Polymerizable Matrix Metalloproteinases' Inhibitors with Potential Application for Dental Restorations.

Collagen cleavage by matrix metalloproteinase (MMP) is considered a major cause of dental resins long term failure. Most MMP inhibitors display significant toxicity and are unsuitable for dental resins' applications. Here we report a study of a new class of inhibitors that display the unique property of being co-polymerizable with other vinyl compounds present in commercial dental resins, limiting their release and potential toxicity. Computational affinity towards the active site of different MMP-1; -2; -8; -9 and -13 of several compounds showed interesting properties and were synthesized. These free compounds were tested concerning their toxicity upon contact with two different cell types, with no substantial decrease in cell viability at high concentrations. Even so, compound's safety can be further improved upon copolymerization with commercial dental resins, limiting their release.

Challenges in Matrix Metalloproteinases Inhibition.

Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented.

Development of Novel Galactosylated PLGA Nanoparticles for Hepatocyte Targeting Using Molecular Modelling.

Doxorubicin-loaded PLGA nanoparticles conjugated with a new galactose-based ligand for the specific recognition by human hepatoma cellular carcinoma cells (Hep G2) were successfully produced. The new targeting compound was selected using molecular docking combined with quantum chemical calculations for modelling and comparing molecular interactions among the H1 subunit of the asialoglycoprotein receptor containing the carbohydrate recognition domain and the ligand. The ligand, bis(1-O-ethyl-ß-D-galactopyranosyl)amine, was synthetized, characterized, and subsequently linked to PLGA. Unloaded (PLGA-di-GAL NP) and doxorubicin-loaded (DOX-PLGA-di-GAL NP) nanoparticles were prepared using an emulsion method and characterized. The produced DOX-PLGA-di-GAL NP are spherical in shape with a size of 258 ± 47 nm, a zeta potential of -62.3 mV, and a drug encapsulation efficiency of 83%. The in vitro drug release results obtained show a three-phase release profile. In vitro cell studies confirmed the interaction between Hep G2 cells and PLGA-di-GAL NP. Cell cytotoxicity tests showed that unloaded NP are nontoxic and that DOX-PLGA-di-GAL NP caused a decrease of around 80% in cellular viability. The strategy used in this work to design new targeting compounds represents a promising tool to develop effective hepatocyte targeting drug delivery systems and can be applied to other tissues/organs.

Doxorubicin-loaded galactose-conjugated poly(d,l-lactide-co-glycolide) nanoparticles as hepatocyte-targeting drug carrier.

The objective of this work is to produce doxorubicin-loaded galactose-conjugated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) to be specifically recognised by human hepatoma cellular carcinoma (Hep G2) cells and assess NPs cytotoxicity. Doxorubicin-unloaded and doxorubicin-loaded galactose-conjugated PLGA NPs were prepared using an emulsion method and characterised for morphology, size, drug release behaviour, Hep G2 recognition and cell cytotoxicity. The produced doxorubicin-loaded PLGA-galactose-conjugate nanoparticles (PLGA-GAL NPs) are spherical in shape with a size of 365 ± 74 nm, a drug encapsulation efficiency of 69% and released in a biphasic pattern with higher release rates at pH 5. In vitro cell studies confirmed the specific interaction between the receptors of Hep G2 and the PLGA-GAL NPs. Cell cytotoxicity tests showed that unloaded NPs are non-toxic and that doxorubicin-loaded NPs caused a cellular viability decrease of around 80%, therefore representing a promising approach to improve liver-specific drug delivery.

Synthesis, Characterization, Antimicrobial and Antitumor Activities of Sucrose Octa(N-ethyl)carbamate.

Sucrose octa(N-ethyl)carbamate was synthesized directly from sucrose and ethyl isocyanate, and its structure was confirmed by various analytical methods, such as (1)H and (13)C NMR, FTIR, m.p., MS, and optical rotation. Its antibacterial, antifungal and cytotoxic activities were investigated. It exhibited strong inhibition against all bacteria tested, namely S. aureus (MIC 0.18±0.006), B. cereus (MIC 0.094±0.000), M. flavus (MIC 0.28±0.01), L. monocytogenes (MIC 0.18±0.006), P. aeruginosa (MIC 0.094±0.002), S. typhimurium (MIC 0.094±0.002), E. coli (MIC 0.18±0.006) and E. cloacae (MIC 0.18±0.006) and strong antifungal activity towards T. viride (MIC 0.09 ± 0.006), A. versicolor (MIC 0.18 ± 0.01), A. ochraceus (MIC 0.375 ± 0.01) and P. ochrochloron (MIC 0.375 ± 0.04). Furthermore, it showed moderate antitumor potential against human breast (GI50 357.20±14.12), colon (GI50 332.43±11.19) and cervical (GI50 282.67±3.97) cell lines and, more important, without hepatotoxicity.

Antimicrobial and cytotoxic activities of 1,2,3-triazole-sucrose derivatives.

A library of 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-1,2,3-triazoles have been investigated for their antibacterial, antifungal and cytotoxic activities. Most of the target compounds showed good inhibitory activity against a variety of clinically and food contaminant important microbial pathogens. In particular, 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-4-(4-pentylphenyl)-1,2,3-triazole (5) was highly active against all the tested bacteria with minimal inhibitory concentrations (MICs) ranging between 1.1 and 4.4 µM and bactericidal concentrations (MBCs) from 2.2 and 8.4 µM. The compound 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-4-(4-bromophenyl)-1,2,3-triazole (3) showed antifungal activity with MICs from 0.6 to 4.8 µM and minimal fungicidal concentrations (MFCs) ranging between 1.2 and 8.9 µM. Furthermore, some of the compounds possessed moderate cytotoxicity against human breast, lung, cervical and hepatocellular carcinoma cell lines, without showing toxicity for non-tumor liver cells. The above mentioned derivatives represent promising leads for the development of new generation of sugar-triazole antifungal agents.

Formation of spherical and core-shell polymeric microparticles from glycopolymers.

6-O-methacryloyl-α-d-glucoside 2 and 4-bromophenyl-6-O-methacryloyl-d-glucothioside 7, obtained by enzyme-catalyzed synthesis, have been homo-polymerized and copolymerized with styrene by a free radical process, yielding polymer materials with sugar moieties, attached to the polymer backbone via ester linkages. The results demonstrated that modifying the structural features of the monomers greatly affected the thermal and rheological properties of the polymers. The polymer materials obtained have been characterized by NMR, MALDI-MS, DSC, AFM, and EWC (equilibrium water content). The AFM images indicated the formation of spherical and core-shell polymeric microparticles.

Recent progress in the field of glycoconjugates.

The ubiquity of glycoconjugates in nature and their role in different biological processes, has led to the development of several methodologies to synthesize these molecules. Synthetic glycoconjugates are now used to answer a variety of glycoconjugate-related biological questions and have provided new potential vaccines against cancer, viral, and bacterial infections and new biotechnological tools. This review aims to collect and compile the recent advances in the field of glycopeptides, glycoproteins, and glycolipid synthesis and also to update the previous reviews made on this subject. Finally, by highlighting the successes and failures of past research, we hope that this review will inspire fruitful research in this important medicinal chemistry field.

Amide-linked N-methacryloyl sucrose containing polymers.

1',2,3,3',4,4',6-Hepta-O-benzyl-6'-N-methacryloyl-6'-deoxysucrose 1, 6'-deoxy-6'-N-methacryloyloxyethylureido sucrose 2 and 6,6'-dideoxy-6,6'-N-dimethacryloyloxyethylureido sucrose 3 have been homo-polymerized and copolymerized with styrene by a free radical process, yielding polymer materials with pendant sucrose moieties, attached to the polymer backbone via amide linkages. The results demonstrated that varying the structural features of the monomers, greatly affected the thermal and rheological properties of the polymers. The polymer materials obtained have been characterized by NMR, MALDI-TOF, DSC, AFM and EWC (equilibrium water content). The efficient synthesis of the three novel, regioisomerically pure, N-methacryloylamide sucrose-containing monomers (1, 2 and 3) have been described.

Efficient microwave assisted synthesis of novel 1,2,3-triazole-sucrose derivatives by cycloaddition reaction of sucrose azides and terminal alkynes.

Novel 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-4-substituted-1,2,3-triazoles were synthesized by microwave assisted copper catalyzed 1,3-dipolar cycloaddition of sucrose derived azides with terminal alkynes in excellent yields and in short reaction times. The compound 1',2,3,3',4,4',6-hepta-O-acetyl-6'-azido-6'-deoxy-sucrose was regioselectively synthesized from sucrose by improved procedure and used for the cycloadditions. By combining carbohydrate and 1,2,3-triazole structural motifs, a library of 1,2,3-triazole-sucrose conjugates have been obtained.

Synthesis of hydrophilic and amphiphilic acryl sucrose monomers and their co-polymerisation with styrene, methylmethacrylate and α- and ß-pinenes.

Herein, we report the synthesis of monomethacryloyl sucrose esters, and their successful free radical homo- and co-polymerisation with styrene, methylmethacrylate, α-and ß-pinene. The chemical, physical, structural and surface chemical properties of these polymers, containing a hydrophobic olefin backbone and hydrophilic sugar moieties as side chains, have been investigated. Biodegradation tests of the copolymer samples by a microbial fungal culture (Aspergillus niger) method showed good biodegradability. The chemical structure and surface chemistry of the synthesized homo- and co-polymers demonstrate their potential technological relevance as amphiphilic and biodegradable polymers.

Novel unsaturated sucrose ethers and their application as monomers.

Novel unsaturated ethers were synthesised in good yields starting from sucrose,using a two-step mild and efficient procedure based on the Gassman method, which consists in forming a vinyl group by the elimination of ethanol from mixed acetals with trimethylsilyl trifluoromethanesulfonate in the presence of alkyl amines. Mixed acetals are readily obtained from the corresponding alcohols and ethyl vinyl ether, using an acidic catalyst. Conventional etherification involving a primary halide was also examined. The monomers thus obtained were successfully polymerised by a free radical mechanism,yielding unbranched linear and soluble polymers with pending sucrose moieties, and some of their physical properties were determined.

Regioselective copolymerization of acryl sucrose monomers.

1',2,3,3',4,4',6-Hepta-O-benzyl-sucrose has been prepared and selectively 6'-O-esterified with small alpha,beta-unsaturated acid derivatives. New chiral copolymers containing sucrose have been synthesized by radical polymerization, and some of their physical properties have been determined.