Convenient preparations of racemic and enantiopure methyl 6-oxopipecolate

Short, convenient syntheses of racemic and enantiopure methyl 6-oxopipecolate are described, starting from either pipecolic acid or (S)-lysine respectively. The sequence for the latter compound relies upon improved methodology for the oxidation of C-6 of lysine.     

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a set of four chiral α,β-unsaturated esters (derived from d-pentoses) as one of the key steps. A full account of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intramolecular reductive amination reaction was then used to create the corresponding enantiopure pyrrolidines, providing access to (2′S,3′S,4′R)-dihydroxyhomoproline and (2′S,3′R,4′S)-dihydroxyhomoproline after deprotection.     

Monte Carlo characterisation of a Compton suppressed broad-energy HPGe detector

GEANT4 Monte Carlo simulations have been successfully utilised to characterise a Compton suppressed broad-energy HPGe detector. The detector setup has been fully recreated in the simulation, which has been optimised to consistently reproduce the detector response. The peak efficiencies for both the primary BEGe detector and NaI(Tl) guard detectors agree with the simulated values for multiple test sources within 3 %. Compton suppression has also been simulated, with good agreement seen between the simulated and actual CSF values (<10 %) for multiple radionuclides. A secondary reference source was also simulated, which contained up to 30 radionuclides in a different geometry to that of the previous source. This showed excellent agreement with experimental data in both unsuppressed and suppressed modes of operation.     

A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice

Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these effects are limited by P-glycoprotein (Pgp/ABCB1) efflux. The current study tested the hypothesis that dihydromyricetin (DHM), a natural product suggested to inhibit Pgp, will enhance IVM potency as measured by changes in EtOH consumption. Using a within-subjects study design and two-bottle choice study, we tested the combination of DHM (10 mg/kg; i.p.) and IVM (0.5–2.5 mg/kg; i.p.) on EtOH intake and preference in male and female C57BL/6J mice. We also conducted molecular modeling studies of DHM with the nucleotide-binding domain of human Pgp that identified key binding residues associated with Pgp inhibition. We found that DHM increased the potency of IVM in reducing EtOH consumption, resulting in significant effects at the 1.0 mg/kg dose. This combination supports our hypothesis that inhibiting Pgp improves the potency of IVM in reducing EtOH consumption. Collectively, we demonstrate the feasibility of this novel combinatorial approach in reducing EtOH consumption and illustrate the utility of DHM in a novel combinatorial approach.     

Real-time detection of DNA interactions with long-period fiber-grating-based biosensor

Using an optical biosensor based on a dual-peak long-period fiber grating, we have demonstrated the detection of interactions between biomolecules in real time. Silanization of the grating surface was successfully realized for the covalent immobilization of probe DNA, which was subsequently hybridized with the complementary target DNA sequence. It is interesting to note that the DNA biosensor was reusable after being stripped off the hybridized target DNA from the grating surface, demonstrating a function of multiple usability.     

A Microfluidic Co-Flow Route for Human Serum Albumin-Drug–Nanoparticle Assembly

Nanoparticles are widely studied as carrier vehicles in biological systems because their size readily allows access through cellular membranes. Moreover, they have the potential to carry cargo molecules and as such, these factors make them especially attractive for intravenous drug delivery purposes. Interest in protein-based nanoparticles has recently gained attraction due to particle biocompatibility and lack of toxicity. However, the production of homogeneous protein nanoparticles with high encapsulation efficiencies, without the need for additional cross-linking or further engineering of the molecule, remains challenging. Herein, we present a microfluidic 3D co-flow device to generate human serum albumin/celastrol nanoparticles by co-flowing an aqueous protein solution with celastrol in ethanol. This microscale co-flow method resulted in the formation of nanoparticles with a homogeneous size distribution and an average size, which could be tuned from ≈100 nm to 1 μm by modulating the flow rates used. We show that the high stability of the particles stems from the covalent cross-linking of the naturally present cysteine residues within the particles formed during the assembly step. By choosing optimal flow rates during synthesis an encapsulation efficiency of 75±24 % was achieved. Finally, we show that this approach achieves significantly enhanced solubility of celastrol in the aqueous phase and, crucially, reduced cellular toxicity.