Short asymmetric synthesis of phenanthroindolizidines through chiral homoallylic sulfinamine

An efficient stereocontrolled preparation of chiral phenanthroindolizidines is detailed. The synthesis relies on the stereoselective indium-mediated allylation of 2-(phenanthren-9-yl)acetaldehyde derivatives with chiral tert-butylsulfinamide. Chemoselective transformations from the corresponding homoallylic sulfinamine allow the synthesis of the phenanthroindolizidines in only three synthetic operations, without any detectable racemization. Following this procedure, the synthesis of natural (−)-tylophorine was successfully accomplished.We thank the Spanish Ministerio de Ciencia e Innovación for their financial support (CTQ2011-24165). C. A.-T. thanks the ISO for a grant

A radical addition/cyclization of diverse ethers to 2-isocyanobiaryls under mildly basic aqueous conditions

Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogenative addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution (BHAS).We thank the Ministerio de Economia y Competitividad (CTQ2015-66624-P) and the University of Alicante (VIGROB-173) for financial support. C. A.-T. thanks the ISO for a grant

Concise asymmetric syntheses of novel phenanthroquinolizidines

The first preparation of enantioenriched phenanthroquinolizidines with a quaternary center at C14a was accomplished in seven steps from readily available starting materials. Key steps were an efficient dynamic kinetic allylation of a diastereomeric mixture of chiral tert-butylsulfinyl ketimines and the construction of a piperidine E ring by rhodium catalyzed hydroformylation. The Stevens rearrangement of the corresponding N-benzyl derivatives took place smoothly, allowing the installation of a benzyl moiety at C9 in a trans relationship with the methyl group. The cytoxicity of the prepared phenanthroquinolizidines was evaluated against different human cancer cell lines.We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24165) and the University of Alicante (VIGROB-173) for financial support. C. A.-T. thanks the ISO for a grant

Syntheses and Cytotoxicity of (R)- and (S)-7-Methoxycryptopleurine

Two efficient protocols are described for the transformation of a key chiral homoallyllic sulfinamine intermediate in four steps into enantioenriched 7-methoxycryptopleurine. While one of the protocols relied on a rhodium catalyzed linear hydroformylation process, the alternative approach was based on a ring-closing metathesis from the corresponding N-allyl-sulfinamine. The cytotoxic evaluation of both enantiomers of the target compound demonstrated that the (R)-compound is much more potent than its antipode against the four cancer cell lines examined.We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24165) for financial support. I.B. acknowledges the Generalitat Valenciana for a postdoctoral fellowship (ACIF/2011/159). C.A.-T. thanks the ISO for a grant

Breaking the Curve with CANDELS: A Bayesian Approach to Reveal the Non-Universality of the Dust-Attenuation Law at High Redshift

Dust attenuation affects nearly all observational aspects of galaxy evolution, yet very little is known about the form of the dust-attenuation law in the distant Universe. Here, we model the spectral energy distributions (SEDs) of galaxies at z = 1.5--3 from CANDELS with rest-frame UV to near-IR imaging under different assumptions about the dust law, and compare the amount of inferred attenuated light with the observed infrared (IR) luminosities. Some individual galaxies show strong Bayesian evidence in preference of one dust law over another, and this preference agrees with their observed location on the plane of infrared excess (IRX, $L_{\text{TIR}}/L_{\text{UV}}$) and UV slope ($\beta$). We generalize the shape of the dust law with an empirical model, $A_{\lambda,\delta}=E(B-V)\ k_\lambda\ (\lambda/\lambda_V)^\delta$ where $k_\lambda$ is the dust law of Calzetti et al. (2000), and show that there exists a correlation between the color excess ${E(B-V)}$ and tilt $\delta$ with ${\delta=(0.62\pm0.05)\log(E(B-V))}$+ ${(0.26~\pm~0.02)}$. Galaxies with high color excess have a shallower, starburst-like law, and those with low color excess have a steeper, SMC-like law. Surprisingly, the galaxies in our sample show no correlation between the shape of the dust law and stellar mass, star-formation rate, or $\beta$. The change in the dust law with color excess is consistent with a model where attenuation is caused by by scattering, a mixed star-dust geometry, and/or trends with stellar population age, metallicity, and dust grain size. This rest-frame UV-to-near-IR method shows potential to constrain the dust law at even higher ($z>3$) redshifts.Comment: 20 pages, 18 figures, resubmitted to Ap

Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model†

OBJECTIVES The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions. METHODS Human mesothelioma xenografts (H-meso-1) were grown in the dorsal skinfold chambers of 28 nude mice. By intravital microscopy, the rolling and recruitment of leukocytes were assessed in tumour vessels following PDT (Visudyne® 400μg/kg, fluence rate 200mW/cm2and fluence 60J/cm2) using intravital microscopy. Likewise, the distribution of fluorescently labelled macromolecular dextran (FITC-dextran, MW 2000kDa) was determined after PDT. Study groups included no PDT, PDT, PDT plus a functionally blocking anti-pan-selectin antibody cocktail and PDT plus isotype control antibody. RESULTS PDT significantly enhanced the extravascular accumulation of FITC-dextran in mesothelioma xenografts, but not in normal tissue. PDT significantly increased leukocyte-endothelial cell interaction in tumour. While PDT-induced leukocyte recruitment was significantly blunted by the anti-pan-selectin antibodies in the tumour xenograft, this manipulation did not affect the PDT-induced extravasation of FITC-dextran. CONCLUSIONS Low-level PDT pre-treatment selectively enhances the uptake of systemically circulating macromolecular drugs in malignant mesothelioma, but not in normal tissue. Leukocyte-endothelial cell interaction is not required for PDT-induced drug delivery to malignant mesotheliom

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

On the Stellar Populations and Evolution of Star-Forming Galaxies at 6.3 < z < 8.6

We study the physical characteristics of galaxies at 6.3 < z < 8.6, selected from deep near-infrared imaging with the Wide Field Camera 3 (WFC3) on board the Hubble Space Telescope. Accounting for the photometric scatter using simulations, galaxies at z ~ 7 have bluer UV colors compared to typical local starburst galaxies at > 4 sigma confidence. Although these colors necessitate young ages (<100 Myr), low or zero dust attenuation, and low metallicities, these are explicable by normal (albeit unreddened) stellar populations, with no evidence for near-zero metallicities and/or top-heavy initial mass functions. The age of the Universe at these redshifts limits the amount of stellar mass in late-type populations, and the WFC3 photometry implies galaxy stellar masses ~ 10^8 - 10^9 Msol for Salpeter initial mass functions to a limiting magnitude of M_1500 ~ -18. The masses of ``characteristic'' (L*) z > 7 galaxies are smaller than those of L* Lyman break galaxies (LBGs) at lower redshifts, and are comparable to less evolved galaxies selected on the basis of their Lyman alpha emission at 3 < z < 6, implying that the 6.3 < z < 8.6 galaxies are the progenitors of more evolved galaxies at lower redshifts. We estimate that Lyman alpha emission is able to contribute to the observed WFC3 colors of galaxies at these redshifts, with an estimated typical line flux of ~ 10^-18 erg s^-1 cm^-2, roughly a factor of four below currently planned surveys. The integrated UV specific luminosity for the detected galaxies at z ~ 7 and z ~ 8 is within factors of a few of that required to reionize the IGM assuming low clumping factors, implying that in order to reionize the Universe galaxies at these redshifts have a high ( ~ 50%) escape fraction of Lyman continuum photons, possibly substantiated by the very blue colors of this population.Comment: Accepted to the Astrophysical Journal; replaced with accepted version. Minor modifications to sample, conclusions are unchange

Neutrinos below 100 TeV from the southern sky employing refined veto techniques to IceCube data

Many Galactic sources of gamma rays, such as supernova remnants, are expected to produce neutrinos with a typical energy cutoff well below 100 TeV. For the IceCube Neutrino Observatory located at the South Pole, the southern sky, containing the inner part of the Galactic plane and the Galactic Center, is a particularly challenging region at these energies, because of the large background of atmospheric muons. In this paper, we present recent advancements in data selection strategies for track-like muon neutrino events with energies below 100 TeV from the southern sky. The strategies utilize the outer detector regions as veto and features of the signal pattern to reduce the background of atmospheric muons to a level which, for the first time, allows IceCube searching for point-like sources of neutrinos in the southern sky at energies between 100 GeV and several TeV in the muon neutrino charged current channel. No significant clustering of neutrinos above background expectation was observed in four years of data recorded with the completed IceCube detector. Upper limits on the neutrino flux for a number of spectral hypotheses are reported for a list of astrophysical objects in the southern hemisphere

Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice

Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1(JRCSF) or the MSM-derived transmitted/founder (T/F) virus HIV-1(THRO) within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1(JRCSF) and HIV-1(THRO), respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1(JRCSF) and 0% (0/6; log rank p = 0.02) for HIV-1(THRO). This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides