Nature-Derived Epoxy Resin Monomers with Reduced Sensitizing Capacity─Isosorbide-Based Bis-Epoxides.

Epoxy resin systems (ERSs) are a class of thermosetting resins that become thermostable and insoluble polymers upon curing. They are widely used as components of protective surfaces, adhesives, and paints and in the manufacturing of composites in the plastics industry. The diglycidyl ether of bisphenol A (DGEBA) is used in 75-90% of ERSs and is thus by far the most used epoxy resin monomer (ERM). Unfortunately, DGEBA is a strong skin sensitizer and it is one of the most common causes of occupational contact dermatitis. Furthermore, DGEBA is synthesized from bisphenol A (BPA), which is a petroleum-derived chemical with endocrine-disruptive properties. In this work, we have used isosorbide, a renewable and nontoxic sugar-based material, as an alternative to BPA in the design of ERMs. Three different bis-epoxide isosorbide derivatives were synthesized: the diglycidyl ether of isosorbide (1) and two novel isosorbide-based bis-epoxides containing either a benzoic ester (2) or a benzyl ether linkage (3). Assessment of the in vivo sensitizing potency of the isosorbide bis-epoxides in the murine local lymph node assay (LLNA) showed that all three compounds were significantly less sensitizing than DGEBA, especially 2 which was nonsensitizing up to 25% w/v. The peptide reactivity showed the same order of reactivity as the LLNA, i.e., 2 being the least reactive, followed by 3 and then 1, which displayed similar peptide reactivity as DGEBA. Skin permeation of 2 and 3 was compared to DGEBA using ex vivo pig skin and static Franz cells. The preliminary investigations of the technical properties of the polymers formed from 1-3 were promising. Although further investigations of the technical properties are needed, all isosorbide bis-epoxides have the potential to be less sensitizing renewable replacements of DGEBA, especially 2 that had the lowest sensitizing potency in vivo as well as the lowest peptide reactivity.

Nature-derived epoxy resins: Synthesis, allergenicity, and thermosetting properties of pinoresinol diglycidyl ether.

We describe a novel nature-derived epoxy resin monomer (ERM) derived from the plant lignan pinoresinol. Epoxy resins are thermosetting materials in global usage owing to their excellent technical properties such as flexibility and durability. However, their adverse health effects are often not considered and affect users of epoxy resins worldwide. Components of epoxy resin systems are strong skin sensitizers and cause allergic contact dermatitis. The reported prevalence attributable to epoxy chemicals is between 11.7 and 12.5% of all cases of occupational allergic contact dermatitis. We are committed to developing epoxy resins with reduced allergenic effect, while maintaining their excellent properties. The novel ERM, pinoresinol diglycidyl ether (PinoDGE), was synthesized in one step from pinoresinol and epichlorohydrin in 88% yield. It was not classified as a skin sensitizer in the in vivo local lymph node assay, at concentrations up to 0.17 m, as it did not cause a stimulation index >3 compared to control. Pinoresinol diglycidyl ether reacted with the model peptide AcPHCKRM in a reactivity assay and was predicted to be a skin sensitizer in the KeratinoSens assay. Preliminary cross-linking studies indicate that it has promising properties compared to commercially used ERMs. Pinoresinol diglycidyl ether could be seen as a lead compound for further development of alternative ERMs with a better safety profile based on natural and renewable sources for construction of epoxy resin polymers.

Coating-relevant properties of high-index optical polymers for automotive applications.

High-transparent polymers exhibiting a refractive index beyond 1.6 enhance the available range of optical plastics. The aim of this study is to evaluate optical polyesters (OKP-1 and OKP-4) and special new polycarbonates (PCs) (EP-6000 and EP-8000) in comparison with the widely used poly-bisphenol-A-based PC. The work is focused on optical properties as well as other properties that are important for the deposition of optical coatings. Plasma ion-assisted deposition is used for the deposition of an abrasion resistant antireflective coating (AR-hard).

Ultraviolet-transparent low-index layers for antireflective coatings.

Nanostructured low-index layers are useful as the last layers of antireflective (AR) coatings because they can broaden their spectral ranges and improve the performance for oblique light incidence. Structuring of evaporated organic layers by plasma opens a route to produce inorganic interference stacks and low-index layers in the same vacuum process. The organic material uracil has been investigated as a template material for AR nanostructures. An additional plasma-treatment step was added to the manufacturing process, which decreases the organic fraction of the coating substantially. As a result, a better environmental stability and higher transmission in the ultraviolet range was achieved.

A scaffold replacement approach towards new sirtuin 2 inhibitors.

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.

Development of New Epoxy Resin Monomers - A Delicate Balance between Skin Allergy and Polymerization Properties.

Epoxy resin monomers (ERMs) are used as building blocks for thermosetting polymers in applications where strong, flexible, and lightweight materials are required. Most epoxy resins are polymers of diglycidyl ether of bisphenol A (DGEBA). It is highly allergenic and causes occupational allergic contact dermatitis and contact allergy in the general population. Thus, measures to prevent exposure by protective clothing and education are not enough. This work describes a continuation of our research aiming at reducing the skin-sensitizing potency of ERMs while maintaining the ability to form polymers. Alternative ERMs were designed and synthesized whereafter the sensitizing potency was determined using the murine local lymph node assay (LLNA). The reactivity of the diepoxides toward a nucleophilic peptide was investigated, and the differences in reactivity explained using computational studies. The diepoxides were reacted with triethylenetetramine, and the formed polymers were tested for technical applicability using thermogravimetric analysis. We had previously shown that the absence of an oxygen atom in the side chains or removal of aromaticity reduced the sensitizing potency compared to that of DGEBA. Thus, a cycloaliphatic analogue 1 of DGEBA without ether oxygen in the side chains was considered promising and was synthesized. As predicted, the sensitizing potency was considerably reduced (10 times) compared to that of DGEBA. However, the technical properties of the polymer of this compound were not considered sufficient. More polar aromatic analogues were investigated, but they could not compete with our previously described ERMs regarding polymerization properties and with 1 regarding low skin sensitization properties. Development of alternative epoxy materials is a delicate balance between allergenic activity and polymerization properties. Tuning of structural properties together with investigation of polymerization conditions combined with skin sensitization studies should be used in industrial research and development. ERM 1 could be used as a lead compound for further studies of aliphatic ERMs.

Identification of the Binding Site of Chroman-4-one-Based Sirtuin 2-Selective Inhibitors using Photoaffinity Labeling in Combination with Tandem Mass Spectrometry.

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.

Chroman-4-one and chromone based somatostatin ß-turn mimetics.

A scaffold approach has been used to develop somatostatin ß-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' ß-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have Ki-values in the low µM range when evaluated for their affinity for the sst2 and sst4 receptors.

Chroman-4-one- and chromone-based sirtuin 2 inhibitors with antiproliferative properties in cancer cells.

Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.

Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors.

A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 µM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.

KHMDS enhanced SmI(2)-mediated reformatsky type alpha-cyanation.

A novel combination of SmI(2), KHMDS, and TsCN can be utilized to introduce a cyano group into structurally diverse and highly sensitive 2-alkyl-chroman-4-ones. Subsequent oxidation allows the formed 2-alkyl-3-cyanochromones to be isolated in yields ranging from 49 to 77%. In addition, alpha-bromoketones and esters were found to undergo equally effective alpha-cyanation.