Liposome surface modification by phospholipid chemical reactions.

Liposomal systems are well known for playing an important role as drug carriers, presenting several therapeutic applications in different sectors, such as in drug delivery, diagnosis, and in many other academic areas. A novel class of this nanoparticle is the actively target liposome, which is constructed with the surface modified with appropriated molecules (or ligands) to actively bind a target molecule of certain cells, system, or tissue. There are many ways to functionalize these nanostructures, from non-covalent adsorption to covalent bond formation. In this review, we focus on the strategies of modifying liposomes by glycerophospholipid covalent chemical reaction. The approach used in this text summarizes the main reactions and strategies used in phospholipid modification that can be carried out by chemists and researchers from other areas. The knowledge of these methodologies is of great importance for planning new studies using this material and also for manipulating its properties.

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to­lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 µM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.

Enhancement of fibroblast growing on the mannosylated surface of cellulose membranes.

Bacterial cellulose membrane is a biomaterial with high value in the biomedical field. Many groups have been making efforts to promote chemical modifications of its structure and, consequently, add new characteristics. Recently, our group has developed a methodology to insert monoester succinic acid in bacterial cellulose membrane without disrupting the microfibril network and bind a protein on it. Considering the role of carbohydrates in the molecular recognition process in biological events, we continued these studies by inserting covalently multiples copies of aryl monosaccharide to bacterial cellulose succinylated and to study the in vitro tissue compatibility using fibroblasts. The mix of synthetical chemistry and material modification was performed to prepare aminoaryl mannoside and conjugate it, via amide bond using ultrasonic irradiation, to succinic group of bacterial cellulose. This material was characterized chemically (IR, UV-vis, 13C NMR CP-MAS) and physically (TGA and AFM). Mannosylated cellulose showed good in vitro compatibility with fibroblasts demonstrating its potential in the tissue engineering field which could provide a tissue compatible scaffold.

Lectin-based drug design: combined strategy to identify lead compounds using STD NMR spectroscopy, solid-phase assays and cell binding for a plant toxin model.

The growing awareness of the sugar code--i.e. the biological functionality of glycans--is leading to increased interest in lectins as drug targets. The aim of this study was to establish a strategic combination of screening procedures with increased biorelevance. As a model, we used a potent plant toxin (viscumin) and lactosides synthetically modified at the C6/C6' positions and the reducing end aglycan. Changes in the saturation transfer difference (STD) in NMR spectroscopy, applied in inhibition assays, yielded evidence for ligand activity and affinity differences. Inhibitory potency was confirmed by the blocking of lectin binding to a glycoprotein-bearing matrix. In cell-based assays, iodo/azido-substituted lactose derivatives were comparatively active. Interestingly, cell-type dependence was observed, indicating the potential of synthetic carbohydrate derivative to interact with lectins in a cell-type (glycan profile)-specific manner. These results are relevant to research into human lectins, glycosciences, and beyond.

Agentes antitumorais inibidores da angiogênese: modelos farmacofóricos para inibidores da integrina alfa nu beta3 / Angiogenesis inhibitors antitumor agents: pharmacophore models to alfuh noo baytuh3 antagonists

O câncer é, atualmente, uma das principais causas de morte no mundo. A angiogênese, formação de novos vasos capilares a partir de células endoteliais, é essencial para vários processos fisiopatológicos, tais como o desenvolvimento e a disseminação dos tumores. As integrinas são uma família de receptores de superfície que estão envolvidos na angiogênese, na qual a integrina alfa nu beta3 exerce papel importante. Os antagonistas da integrina alfa nu beta3 têm efeitos diretos na prevenção do crescimento, angiogênese e metástase tumorais. A avaliação in vitro frente à integrina alfa nu beta3 de coleções de ciclopeptídeos levou a compostos muito ativos e seletivos. Antagonistas não-peptídicos da integrina alfa nu beta3 também foram planejados e sintetizados. A partir da determinação da estrutura tridimensional da integrina alfa nu beta3 complexada com um inibidor, tornou-se possível o planejamento racional de ligantes com alta afinidade. Além disto, estes estudos permitiram a validação e o refinamento de modelo farmacofórico para os inibidores da integrina alfa nu beta3.

Cancer is one of the leading causes of death. Angiogenesis, the growth of new blood vessels, is essential for tumor development and spreading. Integrins are a family of surface receptors that are involved in angiogenesis. The alfuh noo baytuh3 integrin plays an important role in tumor angiogenesis. Alfuh noo baytuh3 inhibitors have direct effects to prevent tumor metastases, growth and angiogenesis. In vitro screening of cyclic peptide libraries led to highly active and alfuh noo baytuh3-selective compounds. Non-peptidic alfuh noo baytuh3 antagonists were also designed and synthesized. The crystal structure of the alfuh noo baytuh3 integrin in complex with RGD ligant allowed structure-based rational design of ligands and validation of pharmacophore model to alfuh noo baytuh3 antagonists.