Sergio Antonio Fernandes

Calixarenes as New Platforms for Drug Design

Calixarenes, macrocyclic compounds of phenolic units linked by methylene groups at the 2,6-positions, present some of the requirements to serve as platforms for the design and synthesis of biological active compounds. They are also interesting host molecules for chemical biology study purposes. Their basic molecular scaffold has potential ability for molecule recognition; it is promptly synthesized in large amounts, and might be easily modified for maximizing molecular interactions toward relevant guest molecules. Calixarenes present well-defined conformational properties and cavities with molecular dimensions that enable to encapsulate guest drugs. Calixarenes have been shown to have antiviral, antibacterial, antifungal, and anticancer activities (including HIV as target). We provide here an overview of the use of calixarenes either as new chemical entity of distinct biological activities or as host for bioactive guest molecules. The importance of calixarenes for drugs development is discussed. The use of Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) techniques for the study of calixarenes as biological molecule hosts is also described.

Potencial da palha de cana-de-açúcar para produção de etanol

Sugarcane straw biomass accounts for 1/3 of the energy potential of sugarcane and represents a rich source of sugars. Studies have been intensified for the use of this biomass along with bagasse for the production of cellulosic ethanol. Development of this technological path will allow for taking full advantage of sugarcane, increasing ethanol production without expanding the area cultivated. However, in order for this technology to be viable certain challenges must be overcome, including establishment of appropriate conditions of pretreatment and hydrolysis of these materials for release of fermentable sugars.

Experimental and theoretical NMR determination of isoniazid and sodium p-sulfonatocalix(n)arenes inclusion complexes

In this work the inclusion complex formation of isoniazid with sodium p-sulfonatocalix[n]arenes is reported aiming to improve the physicochemical and biopharmaceutical properties of isoniazid a first line antibuberculosis drug. The architectures of the complexes were proposed according to NMR data Job plot indicating details on the insertion of the isoniazid in the calix[n]arenes cavities. DFT theoretical NMR calculations were also performed for sodium p-sulfonatocalix[4]arene complex with isoniazid, with various modes of complexation being considered, to provide support for the experimental proposal. A comparison between experimental and theoretical ¹H NMR chemical shifts profiles allowed for the inclusion complex characterization confirming the isoniazid inclusion mode which is preferentially through the hydrazide moiety. The remarkable agreement between experimental and theoretical NMR profiles adds support to their use in the structural characterization of inclusion compounds. Antibacterial activity was evaluated and the results indicated the inclusion complexes as a potential strategy for tuberculosis treatment.

Proparacaine complexation with β‐cyclodextrin and p‐sulfonic acid calix[6]arene, as evaluated by varied 1H‐NMR approaches

This study focused on the use of NMR techniques as a tool for the investigation of complex formation between proparacaine and cyclodextrins (CDs) or p‐sulfonic acid calix[6]arene. The pH dependence of the complexation of proparacaine with β‐CD and p‐sulfonic acid calix[6]arene was studied and binding constants were determined by 1H NMR spectroscopy [diffusion‐ordered spectroscopy (DOSY)] for the charged and uncharged forms of the local anesthetic in β‐CD and p‐sulfonic acid calix[6]arene. The stoichiometries of the complexes was determined and rotating frame Overhauser enhancement spectroscopy (ROESY) 1D experiments revealed details of the molecular insertion of proparacaine into the β‐CD and p‐sulfonic acid calix[6]arene cavities. The results unambiguously demonstrate that pH is an important factor for the development of supramolecular architectures based on β‐CD and p‐sulfonic acid calix[6]arene as the host molecules. Such host–guest complexes were investigated in view of their potential use as new therapeutic formulations, designed to increase the bioavailability and/or to decrease the systemic toxicity of proparacaine in anesthesia procedures. Copyright

Calix[n]arenes in Action: Useful Host-Guest Catalysis in Organic Chemistry

The advent of host-guest catalysis brought about the prospect of a complementary mode of catalysis, with the potential for sav- ings in cost, time and energy, easier experimental procedures, and reductions in chemical waste. Water-soluble calix(n)arene catalytic systems provide additional options in biphasic catalysis for organic chemistry and process engineering. The use of calix(n)arene as host- guest catalysis developed in recent years has shown promising results since calix(n)arenes have been widely used as three-dimensional molecular platforms for the design of artificial molecular receptors, due to the availability of cheap starting materials and the facile modification of the calix(n)arene structure at the wide and narrow rims.

Topology of a ternary complex (proparacaine–β-cyclodextrin–liposome) by STD NMR

The topologies of proparacaine (PPC) in β‐cyclodextrin (β‐CD), PPC in egg phosphatidylcholine (EPC) liposomes and PPC in β‐CD in EPC were investigated using NMR experiments (1D ROESY and saturation transfer difference (STD)). This is the first description of the STD technique applied to PPC–EPC–β‐CD system, revealing that not only PPC was imbedded in EPC bilayer, but β‐CD was also interacting with liposome vesicles. These results are novel and were rationalized as the spontaneous formation of a ternary complex with some β‐CD molecules bound to external liposome vesicles surfaces. Copyright

Induction of the Phenylpropanoid Pathway by Acibenzolar-S-Methyl and Potassium Phosphite Increases Mango Resistance to Ceratocystis fimbriata Infection

This study used both microscopic and biochemical analyses to investigate the possible defense responses induced by acibenzolar-S-methyl (ASM) and potassium phosphite (Phi) in mango plants inoculated with Ceratocystis fimbriata. Disease development was evaluated in the stems of inoculated mango plants and these were examined using fluorescence and light microscopy. High-performance liquid chromatography (HPLC) was used to quantify secondary metabolites in the stem sections. Spraying the plants with ASM and Phi reduced internal necrosis and disease development. The ASM and Phi induced many microscopic defense responses in the stem tissues against C. fimbriata infection. HPLC analysis revealed that the concentrations of two alkaloids (theobromine and 7-methylxanthine) and 10 phenolic compounds (catechin, epicatechin, epigallocatechin, gallic acid, myricetin, p-coumaric acid, p-hydroxybenzoic acid, phloridzin, sinapinic acid, and salicylhydroxamic acid) were higher in the stem tissues of plants sprayed with ASM or Phi than in inoculated control treatment. The concentrations of phenolic compounds were higher in the stem tissues of inoculated plants than in noninoculated plants, while the inverse was observed for alkaloids. Higher concentrations of secondary metabolites in the stem tissues were detected in the early stages of fungal infection, especially in plants treated with inducers. Taken together, the results from the present study clearly support the concept that the phenylpropanoid pathway in the stem tissues of mango plants infected by C. fimbriata can be induced by ASM and Phi.

Efficient synthesis of 2,4-disubstituted quinolines: calix[n]arene-catalyzed Povarov-hydrogen-transfer reaction cascade

A cascade process involving the Povarov reaction and hydrogen transfer catalyzed with p-sulfonic acid calix[4]arene was disclosed and afforded the synthesis of 2,4-disubstituted quinolines in good yields under appropriate conditions in a single pot process.

Calix[n]arenes as Goldmines for the Development of Chemical Entities of Pharmaceutical Interest

Calix[n]arenes are macrocyclic cone-shaped compounds formed from phenolic units linked by methylene groups in the ortho position. Structural features make calix[n]arenes a versatile class of molecules that are of great interest, particularly in the pharmaceutical field. The cavity-like shape gives calix[n]arenes the ability to selectively encapsulate ions or neutral molecules, which can be used to generate carrier systems capable of increasing the solubility and diffusivity of chemical species. These resulting systems can function as deliverers of bioactive guest molecules. Host-guest molecular interactions act as the cornerstone that prompts the application of calix[n]arenes in the pharmaceutical field. Understanding their interactions in host-guest complexes is essential for the development and application of new therapeutics. In the present review, the most utilized analytical techniques for characterizing calix[n]arene inclusion complexes are discussed, and an overview of the ability of a variety of calix[n]arenes to work as host molecules for the development of chemical entities of pharmaceutical interest is also presented.

Preparação e caracterização físico-química de complexos de inclusão entre anestésicos locais e hidroxipropil-beta-ciclodextrina

S(-) Bupivacaine (S(-)BVC) and Lidocaine (LDC) are widely used local anesthetics (LA). Hydroxypropyl b-cyclodextrin (HP-b-CD) is used as a drug-carrier system. The aim of this work was to characterize inclusion complexes between LA and HP-b-CD. The affinity constants determined at different pHs show favourable complexation. The release kinetics experiments showed that S(-)BVC and LDC changed the released profiles in the presence of HP-b-CD. Nuclear magnetic resonance experiments gave information about the interaction between LA and the cyclodextrin cavity. This study focused on the physicochemical characterization of drug-delivery formulations that come out as potentially new therapeutic options for pain treatment.