the role of natural coumarins as important antioxidants is presented and discussed. The benefits of antioxidants to prevent chronic diseases is also discussed in the current review. The most common assays performed to evaluate the antioxidant capacity described in this review are related to different reactive oxygen species involved in the oxidative process. Several reaction mechanisms were studied to investigate the antioxidant profile of coumarins. Among them, hydrogen atom transfer (HAT) and single electron transfer transfer (SET), were highly cited. To make the organization of this overview as clear as possible, coumarin derivatives were dived in: simple coumarins; aliphatic, terpenoid and aromaticcontaining coumarins; ring- fused coumarins and ellagic acid derivatives.