An early method for the technical diagnosis of pin-on-disk tribometers by reference friction measurements in EHL conditions

Reference tests are widely used to calibrate scientific instruments but are potential candidate to establish technical diagnosis procedures for scientific instruments too. A reference test is currently lacking in tribology. Though, it would allow users to check that tribometers are properly working and may also form a yardstick for cross-laboratory comparative studies. In this paper two easy-to-use reference testing procedures for the diagnosis of commercial pin-on-disc tribometers are established resorting to a special no-wear test setup in EHL conditions. Several tests were carried out with two tribometers and two commercial oils, and both standardized testing modes were investigated: unidirectional-rotating and linear-reciprocating mode. The friction curves from more than 350 tests were analyzed to generate meaningful statistics supporting the robustness of these procedures. The test setup proved to be suited to the task since the summary of the results showed an excellent repeatability of friction curves concerning appearance and average values

A Novel Characterization Method for Hard Coatings: Preliminary Results with TiN

Pin-on-disc method is increasingly used to evaluate the tribological behavior of thin hard coatings. At present, ISO 18535 is the only standard applying to hard coatings tribology and it prescribes that investigations do not extend past the coating failure. This approach followed by many researchers is inadequate though for a complete characterization of a coated system. A novel approach is proposed in this paper, at a preliminary stage, to characterize coated systems thoroughly. Friction curves with a suitable shape are resorted to, so that two representative friction coefficients can be extracted, one before and the other after coating failure. Results with a PVD TiN coating are presented showing that it is possible with this coating to get friction curves with the desired shape in specific testing conditions

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.España e Ministerio de Economía y Competitividad (CTQ2016-77270-R

An Intramolecular Hydroaminomethylation-Based Approach to Pyrrolizidine Alkaloids under Microwave-Assisted Heating

A general method for the synthesis of pyrrolizidine derivatives using an intramolecular hydroaminomethylation protocol (HAM) under microwave (MW) dielectric heating is reported. Starting from a 3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-vinylpyrrolidine, MW-assisted intramolecular HAM in the presence of gaseous H2 and CO gave the natural alkaloid hyacinthacine A2 protected as benzyl ether. The same approach gave a lentiginosine analogue starting from the corresponding vinyl N-hydroxypyrrolidine. The nature of the reaction products and the yields were strongly influenced by the relative stereochemistry of the starting pyrrolidines, as well as by the catalyst/ligand employed. The use of ethanol as a solvent provides environmentally friendly conditions, while the ligand/catalyst system can be recovered by separating the alkaloid product with an SCX column and recycling the ethanolic solution. HAM worked up to three times with the recycled catalyst solution without any significant impact on yield

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

The synthesis of new multivalent architectures based on a trihydroxypiperidine α -fucosidase inhibitor is reported herein. Tetrava- lent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne- catalyzed cycloaddition (CuAAC) between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperi- dine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidase

Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)

We report a straightforward synthetic strategy for the preparation of trihydroxypiperidine azasugars decorated with lipophilic chains at both the nitrogen and the adjacent carbon as potential inhibitors of the lysosomal enzyme glucocerebrosidase (GCase), which is involved in Gaucher disease. The procedure relies on the preparation of C-erythrosyl N-alkylated nitrones 10 through reaction of aldehyde 8 and primary amines 13 followed by oxidation of the imines formed in situ with the methyltrioxorhenium catalyst and urea hydrogen peroxide. The addition of octylMgBr to nitrone 10e provided access to both epimeric hydroxylamines 21 and 22 with opposite configuration at the newly created stereocenter in a stereodivergent and completely stereoselective way, depending on the absence or presence of BF3·Et2O. Final reductive amination and acetonide deprotection provided compounds 14 and 15 from low-cost d-mannose in remarkable 43 and 32% overall yields, respectively, over eight steps. The C-2 R-configured bis-alkylated trihydroxypiperidine 15 was the best ligand for GCase (IC50 = 15 μM), in agreement with MD simulations that allowed us to identify the chair conformation corresponding to the best binding affinity.MINECO (CTQ2016- 77270-R) and (PID2019-104090RB-100

Light-triggered control of Glucocerebrosidase inhibitors: towards photoswitchable pharmacological Chaperones

Piperidine-based photoswitchable derivatives have been developed as putative pharmacological chaperones for glucocerebrosidase (GCase), the defective enzyme in Gaucher disease (GD). The structure-activity study revealed that both the iminosugar and the light-sensitive azobenzene are essential features to exert inhibitory activity towards human GCase and a system with the correct inhibition trend (IC50 of the light-activated form lower than IC50 of the dark form) was identified. Kinetic analyses showed that all compounds are non-competitive inhibitors (mixed or pure) of GCase and the enzyme allosteric site involved in the interaction was identified by means of MD simulations. A moderate activity enhancement of mutant GCase assessed in GD patients' fibroblasts (ex vivo experiments) carrying the most common mutation was recorded. This promising observation paves the way for further studies to improve the benefit of the light-to-dark thermal conversion for chaperoning activity