Long-Chain Alkyl Epoxides and Glycidyl Ethers: An Underrated Class of Monomers.

Long-chain epoxides and specifically alkyl glycidyl ethers represent a class of highly hydrophobic monomers for anionic ring-opening polymerization (AROP), resulting in apolar aliphatic polyethers. In contrast, poly(ethylene glycol) is known for its high solubility in water. The combination of hydrophobic and hydrophilic monomers in block and statistical copolymerization reactions enables the synthesis of amphiphilic polyethers for a wide range of purposes, utilizing micellar interactions in aqueous solutions, e.g., viscosity enhancement of aqueous solutions, formation of supramolecular hydrogels, or for polymeric surfactants. Controlled polymerization of these highly hydrophobic long-chain epoxide monomers via different synthesis strategies, AROP, monomer-activated anionic ring-opening polymerization, catalytic polymerization, or via postmodification, enables precise control of the hydrophilic/lipophilic balance. This renders amphiphilic polymers highly interesting candidates for specialized applications, e.g., as co-surfactants in microemulsion systems. Amphiphilic polyethers based on propylene oxide and ethylene oxide, such as poloxamers are already utilized in many established applications due to the high biocompatibility of the polyether backbone. Long alkyl chain epoxides add an interesting perspective to this area and permit structural tailoring. This review gives an overview of the recent developments regarding the synthesis of amphiphilic polyethers bearing long alkyl chains and their applications.

Polymerization of Ethylene Oxide, Propylene Oxide, and Other Alkylene Oxides: Synthesis, Novel Polymer Architectures, and Bioconjugation.

The review summarizes current trends and developments in the polymerization of alkylene oxides in the last two decades since 1995, with a particular focus on the most important epoxide monomers ethylene oxide (EO), propylene oxide (PO), and butylene oxide (BO). Classical synthetic pathways, i.e., anionic polymerization, coordination polymerization, and cationic polymerization of epoxides (oxiranes), are briefly reviewed. The main focus of the review lies on more recent and in some cases metal-free methods for epoxide polymerization, i.e., the activated monomer strategy, the use of organocatalysts, such as N-heterocyclic carbenes (NHCs) and N-heterocyclic olefins (NHOs) as well as phosphazene bases. In addition, the commercially relevant double-metal cyanide (DMC) catalyst systems are discussed. Besides the synthetic progress, new types of multifunctional linear PEG (mf-PEG) and PPO structures accessible by copolymerization of EO or PO with functional epoxide comonomers are presented as well as complex branched, hyperbranched, and dendrimer like polyethers. Amphiphilic block copolymers based on PEO and PPO (Poloxamers and Pluronics) and advances in the area of PEGylation as the most important bioconjugation strategy are also summarized. With the ever growing toolbox for epoxide polymerization, a "polyether universe" may be envisaged that in its structural diversity parallels the immense variety of structural options available for polymers based on vinyl monomers with a purely carbon-based backbone.

Copper-catalyzed intramolecular tandem reaction of (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones: synthesis of (Z)-aurones.

A convenient and efficient method for the copper-catalyzed synthesis of (Z)-aurones via intramolecular tandem reaction of (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones is reported. Moreover, a plausible mechanism for the formation of (Z)-aurones is proposed. This is the first report on the synthesis of (Z)-aurones through copper-catalyzed Ullmann coupling reaction employing epoxides as substrates.

Targeting loop adenines in G-quadruplex by a selective oxirane.

Caught in the oxirane: Naphthalene diimides conjugated to a quinone methide and an oxirane have been synthesized and investigated as selective DNA G-quadruplex alkylating agents. The oxirane derivative generates a stable adduct with a G-quadruplex and shows selective alkylation of the loop adenines, as illustrated.

Site-selective azide incorporation into endogenous RNase A via a "chemistry" approach.

Site-selective labeling of endogenous proteins represents a major challenge in chemical biology, mainly due to the absence of unique reactive groups that can be addressed selectively. Recently, we have shown that surface-exposed lysine residues of two endogenous proteins and a peptide exhibit subtle changes in their individual reactivities. This feature allows the modification of a single residue in a highly site-selective fashion if kinetically controlled labeling conditions are applied. In order to broaden the scope of the "kinetically-controlled protein labeling" (KPL) approach and highlight additional applications, the water-soluble bioorthogonal reagent, biotin-TEO-azido-NHS (11), is developed which enables the site-selective introduction of an azido group onto endogenous proteins/peptides. This bioconjugation reagent features a biotin tag for affinity purification, an azido group for bioorthogonal labeling, a TEO (tetraethylene oxide) linker acting as a spacer and to impart water solubility and an N-hydroxysuccinimidyl (NHS) ester group for reacting with the exposed lysine residue. As a proof of concept, the native protein ribonuclease A (RNase A) bearing ten available lysine residues at the surface is furnished with a single azido group at Lys 1 in a highly site-selective fashion yielding azido-(K1)RNase A. The K1 site-selectivity is demonstrated by the combined application and interpretation of high resolution MALDI-ToF mass spectroscopy, tandem mass spectroscopy and extracted ion chromatography (XIC). Finally, the water soluble azide-reactive phosphine probe, rho-TEO-phosphine (21) (rho: rhodamine), has been designed and applied to attach a chromophore to azido-(K1)RNase A via Staudinger ligation at physiological pH indicating that the introduced azido group is accessible and could be addressed by other established azide-reactive bioorthogonal reaction schemes.

Structural and conformational analysis of 1-oxaspiro[2.5]octane and 1-oxa-2-azaspiro[2.5]octane derivatives by (1) H, (13) C, and (15) N NMR.

A structural and conformational analysis of 1-oxaspiro[2.5]octane and 1-oxa-2-azaspiro[2.5]octane derivatives was performed using (1) H, (13) C, and (15) N NMR spectroscopy. The relative configuration and preferred conformations were determined by analyzing the homonuclear coupling constants and chemical shifts of the protons and carbon atoms in the aliphatic rings. These parameters directly reflected the steric and electronic effects of the substituent bonded to the aliphatic six-membered ring or to C3 or N2. The parameters also were sensitive to the anisotropic positions of these atoms in the three-atom ring. The preferred orientation of the exocyclic substituents directed the oxidative attack.

Self-assembled nanotubes and helical tapes from diacetylene nonionic amphiphiles. Structural studies before and after polymerization.

We synthesized new amphiphiles comprised of a single diacetylenic chain and an oligoethylenoxide polar chain linked by an amide bond. In aqueous medium, they are not soluble at room temperature but form weak gels. Electron microscopy studies have shown that they self-assemble into helical tapes or nanotubes with lengths of several micrometers, and inner and outer diameters of 50 ± 1 and 59 ± 1 nm, respectively. The wall has a thickness of 10 ± 1 nm for both kinds of objects and has an amphiphile bilayer structure. The hydrophobic chains are ordered, and the amide groups are linked with each other by H-bonds. The dissociation of the tubes is a first-order transition with an enthalpy of ca. 40 kJ mol(-1). The nanotubes were photopolymerized to yield purple solutions consisting of helical tapes and almost flat ribbons. The polymers exhibit irreversible thermochromism upon heating.

Dispersing carbon nanotubes by star-like water soluble C60 derivatives.

The properties of three water soluble [3:3] hexakisadducts of C60 1-3 are investigated both in bulk aqueous solutions and at air/water interface. 1-3 have a star-like molecular structure with six hydrophilic quarternary ammonium groups located terminally. 2 and 3 also have increasing number of ethylene oxide groups inserted into their peripheral hydrophilic arms. This molecular structure makes 1-3 highly water soluble, thus difficult to form aggregates in bulk aqueous solutions as revealed by transmission electron microscope observations. But surface tension measurements shows 1-3 still own some amphiphilic properties and can lower the surface tension of water. These unique C60 derivatives are also subjected to disperse carbon nanotubes (CNTs) in water for the first time. It was found the ability of each water soluble C60 derivative to disperse CNTs was mainly dominated by their amphiphilic feature as well as molecular weight.

Thioxophosphoranyl aryl- and heteroaryloxiranes as the representants of a new class of metallocarboxypeptidase inhibitors.

A novel and potent family of metallocarboxypeptidase inhibitors based on thioxophosphoranyl oxiranes is presented. These compounds bear aryl or heteroaryl substituents with trans-stereochemistry with respect to the phosphorylated group and they have been synthesized by the addition of [bis(diisopropylamino)phosphino](trimethylsilyl)carbene to the corresponding aldehydes and the subsequent thiolation of the phosphine. These oxiranes contain a tetrahedral P atom harboring shielded N,N-groups. The screening of their biological activity as metallocarboxypeptidase inhibitors and some structural studies, as well as full experimental details for the new compounds, is disclosed. Thus, from the analysis of their activity against the prototypical metallocarboxypeptidases A and B (CPA and CPB), we have observed that hydrophobic phosphorylated oxiranes perform better as CPB inhibitors, reaching K(i) values comparable to classical synthetic carboxypeptidase inhibitors. X-ray diffraction analysis revealed that the packing in the structure of one phosphorylated oxirane is mediated mainly by hydrophobic contacts and that the N,N-groups are highly flexible. Consequently, phosphorylated oxiranes might constitute an attractive material for subsequent improvements in the design of novel inhibitors against human proteolytic enzymes with enhanced oral availability.

Synthesis of oxiran-2-ylmethyl and oxiran-2-ylmethoxy derivatives of some 4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-diones as potential beta-adrenolytics.

A series of aminoalkanol derivatives of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.0(2.6)]dec-8-ene-3,5-dione and 4-hydroxy-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared. The pharmacological profile of selected compounds was evaluated for their affinities at beta-adrenoceptors. The investigated compounds exhibit modest affinity for these receptors.

Synthesis and antimalarial activity of quinones and structurally-related oxirane derivatives.

A series of eighteen quinones and structurally-related oxiranes were synthesized and evaluated for in vitro inhibitory activity against the chloroquine-sensitive 3D7 clone of the human malaria parasite Plasmodium falciparum. 2-amino and 2-allyloxynaphthoquinones exhibited important antiplasmodial activity (median inhibitory concentrations (IC50) < 10 µM). Oxiranes 6 and 25, prepared respectively by reaction of α-lapachone and tetrachloro-p-quinone with diazomethane in a mixture of ether and ethanol, exhibited the highest antiplasmodial activity and low cytotoxicity against human fibroblasts (MCR-5 cell line). The active compounds could represent a good prototype for an antimalarial lead molecule.

Substituted 2-oxiranecarboxylic acids: a new group of candidate hypoglycaemic drugs.

Drugs to treat diabetes that can be taken orally have long been sought, although the successful management of insulin-dependent diabetes mellitus by simple chemotherapy may be an unachievable goal. The only drugs currently used for the treatment of non-insulin-dependent diabetes have limited effectiveness. In this article Peter Selby and Stanley Sherratt describe the development of a new group of candidate hypoglycaemic drugs, esters of substituted 2-oxiranecarboxylic acids, which merit full clinical evaluation. These drugs are hydrolysed to the free acids which are then converted to their coenzyme A esters in cells. The CoA esters inactivate carnitine palmitoyltransferase I in the outer mitochondrial membrane, thus preventing the excessive oxidation of long-chain fatty acids that occurs in diabetes. This causes a secondary decrease in hepatic gluconeogenesis and an increase in peripheral glucose utilization leading to improved glucose tolerance.

Molecular modeling, synthesis, and preliminary biological evaluation of glutathione-S-transferase inhibitors as potential therapeutic agents.

Changes in the GSH/GST system have been found to correlate with resistance to anticancer alkylating agents, presumably through accelerated detoxification of these drugs since some GSTs have been shown to catalyze the conjugation of GSH to specific antineoplastic agents. GSH-alkyl derivatives were designed by molecular modeling, synthesized, and tested as inhibitors of human GST-Pi.

Osage Orange (Maclura pomifera L.) Seed Oil Poly(α-hydroxydibutylamine) Triglycerides: Synthesis and Characterization.

Milled Osage orange seeds (Maclura pomifera (Raf.) Schneid) were Soxhlet extracted with hexane, and portions of the extract were treated with activated carbon before solvent removal. The crude oil was winterized and degummed by centrifugation at low temperature. Decantation of the centrifugate gave an admixture of the triglycerides and free fatty acids. The free fatty acid content of the oil was removed when portions of the admixture were diluted with hexane and shaken with cold aqueous ammonium hydroxide (0.1 M) solution. The desiccant-dried organic phase was concentrated under reduced pressure to give the cleaned Osage orange triglyceride after solvent removal by rotary evaporation at 67 °C. Epoxidation of the resulting cleaned triglyceride was effected by reaction with in situ generated peroxy performic acid in H2O2. The oxirane rings of the derivatized oil were then opened using N,N-dibutylamine catalyzed by anhydrous ZnCl2 to afford the poly(α-hydroxydibutylamine) triglyceride. The purpose of this work was to derivatize and thereby stabilize this highly unsaturated tree oil for its eventual use in lubrication applications.

Optimal multi-floor plant layout based on the mathematical programming and particle swarm optimization.

In the fields of researches associated with plant layout optimization, the main goal is to minimize the costs of pipelines and pumping between connecting equipment under various constraints. However, what is the lacking of considerations in previous researches is to transform various heuristics or safety regulations into mathematical equations. For example, proper safety distances between equipments have to be complied for preventing dangerous accidents on a complex plant. Moreover, most researches have handled single-floor plant. However, many multi-floor plants have been constructed for the last decade. Therefore, the proper algorithm handling various regulations and multi-floor plant should be developed. In this study, the Mixed Integer Non-Linear Programming (MINLP) problem including safety distances, maintenance spaces, etc. is suggested based on mathematical equations. The objective function is a summation of pipeline and pumping costs. Also, various safety and maintenance issues are transformed into inequality or equality constraints. However, it is really hard to solve this problem due to complex nonlinear constraints. Thus, it is impossible to use conventional MINLP solvers using derivatives of equations. In this study, the Particle Swarm Optimization (PSO) technique is employed. The ethylene oxide plant is illustrated to verify the efficacy of this study.

Core-shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells.

Platinum drug delivery against the detoxification of cytoplasmic thiols is urgently required for achieving efficacy in breast cancer treatment that is over expressed by glutathione (GSH, thiol-oligopeptide). GSH-resistant polymer-cisplatin core-shell nanoparticles were custom designed based on biodegradable carboxylic functional polycaprolactone (PCL)-block-poly(ethylene glycol) diblock copolymers. The core of the nanoparticle was fixed as 100 carboxylic units and the shell part was varied using various molecular weight poly(ethylene glycol) monomethyl ethers (MW of PEGs = 100-5000 g mol(-1)) as initiator in the ring-opening polymerization. The complexation of cisplatin aquo species with the diblocks produced core-shell nanoparticles of 75 nm core with precise size control the particles up to 190 nm. The core-shell nanoparticles were found to be stable in saline solution and PBS and they exhibited enhanced stability with increase in the PEG shell thickness at the periphery. The hydrophobic PCL layer on the periphery of the cisplatin core behaved as a protecting layer against the cytoplasmic thiol residues (GSH and cysteine) and exhibited <5% of drug detoxification. In vitro drug-release studies revealed that the core-shell nanoparticles were ruptured upon exposure to lysosomal enzymes like esterase at the intracellular compartments. Cytotoxicity studies were performed both in normal wild-type mouse embryonic fibroblast cells (Wt-MEFs), and breast cancer (MCF-7) and cervical cancer (HeLa) cell lines. Free cisplatin and polymer drug core-shell nanoparticles showed similar cytotoxicity effects in the HeLa cells. In MCF-7 cells, the free cisplatin drug exhibited 50% cell death whereas complete cell death (100%) was accomplished by the polymer-cisplatin core-shell nanoparticles. Confocal microscopic images confirmed that the core-shell nanoparticles were taken up by the MCF-7 and HeLa cells and they were accumulated both at the cytoplasm as well at peri-nuclear environments. The present investigation lays a new foundation for the polymer-based core-shell nanoparticles approach for overcoming detoxification in platinum drugs for the treatment of GSH over-expressed breast cancer cells.

Surface-engineered nanoparticles for multiple ligand coupling.

The design of surface-engineered nanoparticles for targeting to specific sites is a major challenge. To our knowledge, no study in the literature deals with ligand functionalization of biodegradable nanoparticles through biotin-avidin interactions. With the aim of conceiving small-sized nanoparticles which can be easily functionalized with a variety of ligands or mixtures thereof, biotinylated and PEGylated biotin-poly(ethylene glycol)-poly(epsilon-caprolactone) (B-PEG-PCL) copolymers were synthesized and used to prepare nanoparticles of around 100 nm. Avidin, followed by biotinylated wheat germ agglutinin as a model lectin, were coupled to their surface by taking advantage of the strong biotin-avidin complex formation. The cytotoxicity of the nanospheres towards Caco-2 cells in culture was negligible (more than 82% cell survival for nanoparticle concentrations up to 300 microg/well). The amount of radiolabeled poly(lactic acid) (PLA) or PEG-PLA nanoparticles associated with Caco-2 cells was only 0.7% and 1.5% of the amount added, respectively. This value was increased to 8.5% when a sufficient amount of lectin was bound to the PEG-PLA copolymer. After further studies, the biotin-PEG-coated nanoparticles could be helpful tools for studying the interaction between cells and functionalized nanoparticles with various surface characteristics (PEG layer density and thickness, ligand type and density).

Kinetic modeling of beta-chloroprene metabolism: I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans.

Beta-chloroprene (2-chloro-1,3-butadiene, CD) is carcinogenic by inhalation exposure to B6C3F1 mice and Fischer F344 rats but not to Wistar rats or Syrian hamsters. The initial step in metabolism is oxidation, forming a stable epoxide (1-chloroethenyl)oxirane (1-CEO), a genotoxicant that might be involved in rodent tumorigenicity. This study investigated the species-dependent in vitro kinetics of CD oxidation and subsequent 1-CEO metabolism by microsomal epoxide hydrolase and cytosolic glutathione S-transferases in liver and lung, tissues that are prone to tumor induction. Estimates for Vmax and Km for cytochrome P450-dependent oxidation of CD in liver microsomes ranged from 0.068 to 0.29 micromol/h/mg protein and 0.53 to 1.33 microM, respectively. Oxidation (Vmax/Km) of CD in liver was slightly faster in the mouse and hamster than in rats or humans. In lung microsomes, Vmax/Km was much greater for mice compared with the other species. The Vmax and Km estimates for microsomal epoxide hydrolase activity toward 1-CEO ranged from 0.11 to 3.66 micromol/h/mg protein and 20.9 to 187.6 microM, respectively, across tissues and species. Hydrolysis (Vmax/Km) of 1-CEO in liver and lung microsomes was faster for the human and hamster than for rat or mouse. The Vmax/Km in liver was 3 to 11 times greater than in lung. 1-CEO formation from CD was measured in liver microsomes and was estimated to be 2-5% of the total CD oxidation. Glutathione S-transferase-mediated metabolism of 1-CEO in cytosolic tissue fractions was described as a pseudo-second order reaction; rates were 0.0016-0.0068/h/mg cytosolic protein in liver and 0.00056-0.0022 h/mg in lung. The observed differences in metabolism are relevant to understanding species differences in sensitivity to CD-induced liver and lung tumorigenicity.

Improved synthesis and deployment of (2S,3R)-2-(2Z,5Z-octadienyl)-3-nonyloxirane, a pheromone of the pink moth, Lymantria mathura.

We report two new syntheses of (2S,3R)-2-(2Z,5Z-octadienyl)-3-nonyloxirane, the main sex pheromone component of the pink moth, Lymantria mathura. The key step in the first route was the construction of (Z,Z)-1-bromo-1,4-heptadiene (6), which was coupled in the final step with 2-iodomethyl-3-nonyloxirane 4 via a Grignard reaction. The second approach employed alkylation of 1,4-heptadiynyllithium with epoxy triflates 7 in ether/hexane and provided the pheromone in >/=37% overall yield from alcohol 2. The 4:1 ratio of pheromone enantiomers, reportedly the most attractive to pink moth males, can be directly crafted from appropriately selected Sharpless asymmetric epoxidation conditions.