Using nodal coordinates as variables for the dimensional synthesis of mechanisms

The method of the lower deformation energy has been successfully used for the synthesis of mechanisms for quite a while. It has shown to be a versatile, yet powerful method for assisting in the design of mechanisms. Until now, most of the implementations of this method used the dimensions of the mechanism as the synthesis variables, which has some advantages and some drawbacks. For example, the assembly configuration is not taken into account in the optimization process, and this means that the same initial configuration is used when computing the deformed positions in each synthesis point. This translates into a reduction of the total search space. A possible solution to this problem is the use of a set of initial coordinates as variables for the synthesis, which has been successfully applied to other methods. This also has some additional advantages, such as the fact that any generated mechanism can be assembled. Another advantage is that the fixed joint locations are also included in the optimization at no additional cost. But the change from dimensions to initial coordinates means a reformulation of the optimization problem when using derivatives if one wants them to be analytically derived. This paper tackles this reformulation, along with a proper comparison of the use of both alternatives using sequential quadratic programming methods. In order to do so, some examples are developed and studied.     

Kinetic study on the anelation of heterocycles. 3. Pyrazino[2,3-d]pyrimidine derivatives synthesized by the hinsberg reaction

A kinetic study on the obtainment of pyrazinopyrimidine derivatives (pteridines) was performed. The regioselective synthesis of compounds 6-methylpyrazino[2,3-d]pyrimidin-7(8H)-one (5a) and 7-methylpyraz-ino[2,3-d]pyrimidin-6(5H)-one (5b) , in good yields, was expected by the Hinsberg reaction because the synthesis of both isomers analytically pure was never reported to date. This Hinsberg reaction gave good results to obtain compound 5a , regioselectively and in good yields, either in pH 5 aqueous buffer solution or in methylene chloride, among several organic solvents. However, structural and solvation factors prevented the synthesis of the isomer 5b , which was regioselectively formed in very acid solutions (Ho ? ?0.89), but in very poor yield.     

Comparative kinetic studies on the synthesis of quinoxalinone derivatives and pyrido[2,3-b]pyrazinone derivatives by the hinsberg reaction

Kinetic studies on the anelation of quinoxalinone derivatives 3a-c and pyrido[2,3-b]pyrazinone derivatives 5a-c and 6a-c synthesized by the Hinsberg reaction is reported. o-Phenylenediamine or 2,3-diaminopyridine were treated with bifunctional carbonyl compounds such as glyoxylic, pyruvic and benzoylformic acids under different experimental conditions. When pyridopyrazine derivatives were synthesized both position isomers were achieved applying regioselective reactions. Mixture were avoided by looking for special experimental conditions that led unambiguously to only one of the components of the classic “Hinsberg mixture”. Quinoxalinone derivatives 3a-c were obtained at room temperature in good yields (>90%) using anhydrous methanol or ethanol as solvents. On the other hand, only pyrido[2,3-b]pyrazin-3(4H)-one ( 5a ) was regioselectively attained in aqueous buffer of pH 7 while 3-methylpyridopyrazinone derivatives were regioselectively separated using anhydrous methanol for one isomer, 5b , and anhydrous chloroform for the other isomer, 6b , at room temperature. Yields were higher than 80%. Reactions with benzoylformic acid did not give good yields and only 2-phenylpyrido[2,3-b]pyrazin-3(4H)-one ( 5c ) could be obtained using anhydrous chloroform (yield <30%) as the solvent. Steric hindrance exerted by the phenyl group of the benzoylformic acid is supposed to be responsible of our difficulties to obtain 2-phenylpyrido[2,3-b]pyrazin-3(4H)-one ( 5c ) in good yields applying this technique. The other isomer, 3-phenyl[2,3-b]pyrazin-2(1H)-one ( 6c ) was always formed together with the former isomer and could not be isolated from the mixture, when other solvents than chloroform were used as the reaction media.     

Kinetic study on the anelation of heterocycles. 1. Quinoxalinone derivatives synthesized by hinsberg reaction

Kinetic studies on the Hinsberg condensation were performed trying to improve yields and achieve regio-selectivity in the attainment of benzene-substituted 3-methylquinoxalin-2(1H)-ones. The course of the reactions between o-phenylenediamine (o-PDA) and substituted o-PDA with pyruvic acid ( 2a ) or ethyl pyruvate ( 2b ) were followed by uv spectrophotometry at different pH values. The formation of 3-methylquinoxalin-2(1H)-one ( 6a ) was improved using sulphuric acid-water mixtures, in which the reaction proceeded by a different mechanism. 3-Methyl-7-methoxyquinoxalin-2(1H)-one ( 7b ) was regioselectively synthesized independently of the pH of the reaction media. Reaction of 2-amino-4-methylamine ( 1c ) with 2a or 2b led to a mixture of 6 and 7-quinoxalinone isomers, 6c and 7c , while 2-amino-4-nitroaniline ( 1d ) and 2,4-diaminoaniline ( 1e ) with 2a or 2b did not afford the heterocycle. In every case reactions with 2a were 100–1000 times faster than those with 2b . Mechanisms are proposed trying to account for the experimental results.     

Ex vivo assessment of polyol coated-iron oxide nanoparticles for MRI diagnosis applications: toxicological and MRI contrast enhancement effects

Polyol synthesis is a promising method to obtain directly pharmaceutical grade colloidal dispersion of superparamagnetic iron oxide nanoparticles (SPIONs). Here, we study the biocompatibility and performance as T2-MRI contrast agents (CAs) of high quality magnetic colloidal dispersions (average hydrodynamic aggregate diameter of 16-27 nm) consisting of polyol-synthesized SPIONs (5 nm in mean particle size) coated with triethylene glycol (TEG) chains (TEG-SPIONs), which were subsequently functionalized to carboxyl-terminated meso-2-3-dimercaptosuccinic acid (DMSA) coated-iron oxide nanoparticles (DMSA-SPIONs). Standard MTT assays on HeLa, U87MG, and HepG2 cells revealed that colloidal dispersions of TEG-coated iron oxide nanoparticles did not induce any loss of cell viability after 3 days incubation with dose concentrations below 50 μg Fe/ml. However, after these nanoparticles were functionalized with DMSA molecules, an increase on their cytotoxicity was observed, so that particles bearing free terminal carboxyl groups on their surface were not cytotoxic only at low concentrations (<10 μg Fe/ml). Moreover, cell uptake assays on HeLa and U87MG and hemolysis tests have demonstrated that TEG-SPIONs and DMSA-SPIONs were well internalized by the cells and did not induce any adverse effect on the red blood cells at the tested concentrations. Finally, in vitro relaxivity measurements and post mortem MRI studies in mice indicated that both types of coated-iron oxide nanoparticles produced higher negative T2-MRI contrast enhancement than that measured for a similar commercial T2-MRI CAs consisting in dextran-coated ultra-small iron oxide nanoparticles (Ferumoxtran-10). In conclusion, the above attributes make both types of as synthesized coated-iron oxide nanoparticles, but especially DMSA-SPIONs, promising candidates as T2-MRI CAs for nanoparticle-enhanced MRI diagnosis applications.     

4-Hydroxy-1(2H)-isoquinolone-3-carboxamides synthesis and properties

Reaction of some α-phthalimidoacetamides 1a-i with sodium ethoxide was carried out under drastic conditions. Compounds 1b-g afforded 4-hydroxy-1(2H)-isoquinolone-3-carboxamides 2b-g , while 1h-i afforded the acid 3a-b together with the expected isoquinolones 2h-i. Compound 1a gave phthalimide as the major product. Compounds 2 are acidic and unstable in basic media. The most acidic compounds presented the longest half-life. An explanation of these results was given.     

Polymer Capsules as a Theranostic Tool for a Universal In Vitro Screening Assay—The Case of Lysosomal Storage Diseases

Lysosomal storage disorders are rare genetic diseases characterized by a lysosomal enzyme deficiency. The defect leads to an accumulation of normally degraded substrates within the lysosomes. The accumulation of polymeric capsules inside the lysosomes is exploited to create a universal in vitro theranostic tool for lysosomal storage disorders. The diagnostic ability of this tool based on pH‐sensitive fluorophores is demonstrated by monitoring the lysosomal pH in Krabbe‐disease cell models upon accumulation of the substrate psychosine. Krabbe‐affected cells maintain their normal pH, while the lysosomes of their healthy counterparts undergo alkalinization, which can be correlated to toxicity. The potential of this tool for therapy based on enzymes inside the capsules is evaluated within the context of enzyme replacement therapy. Enzymatic degradation of the capsules inside the lysosome leads to release of the encapsulated active enzyme and the prevention of adverse effects of accumulated psychosine upon capsule‐based delivery of the functional enzyme is confirmed. In Fabry‐affected cells the intracellular enzymatic activity of the drug Replagal released from capsules shows the same kinetics as the free enzyme, which constitutes the current therapy, although the activity is smaller. Encapsulating Replagal nevertheless represents an alternative to receptor‐mediated endocytosis, overcoming limitations such as low or absent receptor expression.