The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides

Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome this, we have developed a new safety-catch linker. The safety-catch concept described here involves the use of a protected catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to aminolysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is activated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form of the linker. Scavengers and deprotection adducts are removed by simple washing and filtration. Upon neutralization of the N-terminal amine, cyclization with concomitant cleavage from the resin yields the cyclic peptide in DMF solution. Workup is simple solvent removal. To exemplify this strategy, several cyclic peptides were synthesized targeted toward the somatostatin and integrin receptors. From this initial study and to show the strength of this method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides.

Pauson-Khand Adducts of N-Boc-propargylamine: A New Approach to 4,5-Disubstituted Cyclopentenones

A new approach to the synthesis of 4,5-disubstituted cyclopentenones is described. The strategy is based on the Pauson-Khand (PK) reaction of norbornadiene and N-Boc-propargylamine as alkyne with a masked leaving group, which can be eliminated at will. This approach to the synthesis of 4,5-disubstituted cyclopentenones overcomes the problem of using the alkylation to introduce the alpha-side-chain. As an example, prostane 13-epi-12-oxo-phytodienoic acid (13-epi-12-oxo-PDA) methyl ester was synthesized.

Pauson-Khand Adducts of N-Boc-propargylamine: A New Approach to 4,5-Disubstituted Cyclopentenones

A new approach to the synthesis of 4,5-disubstituted cyclopentenones is described. The strategy is based on the Pauson-Khand (PK) reaction of norbornadiene and N-Boc-propargylamine as alkyne with a masked leaving group, which can be eliminated at will. This approach to the synthesis of 4,5-disubstituted cyclopentenones overcomes the problem of using the alkylation to introduce the alpha-side-chain. As an example, prostane 13-epi-12-oxo-phytodienoic acid (13-epi-12-oxo-PDA) methyl ester was synthesized.

Pauson-Khand Adducts of N-Boc-propargylamine: A New Approach to 4,5-Disubstituted Cyclopentenones

A new approach to the synthesis of 4,5-disubstituted cyclopentenones is described. The strategy is based on the Pauson-Khand (PK) reaction of norbornadiene and N-Boc-propargylamine as alkyne with a masked leaving group, which can be eliminated at will. This approach to the synthesis of 4,5-disubstituted cyclopentenones overcomes the problem of using the alkylation to introduce the alpha-side-chain. As an example, prostane 13-epi-12-oxo-phytodienoic acid (13-epi-12-oxo-PDA) methyl ester was synthesized.

Her onginþ seo boc: On the loss and retention of grammatical gender in Early Middle English

Tutkielma käsittelee kieliopillisen suvun säilymistä myöhäisessä muinaisenglannissa (Late Old English) ja varhaiskeskienglannissa (Early Middle English). Tutkielman tavoitteena on päätellä, kuinka kieliopillinen suku säilyy kolmessa muinaisenglannin/varhaiskeskienglannin aikakautta edustavassa tekstissä. Lähdeaineisto on valittu edustamaan aikaa (1150-1225), jolloin kieliopillisen suvun on sanottu kadonneen englannin kielestä. Lähdeaineisto myös edustaa kahta eri tekstilajia, ja tarjoaa siten aineistoa niiden väliseen vertailuun. Aineistosta on analysoitu nominien päätteitä, demonstratiivipronomineja sekä anaforisia persoonapronomineja, joissa substantiivien kieliopillinen suku näkyy. Osa anaforisista viittauksista on selitettävissä personifikaatiolla, jolloin elottomiin objekteihin tai käsitteisiin on liitetty inhimillistäviä piirteitä. Tutkimuksen perusteella kieliopillinen suku säilyy vielä joissakin muodoissa 1200- luvulle saakka. Merkittävää on aineistossa esiintyvä runsas vaihtelu ja pyhimyselämänkertojen ja lääketieteellisen tekstin väliset erot.

Mejoramiento de procesos e incidencia en los costos de producción de gases líquidos aplicado en la empresa "British Oxigen Company - Boc Gases - Venezuela"

La presente investigación basó su estudio y aplicación al proceso de “control de costos” de gases líquidos, realizados por la empresa British Oxigen Company - BOC Gases Venezuela, y determinó como la eficiencia propuesta como una alternativa en la gestión, se basa en el control de los procesos productivos, enfocándose en la reducción de costos y la generación de valor en el producto. En cuanto al objetivo de la investigación es “Contribuir en la gestión más eficaz de los procesos en una empresa privada”, mediante la aplicación de la herramienta gerencial de administración de costos, para optimizar los recursos en el cumplimiento de las necesidades del mercado y evaluar la incidencia del cambio de los procesos sobre los resultados de la empresa. En el 2006, British Oxigen Company - BOC Gases Venezuela participa en un proceso de fusión, que generó oportunidades de mejoras y cambios a sus procesos internos y externos, y a su vez las disposiciones gerenciales se enfocaron en la optimización de los procesos de producción, logística, administración y ventas, mediante la optimización por el uso adecuado de sus recursos. Al aplicarse el mejoramiento del proceso de “Control de Costos” mediante la aplicación de la herramienta de costeo y gestión gerencial, la cual sirvió de apoyo en la identificación de oportunidades y en la toma de decisiones gerenciales. Los resultados de la investigación demostraron un mejoramiento del proceso a través del cambio de las actividades del proceso de “Control de Costos” para generar valor en el resultado final del proceso

Conformational heterogeneity of tripeptides containing Boc-Leu-Aib as corner residues in the solid state

A critical analysis of single crystal X-ray diffraction studies on a series of terminally protected tripeptides containing a centrally positioned Aib (alpha-aminoisobutyric acid) residue has been reported. For the tripeptide series containing Boc-Ala-Aib as corner residues, all the reported peptides formed distorted type II beta-turn structures. Moreover, a series of Phe substituted analogues ( tripeptides with Boc-Phe-Aib) have also shown different beta-turn conformations. However, the Leu-modified analogues (tripeptides with Boc-Leu-Aib) disrupt the concept of beta-turn formation and adopt various conformations in the solid state. X-ray crystallography sheds some light on the conformational heterogeneity at atomic resolution. (c) 2007 Elsevier Ltd. All rights reserved.

Solvent-dependent enantioswitching in the Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected cyclohexa-1,2-diamines

Enantiomerically pure mono-N-Boc-protected trans-cyclohexa-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. Using a single enantiomer of the organocatalyst, both enantiomeric forms of the resulting Michael adducts bearing a new quaternary stereocenter are obtained in high yields, by only changing the reaction solvent from chloroform (up to 86% ee) to aqueous DMF (up to 84% ee).

Planeamento das condições operacionais do BOC-HG e UCA do Centro Hospitalar e Universitário de Coimbra EPE

No atual contexto de mudança, impõe-se como desafio das organizações a procura de uma maior economia, eficácia e eficiência das suas operações. Este projeto aborda e desenvolve o planeamento de cirurgias eletivas, em dois Blocos Operatórios do CHUC. Procura-se essencialmente uma melhor resposta, em termos estratégicos, para a redução das listas de espera para cirurgia, bem como a melhoria na eficiência do funcionamento dos serviços. Com este propósito procedeu-se ao levantamento bibliográfico, quer alusivo à integração destes Serviços Hospitalares, em normas e leis de referência nacional, regional e local, quer em conceitos na vertente da otimização/apoio à decisão. De seguida foi realizada uma análise contextual dos serviços em estudo, passando-se para a componente metodológica. Nesta, promoveu-se uma sequência de métodos, iniciando-se com recurso a questionários de forma a indagar sobre a opinião de critérios de otimização por parte dos intervenientes e agentes de suporte à decisão, seguindo-se de uma entrevista para recolha de parâmetros e ideias para um modelo de otimização, finalizando-se na conceção e adaptação do modelo. Os testes ao modelo mostraram bons resultados computacionais e revelaram-se adequados há realidade do bloco operatório. As abordagens propostas no presente projeto proporcionam ainda uma reflexão sobre os problemas de planeamento do Bloco Operatório e no seu desempenho global.

BOC, brother of CDO, is a dorsoventral axon-guidance molecule in the embryonic vertebrate brain

The early axon scaffolding in the embryonic vertebrate brain consists of a series of ventrally projecting axon tracts that grow into a single major longitudinal pathway connected across the midline by commissures. We have investigated the role of Brother of CDO (BOC), an immunoglobulin (Ig) superfamily member distantly related to the Roundabout (Robo) family of axon-guidance receptors, in the development of this embryonic template of axon tracts in the zebrafish brain. A zebrafish homologue of BOC was isolated and shown to be expressed predominantly in the developing neural plate and later in the neural tube and developing brain. Zebrafish boc was initially highly localized to discrete bands in the mid- and hindbrain, but, as the major brain subdivisions emerged, it became more evenly expressed along the rostrocaudal axis, particularly in dorsal regions. The function of zebrafish boc was examined by a loss-of-function approach. Analysis of embryos injected with antisense morpholinos designed against boc revealed highly selective defects in the development of dorsoventrally projecting axon tracts. Loss of boc caused ventrally projecting axons, particularly those arising from the presumptive telencephalon, to follow aberrant trajectories. These data indicate that boc is an axon-guidance molecule playing a fundamental role in pathfinding during the early patterning of the axon scaffold in the embryonic vertebrate brain. (c) 2005 Wiley-Liss, Inc.