Phosphinotripeptidic Inhibitors of Leucylaminopeptidases.

Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is conveniently available from the three-component condensation of appropriate amino components, aldehydes, and hypophosphorous acid. One of the crucial synthetic steps is the careful selection of the protecting groups for all the functionals. Determination of the inhibitor activity of the obtained compounds has been done using UV-Vis spectroscopy and standard substrate L-Leu-p-nitroanilide toward the enzymes isolated from the porcine kidney (SsLAP, Sus scrofa Leucine aminopeptidase) and barley seeds (HvLAP, Hordeum vulgare Leucine aminopeptidase). An efficient procedure for the preparation of phosphinotripeptides has been performed. Activity test shown that introduction of additional residue into P2 position obtains the micromolar range inhibitors of SsLAP and HvLAP. Moreover, careful selection of the residue in the P2 position should improve its selectivity toward mammalian and plant leucyl aminopeptidases.

Carcinomatosis meníngea en el cáncer de mama: del diagnóstico al tratamiento / Meningeal carcinomatosis in breast cancer: from diagnosis to treatment

La aparición de carcinomatosis meníngea en el cáncer de mama es un suceso cada vez más comunicado en la bibliografía. Parece relacionarse con el alargamiento de la vida de las pacientes, la mejor sensibilidad al diagnóstico por imagen y la impermeabilidad de la barrera hematoencefálica a los agentes quimioterápicos. Es una forma evolutiva que afirma la invasión metastásica del espacio subaracnoideo y se correlaciona con una supervivencia limitada. El diagnóstico es difícil, debido a la inespecificidad de los signos clínicos dominados por cefaleas, trastornos cognitivos, y posibles síntomas y signos de lesiones focales progresivas. La resonancia magnética del cerebro y de la médula espinal interpretada por un especialista en neurooncología es el examen de elección en esta indicación, en búsqueda de un incremento en la captación meníngea. El análisis biológico del líquido cefalorraquídeo es un elemento esencial en el diagnóstico. Además del estudio bioquímico, la presencia de células neoplásicas es por sí sola suficiente para confirmar el diagnóstico. El número de falsos negativos es muy común y representa un gran problema diagnóstico que requiere una repetición de las punciones lumbares. Los métodos terapéuticos son estándares, a menudo invasivos, dominados por la quimioterapia intratecal y se basan sobre una evidencia científica de bajo nivel. Se analiza la epidemiología, los factores pronósticos, las herramientas diagnósticas, los tratamientos disponibles en la actualidad y las posibles terapias futuras de la carcinomatosis meníngea en el cáncer de mama (AU)

The appearance of meningeal carcinomatosis in breast cancer is an event that is being reported increasingly more frequently in the literature. It seems to be related with the lengthening of the patients’ lives, improved sensitivity to diagnostic imaging and impermeability of the blood-brain barrier to the chemotherapeutic agents. It is an evolutionary form that affirms the metastatic invasion of the subarachnoidal space and is correlated with limited survival. Its diagnosis is difficult, due to the lack of specificity of the clinical signs dominated by headaches, cognitive disorders and possible signs and symptoms of progressive focal lesions. Magnetic resonance imaging of the brain and the spinal cord interpreted by a specialist in neuro-oncology is the preferred examination in this indication, in the search for an increase in meningeal enhancement. Biological analysis of the cerebrospinal fluid is an essential element in the diagnosis. In addition to the biochemical study, the presence of neoplastic cells is in itself enough to confirm the diagnosis. False negatives are very common and represent an important diagnostic problem that entails the need to repeat the lumbar punctures. The therapeutic methods are standard, often invasive, dominated by intrathecal chemotherapy and are based on low-level scientific evidence. This study analyses the epidemiology, the prognostic factors, the diagnostic tools, currently available treatments and the possible future therapies of meningeal carcinomatosis in breast cancer (AU)

Hetero-Diels-Alder reaction of phosphorylated nitroso alkenes with enol ethers on water: a clean approach toward 1,2-oxazine derivatives.

A concise and eco-friendly synthesis of highly functionalized 1,2-oxazines from phosphinyl- and phosphonyl-nitroso alkenes has been developed. The key step of this process, which involves a two-step sequence of reactions on-water, is a regioselective hetero-Diels-Alder cycloaddition reaction of enol ethers to 4-phosphinyl or 4-phosphonyl nitroso alkenes mediated by water itself. The process has also been performed under solvent-free conditions and in organic solvents for comparison.