I. Development of the In Situ Reductive Ozonolysis of Alkenes with Tertiary Amine N-Oxides. II. Progress toward the Asymmetric Synthesis of Peroxyplakoric Acid A3.

Ozone, first discovered in the mid 1800’s, is a triatomic allotrope of oxygen that is a powerful oxidant. For over a century, research has been conducted into the synthetic application and mechanism of reactions of ozone with organic compounds. One of the major areas of interest has been the ozonolysis of alkenes. The production of carbonyl compounds is the most common synthetic application of ozonolysis. The generally accepted mechanism developed by Rudolf Criegee for this reaction involves the 1,3-electrocyclic addition of ozone to the π bond of the alkene to form a 1,2,3-trioxolane or primary ozonide. The primary ozonide is unstable at temperatures above -100 °C and undergoes cycloreversion to produce the carbonyl oxide and carbonyl intermediates. These intermediates then recombine in another 1,3-electrocyclic addition step to form the 1,2,4-trioxolane or final ozonide. While the final ozonide is often isolable, most synthetic applications of ozonolysis require a subsequent reductive or oxidative step to form the desired carbonyl compound. During investigations into the nucleophilic trapping of the reactive carbonyl oxide, it was discovered that when amines were used as additives, an increased amount of reaction time was required in order to consume all of the starting material. Surprisingly, significant amounts of aldehydes and a suppression of ozonide formation also occurred which led to the discovery that amine N-oxides formed by the ozonation of the amine additives in the reaction were intercepting the carbonyl oxide. From the observed production of aldehydes, our proposed mechanism for the in situ reductive ozonolysis reaction with amine N-oxides involves the nucleophilic trapping of the carbonyl oxide intermediate to produce a zwitterionic adduct that fragments into 1O2, amine and the carbonyl thereby avoiding the formation of peroxidic intermediates. With the successful total syntheses of peroxyacarnoates A and D by Dr. Chunping Xu, the asymmetric total synthesis of peroxyplakorate A3 was investigated. The peroxyplakoric acids are cyclic peroxide natural products isolated from the Plakortis species of marine sponge that have been found to exhibit activity against malaria, cancer and fungi. Even though the peroxyplakorates differ from the peroxyacarnoates in the polyunsaturated tail and the head group, the lessons learned from the syntheses of the peroxyacarnoates have proven to be valuable in the asymmetric synthesis of peroxyplakorate A3. The challenges for the asymmetric synthesis of peroxyplakorate A3 include the stereospecific formation of the 3-methoxy-1,2-dioxane core with a propionate head group and the introduction of oxidation sensitive dienyl tail in the presence of a reduction sensitive 1,2-dioxane core. It was found that the stereochemistry of two of the chiral centers could be controlled by an anti-aldol reaction of a chiral propionate followed by the stereospecific intramolecular cyclization of a hydroperoxyacetal. The regioselective ozonolysis of a 1,2-disubstituted alkene in the presence of a terminal alkyne forms the required hydroperoxyacetal as a mixture of diastereomers. Finally, the dienyl tail is introduced by a hydrometallation/iodination of the alkyne to produce a vinyl iodide followed by a palladium catalyzed coupling reaction. While the coupling reaction was unsuccessful in these attempts, it is still believed that the intramolecular cyclization to introduce the 1,2-dioxane core could prove to be a general solution to many other cyclic peroxides natural products.

Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain

Metformin is treatment of choice for the metabolic consequences seen in polycystic ovary syndrome for its insulin-sensitizing and androgen-lowering properties. Yet, the mechanism of action remains unclear. Two potential targets for metformin regulating steroid and glucose metabolism are AMP-activated protein kinase (AMPK) signaling and the complex I of the mitochondrial respiratory chain. Androgen biosynthesis requires steroid enzymes 17α-Hydroxylase/17,20 lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which are overexpressed in ovarian cells of polycystic ovary syndrome women. Therefore, we aimed to understand how metformin modulates androgen production using NCI-H295R cells as an established model of steroidogenesis. Similar to in vivo situation, metformin inhibited androgen production in NCI cells by decreasing HSD3B2 expression and CYP17A1 and HSD3B2 activities. The effect of metformin on androgen production was dose dependent and subject to the presence of organic cation transporters, establishing an important role of organic cation transporters for metformin's action. Metformin did not affect AMPK, ERK1/2, or atypical protein kinase C signaling. By contrast, metformin inhibited complex I of the respiratory chain in mitochondria. Similar to metformin, direct inhibition of complex I by rotenone also inhibited HSD3B2 activity. In conclusion, metformin inhibits androgen production by mechanisms targeting HSD3B2 and CYP17-lyase. This regulation involves inhibition of mitochondrial complex I but appears to be independent of AMPK signaling.

STUDIES ON THE CLASS I GLYCOPROTEINS OF THE MURINE MAJOR HISTOCOMPATIBILITY COMPLEX (TRANSPLANTATION ANTIGEN, LYMPHOCYTE, CELL SURFACE MOLECULE)

A series of studies were undertaken to analyze and compare various aspects of murine class I glycoproteins. An initial area of investigation characterized the Qa-1 alloantigens using two-dimensional gel electrophoresis. Analysis of the products of the Qa-1('b), Qa-1('c) and Qa-1('d) alleles indicated that these were distinct molecules as determined by their lack of comigration upon comparative two-dimensional gel analysis. The importance of asparagine-linked glycosylation in the cell surface expression of class I molecules was also examined. These studies employed tunicamycin, an inhibitor of N-linked glycosylation. Tunicamycin treatment of activated T lymphocytes diminished the surface expression of Qa-1 to undetectable levels; the levels of other class I molecules exhibited little or no decrease. These results indicated that N-linked glycosylation has a differential importance in the cell surface expression of various class I molecules. The molecular weight diversity of class I molecules was also investigated. Molecular weight determination of both the fully glycosylated and unglycosylated forms of H-2 and Qa/Tla region encoded molecules established that there is a significant variation in the sizes of these forms of various class I molecules. The most significant difference ((TURN)9,000 daltons) exists between the unglycosylated forms of H-2K('b) and Qa-2, suggesting that the structural organization of these two molecules may be very different. A comparative two-dimensional gel analysis of various class I glycoproteins isolated from resting and activated T and B lymphocytes indicated that class I molecules expressed on activated T cells exhibited an isoelectrophoretic pattern that was distinct from the isoelectrophoretic pattern of class I molecules expessed on the other cell populations. This difference was attributed to a lower sialic acid content of the molecules expressed on activated T cells. Analysis of cell homogenates determined that activated T cells contained a higher level of endogenous neuraminidase activity than was detected in the other populations, suggesting that this may be the basis of the lower sialic acid content. The relationship of the Qa-4 and Qa-2 alloantigens was also examined. It was established that upon mitogen activation, the expression of Qa-4 was greatly decreased, whereas Qa-2 expression was not decreased. However, an anti-Qa-2 monoclonal antibody blocked the binding of an anti-Qa-4 monoclonal antibody to resting cells. These studies established that Qa-4 is a determinant restricted to resting cells, which is closely associated on the surface with the Qa-2 molecule. ^

Sea-surface reconstruction of the east-equatorial South Atlantic

In order to reconstruct Late Quatemary variations of surface oceanography in the eastequatorial South Atlantic, time series of sea-surface temperatures (SST) and paleoproductivity were established from cores recovered in the Guinea and Angola Basins, and at the Walvis Ridge. These records, based on sedimentary alkenone and organic carbon concentrations, reveal that during the last 350,000 years surface circulation and productivity changes in the east-equatorial South Atlantic were highiy sensitive to climate forcing at 23- and 100-kyr periodicities. Covarying SST and paleoproductivity changes at the equator and at the Walvis Ridge appear to be driven by variations in zonal trade-wind intensity, which forces intensification or reduction of coastal and equatorial upwelling, as well as enhanced Benguela cold water advection from the South. Phase relationships of precessional variations in the paleoproductivity and SST records from the distinct sites were evaluated with respect to boreal summer insolation over Africa, movements of southem ocean thermal fronts, and changes in global ice volume. The 23-kyr phasing implies a sensitivity of eastem South Atlantic surface water advection and upwelling to West African monsoon intensity and to changes in the position ofthe subtropical high pressure cell over the South Atlantic, both phenomena which modulate zonal strength of southeasterly trades. SST and productivity changes north of 20°S lack significant variance at the 41-kyr periodicity; and at the Walvis Ridge and the equator lead changes in ice volume. This may indicate that obliquity-driven clirnate change, characteristic for northem high latitudes, e.g fluctuations in continental ice masses, did not substantially influence subtropical and tropical surface circulation in the South Atlantic. At the 23-kyr cycle SST and productivity changes in the eastern Angola Basin lag those in the equatorial Atlantic and at the Walvis Ridge by about 3500 years. This lag is explained by variations in cross-equatorial surface water transport and west-east countercurrent retum flow modifying precessional variations of SST and productivity in the eastem Angola Basin relative to those in the mid South Atlantic area under the central field of zonal trade winds. Sea level-related shifts of upwelling cells in phase with global clirnate change may be also recorded in SST and productivity variability along the continental margin off Southwest Africa. They may account for the delay of the paleoceanogreaphic signal from continental margin sites with respect to that from the pelagic sites at the equator and the Walvis Ridge.

Water, bottom deposits, and macrobenthos in the south part of the East Siberian Sea in September 2003

Macrobenthos biomass and bottom biocoenoses were studied in the sublittoral zone of the southern East Siberian Sea. The macrobenthos is characterized by relatively high abundance (from 30 to 2680 #/m**2), biomass (from 0.25 to 578.8 g/m**2), and diversity (83 species in total). Lateral distribution of macrobenthos biomass correlates with a substrate type and salinity and is substantially higher in areas washed by the Arctic water mass than in estuaries with mixed fresh and Arctic waters and shows a tendency to decreasing in the convergence zone of different water masses. The highest macrobenthos biomass is observed in cores of water masses in the Long Strait area and in the eastern part of the sea.

Updated bathymetric chart of the East Aral Sea

The Aral Sea is located in an arid region with much sand and salt deposits in the surrounding barren open land. Hence, significant displacements of sediments into the lakebed by the action of wind, water, gravity, or snow are likely. The bathymetry of the lake was last observed in the 1960s, and within the last half century, the structure of the lakebed has changed. Based on satellite observations of the temporal changes of shoreline (Landsat optical remote sensing) and water level (multi-mission satellite altimetry) over more than one decade an updated bathymetric chart for the East Basin of the Aral Sea has been generated. During this time, the geometry of the shallow East Basin experienced strong fluctuations due to the occurrence of periods of drying and strong inflow. By the year 2014 the East Basin fell dry. The dynamic behavior of the basin allowed for estimating the lake's bathymetry from a series of satellite-based information. The river mouth made its impression in the present East Aral Sea, because its shrinking led to the inflow of much sediment into the lake's interior. In addition, salt deposits along the shorelines increased the corresponding elevation, a phenomenon that is more pronounced in the reduced lakebed because of increased salinity. It must be noted that height estimates from satellite altimetry were only possible down to a minimum elevation of 27 m above sea level due to a lack of reliable altimetry data over the largely reduced water surface. In order to construct a complete bathymetric chart of the lakebed of the East Aral Sea heights below 27 m were obtained solely from Landsat optical images following the SRB (Selected Region Boundary) approach as described by Singh et al. (2015).

Chemical composition and accumulation rates of chemical elements in metalliferous sediments from axial zones of the East Pacific Rise and the Mid-Atlantic Ridge

In the monograph metalliferous sediments of the East Pacific Rise near 21°S are under consideration. Distribution trends of chemical, mineral and grain size compositions of metalliferous sediments accumulated near the axis of this ultrafast spreading segment of the EPR are shown. On the basis of lithological and geochemical investigations spatial and temporal variations of hydrothermal activity are estimated. Migration rates of hydrothermal fields along the spreading axis are calculated. The model of cyclic hydrothermal process is suggested as a result of tectono-magmatic development of the spreding centre.