Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans: scope and mechanism.

A novel Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans is reported. Mechanistic studies by (13)C-labeling experiments confirm oxidative addition of Pt(II) regioselectively to the least substituted carbon-carbon bond of the cyclopropane to form a platinacyclobutane intermediate. To our knowledge, this is the first alkoxy-substituted platinacyclobutane that has been observed spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described.

Chiral Resolution of the Enantiomers of the Slow-Onset Dopamine Reuptake Inhibitor CTDP-32476 and Their Activities.

An improved synthesis was developed for CDTP-32476, a potent slow-onset dopamine reuptake blocker that may have utility as a treatment for cocaine abuse. The enantiomers of the compound were separated by fractional crystallization with N-acetylleucine enantiomers. An X-ray crystal structure was obtained of the RR enantiomer paired with N-acetyl-d-leucine. Chiral chromatography showed that the resolved enantiomers were pure with little contamination by the other enantiomer. The enantiomers were tested for their ability to block the reuptake of monoamines at their respective transporters and to stimulate locomotor activity in mice. Both enantiomers potently blocked the reuptake of dopamine and stimulated locomotor activity in mice. The RR enantiomer that corresponds to the active RR enantiomer of methylphenidate was slightly more potent at the dopamine reuptake site. The RR enantiomer also was found to be about twice as selective for the dopamine transporter relative to the norepinephrine transporter, which may have clinical implications. A method for designing slow-onset stimulants is proposed since there is increasing evidence that such activity is an important factor in stimulants that may have limited abuse potential.

New photoactivators for multiphoton excited three-dimensional submicron cross-linking of proteins: bovine serum albumin and type 1 collagen.

We report the synthesis and optical characterization of two new photoactivators and demonstrate their use for multiphoton excited three-dimensional free-form fabrication with proteins. These reagents were developed with the goal of cross-linking Type 1 collagen. This cross-linking process produces structures on the micron and submicron size scales. A rose bengal diisopropyl amine derivative combines the classic photoactivator and co-initiator system into one molecule, reducing the reaction kinetics and increasing cross-linking efficiency. This derivative was successful at producing stable structures from collagen, whereas rose bengal alone was not effective. A benzophenone dimer connected by a flexible diamine tether was also synthesized. This activator has two photochemically reactive groups and is highly efficient in cross-linking bovine serum albumin and Type 1 collagen to form stable, robust structures. This approach is more flexible in terms of cross-linking a variety of proteins than by traditional benzophenone photochemistry. The photophysical properties vary greatly from that of benzophenone, with the appearance of a new, lower energy absorption band (lambda max approximately 370 nm in water) and broad, visible emission band (approximately 500 nm maximum). This absorption band is highly solvatochromic, suggesting it arises, at least in part, from a charge transfer interaction. Collagens are typically difficult to cross-link photochemically, and the results here suggest that these two new activators will be suitable for cross-linking other forms of collagen and additional proteins for biomedical applications such as the de novo assembly of biomimetic tissue scaffolds.

Multiphoton excited fabrication of collagen matrixes cross-linked by a modified benzophenone dimer: bioactivity and enzymatic degradation.

Multiphoton excited (MPE) photochemistry is used to fabricate model tissue engineering scaffolds directly from types I, II, and IV collagen. A modified benzophenone dimer (BPD) provides the photoactivation and becomes incorporated into the resulting collagen matrixes. Unlike xanthene photochemistries, the benzophenone dimer can be used in acidic environments, where most forms of collagen have the greatest solubility. The minimum feature sizes are investigated by using two- and three-photon excitation, where the latter provides for superior "resolution" and suggests that collagen structures can be fabricated on the size scales of focal contacts. The resulting structures display excellent retention of bioactivity as evidenced by highly specific cell adhesion as well as immunofluorescence labeling. Structural and chemical aspects of the collagen matrixes are probed through measuring the enzymatic degradation through specific and nonspecific proteases, as the resulting relative rates are consistent with the activity of these enzymes. The degradation rates can also be controlled through varying the cross-link density in the matrixes, which is achieved through tuning the exposure dose during the fabrication process. The degradation rates are also found to be consistent with swelling/shrinking measurements and thus the average mesh size of the matrixes. In all cases the enzymatic degradations are well-fit single exponentials, suggesting that the matrixes can be fabricated with a priori knowledge of their structural properties. These results coupled with the resulting bioactivity suggest that the multiphoton fabrication process may be a powerful tool for the creation of cell-sized tissue engineering scaffolds.

Directed ring-opening of 1,5-dioxaspiro[3.2]hexanes: selective formation of 2,2-disubstituted oxetanes.

1,5-Dioxaspiro[3.2]hexanes undergo ring-opening reactions with many heteroatom nucleophiles to provide alpha-substituted-beta'-hydroxy ketones. However, certain Lewis acidic nucleophiles provide 2,2-disubstituted oxetanes. Herein, the results of reactions of 3-phenyl-1,5-dioxaspiro[3.2]hexane with a variety of nitrogen-containing heteroaromatic bases are reported. There appears to be a correlation between the pK(a) of the nucleophile and the reaction outcome with more acidic nucleophiles providing 2,2-disubstituted oxetanes. Moreover, the mode of ring opening can be directed toward the substituted oxetane by the addition of a Lewis acid. These results are rationalized by calculation of stationary points on the potential energy surfaces for the various possible reaction pathways using ab initio molecular orbital methods.

Sindrome de resuuesta inflamatoria sistemica en neonatos / The systemic inflammatory response syndrome in newborns

Un estudio observacional fue realizado durante 9 meses en el Hospital Materno Infantil 10 de Octubre, en Ciudad de La Habana, donde se incluyeron todos los pacientes que fueron ingresados en el Servicio de Neonatología en ese período. El objetivo de este estudio fue determinar el comportamiento del Síndrome de Respuesta Inflamatoria Sistémica (SIRS) en recién nacidos y evaluar los principales factores perinatales que se relacionaron con la mortalidad. La definición del SIRS fue modificada y también definimos el Síndrome de Disfunción Múltiple de Organos (MODS). Todos los pacientes fueron evaluados entre 24- 48 horas después de haber sido ingresados. Fueron clasificados 47 niños de 351 como SIRS (13,4%), así como 40 de 351 como MODS (11,4%). Mientras más órganos fueron afectados, la mortalidad fue más alta. Solamente 12 niños fallecieron, 10 de ellos con MODS (83,3%). Concluimos que aunque el SIRS y el MODS son difíciles de diagnosticar en el periodo neonatal, cuando los hallazgos clínicos de ambos síndromes estuvieron presentes, los pacientes tuvieron mayor mortalidad.

An observational study was made in "10 de October", Infant-Maternity Hospital, in Havana City. All patients admit ted in the Neonatology Service during 9 months were enrolled. The objective of this study was to determine the systemic inflammatory response syndrome (SIRS) in newborns and to evaluate perinatal factors in the mortality. The SIRS definition was modified as well as the multiple dysfunction syndrome (MODS). All patients were evaluated between 24-48 hours right after their admission, 47 babies out of 351 (13,4 %) were classified as SIRS, while 40 out of 351 (11,4 %) as MODS, the more organs affected, the higher the mortality rate was. We arrived to the conclusion that although SIRS and MODS were difficult to diagnose in this kind of patients, clinical findings showed that the mortality rate increased when both syndromes are present.