Kinetic Resolution in Asymmetric Epoxidation using Iminium Salt Catalysis

The first reported examples of kinetic resolution in epoxidation reactions using iminium salt catalysis are described, providing up to 99% ee in the epoxidation of racemic cis-chromenes

Formal synthesis of (+)-lactacystin from l-serine

A formal, stereocontrolled synthesis of lactacystin has been completed from t-Bu-O-l-serine, providing the key intermediate 13, also useful for the generation of a range of C-9 analogues

Asymmetric Oxidation of Enol Derivatives to α-Alkoxy Carbonyls Using Iminium Salt Catalysts: A Synthetic and Computational Study

We report herein the first examples of asymmetric oxidation of enol ether and ester substrates using iminium salt organocatalysis, affording moderate to excellent enantioselectivities of up to 98% ee for tetralone-derived substrates in the α-hydroxyketone products. A comprehensive density functional theory study was undertaken to interpret the competing diastereoisomeric transition states in this example in order to identify the origins of enantioselectivity. The calculations, performed at the B3LYP/6-31G(D) level of theory, gave good agreement with the experimental results, in terms of the magnitude of the effects under the specified reaction conditions, and in terms of the preferential formation of the (R)-enantiomer. Just one of the 30 characterized transition states dominates the enantioselectivity, which is attributed to the adoption of an orientation relative to stereochemical features of the chiral controlling element that combines a CH interaction between a CH 2 group in the substrate and one of the aromatic rings of the biaryl section of the chiral auxiliary with a good alignment of the acetoxy group with the other biaryl ring, and places the smallest substituent on the alkene (a hydrogen atom) in the most sterically hindered position

Synthesis and activity of a novel Autotaxin inhibitor-Icodextrin conjugate

© Copyright 2018 American Chemical Society. Autotaxin is an extracellular phospholipase D that catalyses the hydrolysis of lysophosphatidyl choline (LPC) to generate the bioactive lipid lysophosphatidic acid (LPA). Autotaxin has been implicated in many pathological processes relevant to cancer. Intraperitoneal administration of an autotaxin inhibitor may benefit patients with ovarian cancer, however low molecular mass compounds are known to be rapidly cleared from the peritoneal cavity. Icodextrin is a polymer that is already in clinical use because it is slowly eliminated from the peritoneal cavity. Herein we report conjugation of the autotaxin inhibitor HA-155 to icodextrin. The conjugate inhibits autotaxin activity (IC50 = 0.86 ± 0.13 μg mL-1) and reduces cell migration. Conjugation of the inhibitor increased its solubility, decreased its membrane permeability and improved its intraperitoneal retention in mice. These observations demonstrate the first application of icodextrin as a covalently-bonded drug delivery platform with potential use in the treatment of ovarian cancer

CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?

The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy

New biphenyl iminium salt catalysts for highly enantioselective asymmetric epoxidation: role of additional substitution and dihedral angle

New biaryl iminium salt catalysts for enantioselective alkene epoxidation containing additional substitution in the heterocyclic ring are reported. The effects upon conformation and enantioselectivity of this additional substitution, and the influence of dihedral angle in these systems, has been investigated using a synthetic approach supported by density functional theory. Enantioselectivities of up to 97% ee were observed

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways