Novel hydroxystearoyl-, heterocyclic and carbocyclic derivatives: synthesis and applications in biological field

This PhD project has been mainly focused on the synthesis of novel organic compounds containing heterocyclic and/or carbocyclic scaffold and on the study of stearic acid derivatives and their applications in biological field. The synthesis of novel derivatives of 9-hydroxystearic acid (9-HSA) evidenced how the presence of substituents on C9, able to make hydrogen bonds is of crucial importance for the biological activity. Also the position of the hydroxy group along the chain of hydroxystearic acids was investigated: regioisomers with the hydroxy group bound to odd carbons resulted more active than those bearing the hydroxy group on even carbons. Further, the insertion of (R)-9-HSA in magnetic nanoparticles gave a novel material which characterization remarked its suitability for drug delivery. Structural hybrids between amino aza-heterocycles and azelaic acid have been synthesized and some of them showed a selective activity towards osteosarcoma cell line U2OS. Several Apcin analogues bearing indole, benzothiazole, benzofurazan moieties connected to tryptaminyl-, amino pyridinyl-, pyrimidinyl- and pyrazinyl ring through a 1,1,1-trichloroethyl group were synthesized. Biological tests showed the importance of both the tryptaminyl and the pyrimidinyl moieties, confirming the effectiveness against acute leukemia models. The SNAr between 2-aminothiazole derivatives and 7-chlorodinitrobenzofuroxan revealed different behaviour depending from amino substituent of the thiazole. The reaction with 2-N-piperidinyl-, 2-N-morpholinyl-, or 2-N-pyrrolidinyl thiazole gave two isomeric species derived from the attack on C-5 of thiazole ring. Thiazoles substituted with primary- or not-cyclic secondary amines reacted with the exocyclic amino nitrogen atom giving a series of compounds whose biological activity have highlighted as they might be promising candidates for further development of antitumor agents. A series of 9-fluorenylidene derivatives, of interest in medical and optoelectronic field as organic scintillators, was synthesized through Wittig or Suzuky reaction and will be analyzed to test their potential scintillatory properties.

Catalytic reduction of levulinic acid derivatives to bio-fuel components

Levulinic Acid and its esters are polyfunctional molecules obtained by biomass conversion. The most investigated strategy for the valorization of LA is its hydrogenation towards fuel additives, solvents and other added-value bio-based chemicals and, in this context, heterogeneous and homogeneous catalysts are widely used. Most commonly, it is typically performed with molecular hydrogen (H2) in batch systems, with high H2 pressures and noble metal catalysts. Several works reported the batch liquid-phase hydrogenation of LA and its esters by heterogenous catalysts which contained support with Brønsted acidity in order to obtain valeric acid and its esters. Furthermore, bimetallic and monometallic systems composed by both a metal for hydrogen activation and a promoter were demonstrated to be suitable catalysts for reduction of carboxylic group. However, there were no studies in the literature reporting the hydrogenation of alkyl levulinates to 1-pentanol (1-PAO). Therefore, bimetallic and monometallic catalysts were tested for one-pot hydrogenation of methyl levulinate to 1-PAO. Re-based catalysts were investigated, this way proving the crucial role of the support for promoting the ring-opening of GVL and its consecutive reduction to valeric compounds. All the reactions were performed in neat without the need of any additional solvents. In these conditions, bimetallic Re-Ru-O/HZSM-5 afforded methyl valerate and valeric acid (VA) with a productivity of 512 mmol gmetal-1 h-1, one of the highest reported in literature to date. Rhenium can also promote the reduction of valeric acid/esters to PV through the formation of 1-pentanol and its efficient esterification/transesterification with the starting material. However, it was proved that Re-based catalysts may undergo leaching of active phase in presence of carboxylic acids, especially by working in neat with VA. Furthermore, the over-reduction of rhenium affects catalytic performance, suggesting not only that a pre-reduction step is unnecessary but also that it could be detrimental for catalyst’s activity.

Study and characterization of polymorphs of BTBT derivatives and their application in organic electronics

The perquisites of organic semiconductors (OSCs) in the field of organic electronics have attracted much attention due to the advantages like cost-effectiveness, solution processibility, etc. A key property in OSCs is charge carrier mobility, which depends on molecular packing, as even the slightest changes in the packing of OSC can significantly impact the mobility. Organic molecules are constructed by weak interactions, which makes the OSCs prone to adopt multiple packing arrangements, thus giving rise to polymorphism. Therefore, polymorph screening in bulk and thin films is crucial for material development. This thesis aims to present a systematic study of polymorphism of [1]benzothieno[3,2-b]benzothiophene (BTBT) derivatives functionalized with different side chains. The role of peripheral side chains has been studied since they can promote different packing arrangements. The bulk polymorph screening of OSCs was approached with conventional solution mediated recrystallization experiments like evaporation, slurry maturation, anti-solvent precipitation, etc. Each of the polymorphs were inspected for their relative stability and the kinetics of transformation was evaluated. Polymorphism in thin films was also investigated for selected OSCs. Non-equilibrium methods like, thermal gradient and solution shearing were employed to examine the nucleation, crystal growth and morphology in controlled crystallization conditions. After careful analysis of crystal phases in bulk and thin films, OFETs have been fabricated by optimizing the manufacturing conditions and the hole mobility values were extracted. The charge transport property of the OSCs tested for OFETs was supported by the ionization potential and transfer integrals calculation. An attempt to correlate the solid-state structure to electronic properties was carried out. For some of the molecules, mechanical properties have been also investigated, as the response to mechanical stress is highly susceptible to packing arrangements and the intermolecular interaction energy contributions. Additionally, collaborative research was carried out by solving and analysing the crystal structures of six oligorylene molecules.

Direct C–H silylation and borylation of biomass derivatives by iridium heterogeneous catalysts

Furfural and its derivatives represent renewable and readily available platforms for a wide range of chemicals. Much attention has been devoted to their functionalization over the last years. TM-catalysed C–H activation has emerged as a powerful tool for synthesizing new C–C and C–X bonds. Moreover, it provides a sustainable way to obtain molecules by reducing waste and saving steps. At the same time, iridium catalysts have proven to be very active in some C–H functionalizations of several (hetero)arenes. Although very promising, this technique is still poorly applied on an industrial scale due to the severe conditions required. Continuous flow chemistry using heterogeneous catalysts appears to be a valuable way to overcome these problems. In this work, we present different solutions for the immobilization of homogeneous iridium complexes on silica gels, using bidentate amines and phosphines as anchoring ligands. We successfully employed the catalysts in C–H silylation and borylation of furfural, using C2 located directing group. In this way, we finally obtained a suitable catalyst that could be potentially applied in continuous-flow chemistry.

Applying The Maternal Near Miss Approach For The Evaluation Of Quality Of Obstetric Care: A Worked Example From A Multicenter Surveillance Study.

To assess quality of care of women with severe maternal morbidity and to identify associated factors. This is a national multicenter cross-sectional study performing surveillance for severe maternal morbidity, using the World Health Organization criteria. The expected number of maternal deaths was calculated with the maternal severity index (MSI) based on the severity of complication, and the standardized mortality ratio (SMR) for each center was estimated. Analyses on the adequacy of care were performed. 17 hospitals were classified as providing adequate and 10 as nonadequate care. Besides almost twofold increase in maternal mortality ratio, the main factors associated with nonadequate performance were geographic difficulty in accessing health services (P < 0.001), delays related to quality of medical care (P = 0.012), absence of blood derivatives (P = 0.013), difficulties of communication between health services (P = 0.004), and any delay during the whole process (P = 0.039). This is an example of how evaluation of the performance of health services is possible, using a benchmarking tool specific to Obstetrics. In this study the MSI was a useful tool for identifying differences in maternal mortality ratios and factors associated with nonadequate performance of care.

Molecular Variations In Aromatic Cosolutes: Critical Role In The Rheology Of Cationic Wormlike Micelles.

Wormlike micelles formed by the addition to cetyltrimethylammonium bromide (CTAB) of a range of aromatic cosolutes with small molecular variations in their structure were systematically studied. Phenol and derivatives of benzoate and cinnamate were used, and the resulting mixtures were studied by oscillatory, steady-shear rheology, and the microstructure was probed by small-angle neutron scattering. The lengthening of the micelles and their entanglement result in remarkable viscoelastic properties, making rheology a useful tool to assess the effect of structural variations of the cosolutes on wormlike micelle formation. For a fixed concentration of CTAB and cosolute (200 mmol L(-1)), the relaxation time decreases in the following order: phenol > cinnamate> o-hydroxycinnamate > salicylate > o-methoxycinnamate > benzoate > o-methoxybenzoate. The variations in viscoelastic response are rationalized by using Mulliken population analysis to map out the electronic density of the cosolutes and quantify the barrier to rotation of specific groups on the aromatics. We find that the ability of the group attached to the aromatic ring to rotate is crucial in determining the packing of the cosolute at the micellar interface and thus critically impacts the micellar growth and, in turn, the rheological response. These results enable us for the first time to propose design rules for the self-assembly of the surfactants and cosolutes resulting in the formation of wormlike micelles with the cationic surfactant CTAB.

Oxidative Stress And Susceptibility To Mitochondrial Permeability Transition Precedes The Onset Of Diabetes In Autoimmune Non-obese Diabetic Mice.

Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7'-dichlorodihydrofluorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death.

Atomic Charge Transfer-counter Polarization Effects Determine Infrared Ch Intensities Of Hydrocarbons: A Quantum Theory Of Atoms In Molecules Model.

Atomic charge transfer-counter polarization effects determine most of the infrared fundamental CH intensities of simple hydrocarbons, methane, ethylene, ethane, propyne, cyclopropane and allene. The quantum theory of atoms in molecules/charge-charge flux-dipole flux model predicted the values of 30 CH intensities ranging from 0 to 123 km mol(-1) with a root mean square (rms) error of only 4.2 km mol(-1) without including a specific equilibrium atomic charge term. Sums of the contributions from terms involving charge flux and/or dipole flux averaged 20.3 km mol(-1), about ten times larger than the average charge contribution of 2.0 km mol(-1). The only notable exceptions are the CH stretching and bending intensities of acetylene and two of the propyne vibrations for hydrogens bound to sp hybridized carbon atoms. Calculations were carried out at four quantum levels, MP2/6-311++G(3d,3p), MP2/cc-pVTZ, QCISD/6-311++G(3d,3p) and QCISD/cc-pVTZ. The results calculated at the QCISD level are the most accurate among the four with root mean square errors of 4.7 and 5.0 km mol(-1) for the 6-311++G(3d,3p) and cc-pVTZ basis sets. These values are close to the estimated aggregate experimental error of the hydrocarbon intensities, 4.0 km mol(-1). The atomic charge transfer-counter polarization effect is much larger than the charge effect for the results of all four quantum levels. Charge transfer-counter polarization effects are expected to also be important in vibrations of more polar molecules for which equilibrium charge contributions can be large.

A New Goniothalamin N-acylated Aza-derivative Strongly Downregulates Mediators Of Signaling Transduction Associated With Pancreatic Cancer Aggressiveness.

In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 μM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 μM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.

Action Of Essential Oils From Brazilian Native And Exotic Medicinal Species On Oral Biofilms.

Essential oils (EO) obtained from twenty medicinal and aromatic plants were evaluated for their antimicrobial activity against the oral pathogens Candida albicans, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus sanguis and Streptococcus mitis. The antimicrobial activity of the EO was evaluates by microdilution method determining Minimal Inhibitory Concentration. Chemical analysis of the oils compounds was performed by Gas chromatography-mass spectrometry (CG-MS). The most active EO were also investigated as to their actions on the biolfilm formation. The most of the essential oils (EO) presented moderate to strong antimicrobial activity against the oral pathogens (MIC--Minimal Inhibitory Concentrations values between 0.007 and 1.00 mg/mL). The essential oil from Coriandrum sativum inhibited all oral species with MIC values from 0.007 to 0.250 mg/mL, and MBC/MFC (Minimal Bactericidal/Fungicidal Concentrations) from 0.015 to 0.500 mg/mL. On the other hand the essential oil of C. articulatus inhibited 63.96% of S. sanguis biofilm formation. Through Scanning Eletronic Microscopy (SEM) images no changes were observed in cell morphology, despite a decrease in biofilm formation and changes on biofilm structure. Chemical analysis by Gas Chromatography-Mass Spectrometry (GC-MS) of the C. sativum essential oil revealed major compounds derivatives from alcohols and aldehydes, while Cyperus articulatus and Aloysia gratissima (EOs) presented mono and sesquiterpenes. In conclusion, the crude oil from C. articulatus exhibited the best results of antimicrobial activity e ability to control biofilm formation. The chemical analysis showed the presence of terpenes and monoterpenes such as a-pinene, a-bulnesene and copaene. The reduction of biofilms formation was confirmed from SEM images. The results of this research shows a great potential from the plants studied as new antimicrobial sources.

Anthocyanin And Other Phenolic Compounds In Ceylon Gooseberry (dovyalis Hebecarpa) Fruits.

Ceylon gooseberry is a deep-purple exotic berry that is being produced in Brazil with great market potential. This work aimed to determine major phenolic compounds in this specie by HPLC-PDA-ESI/MS. Samples were collected in two different seasons. Pulp and skin were analyzed separately. Non-acylated rutinoside derivatives of delphinidin (∼60-63%) and cyanidin (∼17-21%) were major anthocyanins tentatively identified. All anthocyanins had higher concentration in skin than in pulp (64-82 and 646-534mg of cyaniding-3-glucoside equivalents/100g skin and pulp, respectively). Moreover, anthocyanin profile changed between sampling dates (p<0.05). Mainly for delphinidin-3-rutinoside which could be a result of season variation. In this specie, non-anthocyanin polyphenols represent less than 35% of total extracted polyphenols. The tentative identification proposed a flavonol and three ellagitannins as major compounds of the non-anthocyanin phenolics fraction. Finally, anthocyanin is the major phenolic class in this fruit and its composition and content are significantly affected by season.