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1.
Megan L. Qualls Dr. Jinchao Lou Dillon P. McBee Prof. Joshua A. Baccile Prof. Michael D. Best 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(45):e202201164
Liposomes are effective therapeutic delivery nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of therapeutics. Two primary areas in which improvement is needed for liposomal drug delivery is to enhance the ability to infiltrate cells and to facilitate derivatization of the liposome surface. Herein, we report a liposome platform incorporating a cyclic disulfide lipid (CDL) for the dual purpose of enhancing cell entry and functionalizing the liposome membrane through thiol-disulfide exchange. In order to accomplish this, CDL-1 and CDL-2 , composed of lipoic acid (LA) or asparagusic acid (AA) appended to a lipid scaffold, were designed and synthesized. A fluorescence-based microplate immobilization assay was implemented to show that these compounds enable convenient membrane decoration through reaction with thiol-functionalized small molecules. Additionally, fluorescence microscopy experiments indicated dramatic enhancements in cellular delivery when CDLs were incorporated within liposomes. These results demonstrate that multifunctional CDLs serve as an exciting liposome system for surface decoration and enhanced cellular delivery. 相似文献
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Jinchao Lou Megan L. Qualls Macy M. Hudson Dillon P. McBee Prof. Joshua A. Baccile Prof. Michael D. Best 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(46):e202201057
We report boronate-caged guanidine-lipid 1 that activates liposomes for cellular delivery only upon uncaging of this compound by reactive oxygen species (ROS) to produce cationic lipid products. These liposomes are designed to mimic the exceptional cell delivery properties of cell-penetrating peptides (CPPs), while the inclusion of the boronate cage is designed to enhance selectivity such that cell entry will only be activated in the presence of ROS. Boronate uncaging by hydrogen peroxide was verified by mass spectrometry and zeta potential (ZP) measurements. A microplate-based fluorescence assay was developed to study the ROS-mediated vesicle interactions between 1 -liposomes and anionic membranes, which were further elucidated via dynamic light scattering (DLS) analysis. Cellular delivery studies utilizing fluorescence microscopy demonstrated significant enhancements in cellular delivery only when 1 -liposomes were incubated with hydrogen peroxide. Our results showcase that lipid 1 exhibits strong potential as an ROS-responsive liposomal platform for targeted drug delivery applications. 相似文献
4.
Kevin Doyle Maxine Roberts Jenna Harvey Richard Hewer Matthias Zebisch Victor Rangel Meigang Gu Yiming Wu Lichao Yang Mark Carlton Lee Dawson Roland Bürli 《Helvetica chimica acta》2023,106(9):e202300080
Brain concentrations of nicotinamide adenine dinucleotide (NAD+), an important cellular co-factor, tend to decrease with age and in neurodegeneration. As the NADase cluster of differentiation 38 (CD38) significantly contributes to NAD+ consumption, we reasoned that CD38 inhibition may be of therapeutic value for CNS disorders. The new pyrazole compound was designed based on a known CD38 inhibitor and showed good inhibitory potency. Several attempts to co-crystallise this pyrazole with CD38 and cyclic adenosine diphosphate ribose (cADPR) culminated in a high-resolution X-ray structure, in which the pyrazolyl group in the new compound formed a covalent bond with one of the ribosyl units of cADPR. This reaction proceeded under retention of configuration and resulted in a neutral ribosyl-pyrazole conjugate that is embedded within the active site of the enzyme. An analysis of this structural complex gave rise to design principles that enabled the preparation of more potent CD38 inhibitors with drug-like properties. 相似文献
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Meighan I. Dillon 《代数通讯》2017,45(8):3515-3530
The ?-grading determined by a long simple root of a rank n+1 a?ne Lie algebra over ? arises from a representation of a rank n semi-simple complex Lie algebra. Analysis of the relationship between the grading and the representation yields constructions that generalize the minuscule and adjoint algorithms as well as Kac’s construction of nontwisted a?ne Lie algebras. 相似文献
7.
Ahmed M. Rozza Marcell Papp Neil R. McFarlane Prof. Jeremy N. Harvey Dr. Julianna Oláh 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(49):e202200930
The binding of small gas molecules such as NO and CO plays a major role in the signaling routes of the human body. The sole NO-receptor in humans is soluble guanylyl cyclase (sGC) – a histidine-ligated heme protein, which, upon NO binding, activates a downstream signaling cascade. Impairment of NO-signaling is linked, among others, to cardiovascular and inflammatory diseases. In the present work, we use a combination of theoretical tools such as MD simulations, high-level quantum chemical calculations and hybrid QM/MM methods to address various aspects of NO binding and to elucidate the most likely reaction paths and the potential intermediates of the reaction. As a model system, the H-NOX protein from Shewanella oneidensis (So H-NOX) homologous to the NO-binding domain of sGC is used. The signaling route is predicted to involve NO binding to form a six-coordinate intermediate heme-NO complex, followed by relatively facile His decoordination yielding a five-coordinate adduct with NO on the distal side with possible isomerization to the proximal side through binding of a second NO and release of the first one. MD simulations show that the His sidechain can quite easily rotate outward into solvent, with this motion being accompanied in our simulations by shifts in helix positions that are consistent with this decoordination leading to significant conformational change in the protein. 相似文献
8.
Abstract Intrareaction occurs between moieties attached to copolystyrene-2% divinylbenzene resin as used in solid phase synthesis even when only 0.5% of the phenyl residues are functionalized. Evidence for this interaction has been obtained from the dimeric products resulting from Dieckmann cyclization of resin bound sebacates and ω-cyanopelargonyl thiol resin esters, from kinetic and product data on radioactivity scrambling during the Dieckmann cyclization of uniquely singly labeled tertiary alkyl pimeloyl resin esters, and from anhydride formation with carboxymethyl resin. The extent to which site-site interactions can occur as a function of the percentage functionalization has been measured quantitatively by radiotracer studies on intraresin anhydride formation from carboxymethyl substituted resin. The synthesis and characterization of the resin bound re-actants is described, and the significance of these observations is discussed. 相似文献
9.
Variation in the position of CF3 groups in several aromatic Group‐14 compounds was studied by 19F‐NMR spectroscopy. In these compounds RnECl4?n (n=1 or 2; E=Si, Ge, or Sn; R=2,4,6‐(CF3)3C6H2 (=Ar), 2,6‐(CF3)2C6H3 (=Ar′), or 2,4‐(CF3)2C6H3 (=Ar″)), Ar, Ar′, and Ar″ are all bulky, strongly electron‐withdrawing ligands. The 19F‐NMR studies of the variation in position of the CF3 substituents in these compounds as revealed by chemical shifts could be correlated with the electronegativities of the central elements E, and with intramolecular E–F interactions derived from single‐crystal X‐ray diffraction data. These interactions are considered to play an important role in the stabilization of these compounds. 相似文献
10.
Zbyněk Brůža Dr. Jiří Kratochvíl Prof. Jeremy N. Harvey Dr. Lubomír Rulíšek Dr. Lucie Nováková Jana Maříková Dr. Jiří Kuneš Prof. Pavel Kočovský Prof. Milan Pour 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(34):8053-8060
Pyran-2-ones 3 undergo a novel Pd0-catalyzed 1,3-rearrangement to afford isomers 6 . The reaction proceeds via an η2-Pd complex, the pyramidalization of which (confirmed by quantum chemistry calculations) offers a favorable antiperiplanar alignment of the Pd−C and allylic C−O bonds ( C ), thus allowing the formation of an η3-Pd intermediate. Subsequent rotation and rate-limiting recombination with the carboxylate arm then gives isomeric pyran-2-ones 6 . The calculated free energies reproduce the observed kinetics semi-quantitatively. 相似文献