Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high‐pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.     

Nondestructive monitoring of the photochromic state of dithienylethene monolayers by surface plasmon resonance

The use of surface plasmon resonance (SPR) as a nondestructive, nonerasing readout of the isomerization state of a photochromic dithienylethene covalently linked to a chemically modified gold surface was investigated. Four different binding layers were examined: 11-mercaptoundecanol (MUO), an amine-modified 11-mercaptoundecanol (MUO-NH2), dextran, and an amine-modified dextran. The binding of dithienylethene to the modified gold surface and photoisomerization of the photochrome in the bound state were established by FTIR. Solvent effects were measured for every layer tested using ethanol and hexanes. In general, large, easily measurable SPR signal changes could be detected under conditions where photoisomerization of the dithienylethene photochrome was not quenched by the gold plasmon, establishing SPR as a viable form of readout for potential dithienylethene-based optical data storage or processing devices. Dextran-bound photochrome in ethanol exhibited the largest SPR response upon photoisomerization, but is more prone to time-dependent fluctuations resulting from swelling of the dextran layer (caused by slow diffusion of the solvent) than the other layers. Large responses are also provided by MUO-NH2 and MUO, and the signal is much more stable than that for dextran.     

Palladium-gold oxo complexes

Treatment of L2PdCl2(L2= 4,4-di-tert-butyl-2,2-bipyridine) with [(L'Au)3(mu3-O)]BF4(L'= PPh3) has yielded cationic oxo complexes with core formulas Pd2Au2O2 and Pd4AuO3 thereby doubling the number of structurally characterized Pd oxo complexes.     

Spontaneous emergence of membrane-forming protoamphiphiles from a lipid–amino acid mixture under wet–dry cycles

Dynamic interplay between peptide synthesis and membrane assembly would have been crucial for the emergence of protocells on the prebiotic Earth. However, the effect of membrane-forming amphiphiles on peptide synthesis, under prebiotically plausible conditions, remains relatively unexplored. Here we discern the effect of a phospholipid on peptide synthesis using a non-activated amino acid, under wet–dry cycles. We report two competing processes simultaneously forming peptides and N-acyl amino acids (NAAs) in a single-pot reaction from a common set of reactants. NAA synthesis occurs via an ester–amide exchange, which is the first demonstration of this phenomenon in a lipid–amino acid system. Furthermore, NAAs self-assemble into vesicles at acidic pH, signifying their ability to form protocellular membranes under acidic geothermal conditions. Our work highlights the importance of exploring the co-evolutionary interactions between membrane assembly and peptide synthesis, having implications for the emergence of hitherto uncharacterized compounds of unknown prebiotic relevance.

Synthesis of lipoamino acids via ester–amide exchange under prebiotically plausible wet-dry cycling conditions that results in vesicles at acidic pH.     

Arene ruthenium complexes incorporating immine/azine hybrid-chelating N-N donor ligands: synthetic, spectral, structural aspects and DFT studies

New series of mono and binuclear arene ruthenium complexes [{(η⁶-arene)RuCl(L)}]⁺ and [{(η⁶-arene)RuCl}₂(μ-L)₂]²⁺ (arene=benzene, p-cymene or hexamethylbenzene), {L=pyridine-2-carbaldehyde azine (paa), p-phenylene-bis(picoline)-aldimine (pbp) and p-bi-phenylene-bis(picoline)-aldimine (bbp)} are reported. The complexes have been fully characterized and molecular structure of the representative mononuclear complex [(η⁶-C₆Me₆)RuCl(paa)]BF₄ (1), binuclear complexes [{(η⁶-C₁₀H₁₄)RuCl}₂(μ-paa)](BF₄)₂ (3) and [{(η⁶-C₁₀H₁₄)RuCl}₂(μ-pbp)](BF₄)₂ (6) have been determined by single crystal X-ray diffraction analyses. Single crystal X-ray structure determination revealed that in the binuclear complexes the [(η⁶-C₁₀H₁₄)RuCl]⁺ units are trans disposed. Further, the crystal packing in the complexes 1, 3 and 6 is stabilized by C-H?X type (X=Cl, F) inter, intramolecular hydrogen bonding and π-π stacking (3). To explore the ambiguous nature of the bonding between pyridine-2-carbaldehyde azine (paa) with ruthenium containing units [(η⁶-arene)RuCl]⁺, DFT/B3LYP calculations have been performed on the complexes [(η⁶-arene)RuCl(paa)]⁺ (arene=C₆H₆, I; C₆Me₆, II; C₁₀H₁₄, III).     

An explicitly designed paratope of amyloid-β prevents neuronal apoptosis in vitro and hippocampal damage in rat brain

Synthetic antibodies hold great promise in combating diseases, diagnosis, and a wide range of biomedical applications. However, designing a therapeutically amenable, synthetic antibody that can arrest the aggregation of amyloid-β (Aβ) remains challenging. Here, we report a flexible, hairpin-like synthetic paratope (SP1, ∼2 kDa), which prevents the aggregation of Aβ monomers and reverses the preformed amyloid fibril to a non-toxic species. Structural and biophysical studies further allowed dissecting the mode and affinity of molecular recognition events between SP1 and Aβ. Subsequently, SP1 reduces Aβ-induced neurotoxicity, neuronal apoptosis, and ROS-mediated oxidative damage in human neuroblastoma cells (SH-SY5Y). The non-toxic nature of SP1 and its ability to ameliorate hippocampal neurodegeneration in a rat model of AD demonstrate its therapeutic potential. This paratope engineering module could readily implement discoveries of cost-effective molecular probes to nurture the basic principles of protein misfolding, thus combating related diseases.

Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically illuminated in vitro and in vivo against Aβ aggregation. The probe demonstrates remarkable potency for attenuating neurotoxicity and hippocampal damage.     

Joint analyses by laser-induced breakdown spectroscopy (LIBS) and Raman spectroscopy at stand-off distances

Raman spectroscopy and laser-induced breakdown spectroscopy (LIBS) of solid samples have both been shown to be feasible with sample-to-instrument distances of many meters. The two techniques are very useful together, as the combination of elemental compositions from LIBS and molecular vibrational information from Raman spectroscopy strongly complement each other. Remote LIBS and Raman spectroscopy spectra were taken together on a number of mineral samples including sulfates, carbonates and silicates at a distance of 8.3 m. The complementary nature of these spectra is highlighted and discussed. A factor of approximately 20 difference in intensity was observed between the brightest Raman line of calcite, at optimal laser power, and the brighter Ca I LIBS emission line measured with 55 mJ/pulse laser power. LIBS and Raman spectroscopy have several obstacles to devising a single instrument capable of both techniques. These include the differing spectral ranges and required detection sensitivity. The current state of technology in these areas is discussed.     

Highly efficient and selective biocatalytic acylation studies on triazolylsugars

Different acid anhydrides (of C₂ to C₇ aliphatic fatty acids and benzoic acid) have been used to study the selective acylation of primary/secondary hydroxyl groups in 2-phenyl-4-(d-threo-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-erythro-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-arabino-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole and 2-phenyl-4-(d-lyxo-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole in the presence of Candida antarctica lipase B in diisopropyl ether. Among the different acid anhydrides, butanoic anhydride was found to be the most efficient acylating agent (for butanoylation); for acetylation, vinyl acetate gave the best results. The reactions with both these acylating agents were highly selective and efficient yielding exclusively the monoacylated products in 95-99% yields in 1-5 h.     

Axially symmetric stationary solutions of Einstein-Maxwell equations

A scheme is presented by which we can obtain static electrovac exterior solutions from the stationary gravitational fields given by Kerr and Tomimatsu and Sato. A five-parameter solution of the combined Einstein-Maxwell equations is given that describes a source containing mass, electric charge, magnetic dipole, higher multipole moments of all three kinds and angular momentum. These are generated by using Kinnersley's method from Wang's electrovac solutions, which, in turn, were generated from the gravitational fields of Tomimatsu and Sato for =2–3. All the solutions are asymptotically flat.     

Ultrafast photoinduced charge separation in naphthalene diimide based multichromophoric systems in liquid solutions and in a lipid membrane

The photophysical properties of multichromophoric systems consisting of eight red or blue naphthalene diimides (NDIs) covalently attached to a p-octiphenyl scaffold, as well as a blue bichromophoric system with a biphenyl scaffold, have been investigated in detail using femtosecond time-resolved spectroscopy. The blue octachromophoric systems have been recently shown to self-assemble as supramolecular tetramers in lipid bilayer membranes and to enable generation of a transmembrane proton gradient upon photoexcitation ( Bhosale, S. ; Sisson, A. L. ; Talukdar, P. ; Fürstenberg, A. ; Banerji, N. ; Vauthey, E. ; Bollot, G. ; Mareda, J. ; R?ger, C. ; Würthner, F. ; Sakai, N. ; Matile, S. Science 2006, 313, 84 ). A strong reduction of the fluorescence quantum yield was observed when going from the single NDI units to the multichromophoric systems in methanol, the effect being even stronger in a vesicular lipid membrane. Fluorescence up-conversion measurements reveal ultrafast self-quenching in the multichromophoric systems, whereas the formation of the NDI radical anion, evidenced by transient absorption measurements, points to the occurrence of photoinduced charge separation. The location of the positive charge could not be established unambiguously from the transient absorption measurements, but energetic considerations indicate that charge separation should occur between two NDI units in the blue systems, whereas both an NDI unit and the p-octiphenyl scaffold could act as electron donor in the red system. The lifetime of the charge-separated state was found to increase from 22 to 45 ps by going from the bi- to the octachromophoric blue systems in methanol, while a 400 ps decay component was observed in the lipid membrane. This lifetime lengthening is explained in terms of charge migration that is most efficient when the octachromophoric systems are assembled as supramolecular tetramers in the lipid membrane. Furthermore, the average charge-separated state lifetime of the red system in methanol is even larger and amounts to 750 ps. This effect cannot be simply explained in terms of Marcus inverted regime as the driving force for charge recombination in the red system is only slightly larger than in the blue one. A better spatial separation of the charges in the red system stemming from the localization of the hole on the p-octiphenyl scaffold could additionally contribute to the slowing down of charge recombination.