Ultrasound-Assisted Heterogeneous Synthesis of Bio-Based Oligo-Isosorbide Glycidyl Ethers: Towards Greener Epoxy Precursors.

The substitution of toxic precursors such as bisphenol A by renewable and safer molecules has become a major challenge. To overcome this challenge, the 12 principles of green chemistry should be taken into account in the development of future sustainable chemicals and processes. In this context, this paper reports the highly efficient synthesis of oligo-isosorbide glycidyl ethers from bio-based starting materials by a rapid one-pot heterogeneous ultrasound-assisted synthesis. It was demonstrated that the use of high-power ultrasound in solvent-free conditions with sodium hydroxide microbeads led for the first time to a fully epoxidated prepolymer with excellent epoxy equivalent weight (EEW). The structure of the epoxy precursor was characterized by FT-IR, NMR spectroscopy and high-resolution mass spectrometry (HRMS). The efficiency of the ultrasound-assisted synthesis was attributed to the physical effects caused by micro-jets on the surface of the solid sodium hydroxide microspheres following the asymmetrical collapse of cavitation bubbles.

Preparation and Characterization of Isosorbide-Based Self-Healable Polyurethane Elastomers with Thermally Reversible Bonds.

Polyurethane (PU) is a versatile polymer used in a wide range of applications. Recently, imparting PU with self-healing properties has attracted much interest to improve the product durability. The self-healing mechanism conceivably occurs through the existence of dynamic reversible bonds over a specific temperature range. The present study investigates the self-healing properties of 1,4:3,6-dianhydrohexitol-based PUs prepared from a prepolymer of poly(tetra-methylene ether glycol) and 4,4'-methylenebis(phenyl isocyanate) with different chain extenders (isosorbide or isomannide). PU with the conventional chain extender 1,4-butanediol was prepared for comparison. The urethane bonds in 1,4:3,6-dianhydrohexitol-based PUs were thermally reversible (as confirmed by the generation of isocyanate peaks observed by Fourier transform infrared spectroscopy) at mildly elevated temperatures and the PUs showed good mechanical properties. Especially the isosorbide-based polyurethane showed potential self-healing ability under mild heat treatment, as observed in reprocessing tests. It is inferred that isosorbide, bio-based bicyclic diol, can be employed as an efficient chain extender of polyurethane prepolymers to improve self-healing properties of polyurethane elastomers via reversible features of the urethane bonds.

Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease.

Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100µM. The compound 1e also showed dose-response (IC50=36±3µM) and inhibited the protease mutants D168A and V170A at 100µM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.

Synthesis of 2-[(18)F]Fluoro-2-deoxyisosorbide 5-mononitrate and Assessment of Its in vivo Biodistribution as Determined by Dynamic Positron Emission Tomography (PET).

Herein we disclose the synthesis of 2-fluoro-2-deoxyisosorbide 5-mononitrate (2F-IS-5MN), a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5-mononitrate (IS-5MN). X-ray structural data for IS-5MN and its C2-epimeric congener IM-5MN are presented together with structural data for 2F-IS-5MN. Radioisotope labeling of 2F-IS-5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild-type mice.

Novel injectable biomaterials for bone augmentation based on isosorbide dimethacrylic monomers.

Drawbacks with the commonly used PMMA-based bone cements, such as an excessive elastic modulus and potentially toxic residual monomer content, motivate the development of alternative cements. In this work an attempt to prepare an injectable biomaterial based on isosorbide-alicyclic diol derived from renewable resources was presented. Two novel dimethacrylic monomers ISDGMA - 2,5-bis(2-hydroxy-3-methacryloyloxypropoxy)-1,4:3,6-dianhydro-sorbitol and ISETDMA - dimethacrylate of ethoxylated isosorbide were synthesized and used to prepare a series of low-viscosity compositions comprising bioactive nano-sized hydroxyapatite in the form of a two-paste system. Formulations exhibited a non-Newtonian shear-thinning behavior, setting times between 2.6 min and 5.3 min at 37°C and maximum curing temperatures of 65°C. Due to the hydrophilic nature of ISDGMA, cured compositions could absorb up to 13.6% water and as a result the Young's modulus decreased from 1,429 MPa down to 470 MPa. Both, poly(ISDGMA) and poly(ISETDMA) were subjected to a MTT study on mice fibroblasts (BALB/3T3) and gave relative cell viabilities above 70% of control. A selected model bone cement was additionally investigated using human osteosarcoma cells (SaOS-2) in an MTS test, which exhibited concentration-dependent cell viability. The preliminary results, presented in this work reveal the potential of two novel dimethacrylic monomers in the preparation of an injectable biomaterial for bone augmentation, which could overcome some of the drawbacks typical for conventional acrylic bone cement.

Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands.

The design, synthesis, and biological evaluation of a series of six HIV-1 protease inhibitors incorporating isosorbide moiety as novel P2 ligands are described. All the compounds are very potent HIV-1 protease inhibitors with IC50 values in the nanomolar or picomolar ranges (0.05-0.43 nM). Molecular docking studies revealed the formation of an extensive hydrogen-bonding network between the inhibitor and the active site. Particularly, the isosorbide-derived P2 ligand is involved in strong hydrogen bonding interactions with the backbone atoms.

Synthesis of five-membered cyclic ethers by reaction of 1,4-diols with dimethyl carbonate.

The reaction of 1,4-diols with dimethyl carbonate in the presence of a base led to selective and high-yielding syntheses of related five-membered cyclic ethers. This synthetic pathway has the potential for a wide range of applications. Distinctive cyclic ethers and industrially relevant compounds were synthesized in quantitative yield. The reaction mechanism for the cyclization was investigated. Notably, the chirality of the starting material was maintained. DFT calculations indicated that the formation of five-membered cyclic ethers was energetically the most favorable pathway. Typically, the selectivity exhibited by these systems could be rationalized on the basis of hard-soft acid-base theory. Such principles were applicable as far as computed energy barriers were concerned, but in practice cyclization reactions were shown to be entropically driven.

Investigation on synthesis and properties of isosorbide based bis-GMA analogue.

The aim of this work was to synthesize and investigate properties of a novel dimethacrylic monomer based on bioderived alicyclic diol--isosorbide. Its potential as a possible substitute of 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy)phenyl]propane (BISGMA), widely used in dental restorative materials and suspected for toxicity was assessed. The novel monomer was obtained in a three-step synthesis. First, isosorbide was etherified by a Williamson nucleophilic substitution and subsequently oxidized to isosorbide diglycidyl ether (ISDGE). A triphenyl phosphine catalyzed addition of methacrylic acid to ISDGE resulted in 2,5-bis(2-hydroxy-3-methacryloyloxypropoxy)- 1,4:3,6-dianhydro-sorbitol (ISDGMA). The monomer obtained was photopolymerized using camphorquinone/2-(dimethylamino)ethyl methacrylate initiating system. Next, compositions with triethylene glycol dimethacrylate (TEGDMA) were prepared and polymerized. Double bond conversion, polymerization shrinkage and water sorption of resulting polymers were determined. Selected mechanical (flexular strength and modulus, Brinell hardness) and thermomechanical (DMA analysis) properties were also investigated. BISGMA based materials were prepared as reference for comparison of particular properties.

Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.

Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups.

Aspirin prodrugs and related nitric oxide releasing compounds hold significant therapeutic promise, but they are hard to design because aspirin esterification renders its acetate group very susceptible to plasma esterase mediated hydrolysis. Isosorbide-2-aspirinate-5-salicylate is a true aspirin prodrug in human blood because it can be effectively hydrolyzed to aspirin upon interaction with plasma BuChE. We show that the identity of the remote 5-ester dictates whether aspirin is among the products of plasma-mediated hydrolysis. By observing the requirements for aspirin release from an initial panel of isosorbide-based esters, we were able to introduce nitroxymethyl groups at the 5-position while maintaining ability to release aspirin. Several of these compounds are potent inhibitors of platelet aggregation. The design of these compounds will allow better exploration of cross-talk between COX inhibition and nitric oxide release and potentially lead to the development of selective COX-1 acetylating drugs without gastric toxicity.

Discovery of a "true" aspirin prodrug.

Aspirin prodrugs formed by derivatization at the benzoic acid group are very difficult to obtain because the promoiety accelerates the rate of hydrolysis by plasma esterases at the neighboring acetyl group, generating salicylic acid derivatives. By tracing the hydrolysis pattern of the aspirin prodrug isosorbide-2,5-diaspirinate (ISDA) in human plasma solution, we were able to identify a metabolite, isosorbide-2-aspirinate-5-salicylate, that undergoes almost complete conversion to aspirin by human plasma butyrylcholinesterase, making it the most successful aspirin prodrug discovered to date.

Novel isosorbide-based substrates for human butyrylcholinesterase.

Butyrylcholinesterase [EC 3.1.1.8] present widely in mammalian tissue does not have a precisely defined biological function or known endogenous substrate. However, it plays an important role in the detoxification of certain xenobiotics and is an established vector for the systemic liberation of other drugs from their prodrugs. While investigating a series of isosorbide-based prodrugs, we discovered that BuChE catalyses the hydrolysis of esters of the simple sugar isosorbide with unusually rapidity and in some cases with remarkable regioselectivity. In this study, a series of isosorbide esters were synthesised and their rates of hydrolysis measured by HPLC following incubation in diluted plasma solution. In general, little hydrolysis of the 5-ester group could be observed but the 2-ester group was usually hydrolysed very rapidly and the hydrolysis rate exhibited an unusual dependence on the identity of the 5-group. The results indicate that while the 5-ester group is not itself hydrolysed it is important for productive binding in isosorbide diesters.

Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate.

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.