Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort

STUDY FUNDING The data were collected by a Research into Ageing programme grant; research continues as part of the Age UK–funded Disconnected Mind project. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1), with funding from the BBSRC and Medical Research Council. Imaging and image analysis was performed at the Brain Research Imaging Centre (sbirc.ed.ac.uk/), Edinburgh, supported by the Scottish Funding Council SINAPSE Collaboration. Derivation of mean cortical thickness measures was funded by the Scottish Funding Council’s Postdoctoral and Early Career Researchers Exchange Fund awarded by SINAPSE to David Alexander Dickie. L.C.A.C. acknowledges funding from the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division.Peer reviewedPublisher PD

Synthesis of 1‑Deoxymannojirimycin from d‑Fructose using the Mitsunobu Reaction

Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route)

Cyclodehydration of <i>N</i>‑(Aminoalkyl)benzamides under Mild Conditions with a Hendrickson Reagent Analogue

Methods for the cyclodehydration of <i>N</i>-(aminoalkyl)­benzamides are few and employ harsh reaction conditions. We have found that the easily prepared phosphonium anhydrides <b>1</b> (Hendrickson reagent) or <b>2</b> can be used for cyclodehydration of <i>N</i>-(aminoalkyl)­benzamides under very mild conditions (room temperature) to produce five-, six-, and seven-membered cyclic amidines. Good yields are obtained by employing a temporary trityl group protection strategy. Cyclic analogue <b>2</b> can be used when the product cyclic amidine is organic-soluble, thus producing water-soluble byproducts

Formation of an Unusual Four-Membered Nitrogen Ring (Tetrazetidine) Radical Cation

Treatment of triphenylphosphine (Ph₃P) with an excess of diisopropyl azodicarboxylate at 0–25 °C resulted in the formation of a symmetrical tetraalkyl tetrazetidinetetracarboxylate radical cation, containing the elusive cyclic N₄ ring system. Electron paramagnetic resonance (EPR) spectroscopy revealed a 9-line spectrum, with hyperfine coupling constants indicative of four almost magnetically equivalent nitrogen atoms. The radical species was surprisingly long-lived, and could still be observed several hours after generation and standing at 25 °C. Expansion of the central resonance revealed further splitting into a pentet (hyperfine coupling to the four methine protons). Three mechanistically plausible structures containing the tetrazetidine substructure were proposed based on the 9-line EPR spectrum. Following DFT calculations, the predicted hyperfine coupling constants were used to simulate the EPR spectra for the three candidate structures. The combined calculations and simulations were consistent with a radical cation species, but not a radical anion or radical-carbenoid structure. The lowest energy conformation of the N₄ ring was slightly puckered, with the alkyl carboxylate groups all <i>trans</i> and the four carbonyl groups aligned in a pinwheel arrangement around the ring. Analogous results were obtained with the original Mitsunobu reagents, Ph₃P and diethyl azodicarboxylate, but not with Ph₃P and di-<i>tert</i>-butyl azodicarboxylate. A mechanism is proposed based on a radical version of the Rauhut–Currier or Morita–Baylis–Hillman reactions

Will Robots Take Your Job?

A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson’s patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson’s patient-derived cell lines

Total Synthesis of Thiaplakortone A: Derivatives as Metabolically Stable Leads for the Treatment of Malaria

Thiaplakortone A (<b>3a</b>), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds <b>3a</b>–<b>d</b> showed nanomolar activity against the chloroquine-sensitive (3D7) <i>Plasmodium falciparum</i> line and were more active against the chloroquine- and mefloquine-resistant (Dd2) <i>P. falciparum</i> line. All compounds are “Rule-of-5” compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product

Euodenine A: A Small-Molecule Agonist of Human TLR4

A small-molecule natural product, euodenine A (<b>1</b>), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. <b>1</b> is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like <b>1</b> could modulate the Th2 immune response without causing lung damage