Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation

Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H₂S), play a central role in cellular physiology and disease. Exogenously enhancing these species in cells is an emerging therapeutic paradigm for mitigating oxidative stress and inflammation that are associated with several diseases. In this study, we present a unique approach of using the cell''s own enzyme machinery coupled with an array of artificial substrates to enhance the cellular sulfane sulfur pool. We report the synthesis and validation of artificial/unnatural substrates specific for 3-mercaptopyruvate sulfurtransferase (3-MST), an important enzyme that contributes to sulfur trafficking in cells. We demonstrate that these artificial substrates generate persulfides in vitro as well as mediate sulfur transfer to low molecular weight thiols and to cysteine-containing proteins. A nearly 100-fold difference in the rates of H₂S production for the various substrates is observed supporting the tunability of persulfide generation by the 3-MST enzyme/artificial substrate system. Next, we show that the substrate 1a permeates cells and is selectively turned over by 3-MST to generate 3-MST-persulfide, which protects against reactive oxygen species-induced lethality. Lastly, in a mouse model, 1a is found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfides in vitro and in vivo using a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications.

A persulfide/hydrogen sulfide generation strategy through artificial substrates for 3-mercaptopyruvate sulfurtransferase (3-MST) is reported, which enhances cellular persulfides, attenuates reactive oxygen species (ROS), and alleviates inflammation.     

Syntheses,structures and electrochemistry of manganese(III) complexes derived from N,N′-o-phenylenebis(3-ethoxysalicylaldimine): Efficient catalyst for styrene epoxidation

Syntheses, characterizations, electrochemistry and catalytic properties for styrene epoxidation of three manganese(III) compounds [Mn^IIIL¹(H₂O)(MeOH)](ClO₄) (1) [Mn^IIIL¹(N₃)(H₂O)]·dmf (2) [Mn^IIIL¹(Cl)(H₂O)] (3) derived from the Schiff base compartmental ligand N,N′-o-phenylenebis(3-ethoxysalicylaldimine) (H₂L¹) are reported. The three compounds are characterized by elemental analyses, IR, mass and UV–Vis spectra and conductance values. Single crystal X-ray structures of 1 and 2 have been determined. The structures of 1 and 2 show that these are mononuclear compounds having a salen type structure. In both structures, a dinuclear species is formed by bifurcated hydrogen bonding involving coordinated water molecule. The coordination of chloride in 3 is shown by conductance measurements. The compounds have also been characterized by UV–Vis and mass spectroscopic studies. Cyclic voltammetric and square wave voltammetric studies of the three compounds reveal that these undergo Mn(III)/Mn(II) reduction reversibly with the order of the ease of reduction as 3 > 2 > 1. This order has been explained proposing the composition of active species in solution. Catalytic properties for epoxidation of styrene by all the three complexes using PhIO and NaOCl as oxidant have been studied. The order of both the styrene conversion and styrene epoxidation using the three title compounds is 3 > 1 > 2. Again, it has been observed that more efficient conversion and epoxidation take place when PhIO is used as oxidant.     

Cytotoxic prenylated xanthones from the young fruit of Garcinia mangostana

Three new prenylated xanthones, mangostenones C (1), D (2), and E (3), together with 16 known xanthones 4-19, were isolated from the young fruit (7-week maturity stage) of Garcinia mangostana. The structural elucidation of the new compounds was mainly established on the basis of 1D and 2D NMR and HR-MS spectroscopic analysis. Compound 1 showed cytotoxic properties against three human cancer cell lines, epidermoid carcinoma of the mouth (KB), breast cancer (BC-1), and small cell lung cancer (NCI-H187), with IC50 values of 2.8, 3.53, and 3.72 microg/ml, respectively. Among the isolates, alpha-mangostin (12), the major metabolite, exhibited the most potent effects against the BC-1 cells with an IC50 value of 0.92 microg/ml, an activity greater than that of the standard drug ellipticine (IC50 = 1.46 microg/ml). Compound 12 also showed the highest activity against KB cells, while gartanin (10) displayed the strongest activity against the NCI-H187 cells at the respective IC50 values of 2.08 microg/ml and 1.08 microg/ml.     

Bioactive constituents of the root bark of Artocarpus rigidus subsp. rigidus

Investigation of the chemical constituents of the root bark of Artocarpus rigidus BLUME subsp. rigidus has led to the isolation of six, structurally diverse phenolic compounds. These included two new compounds with modified skeletons, the flavonoid 7-demethylartonol E (1) and the chromone artorigidusin (2), together with four known phenolic compounds, the xanthone artonol B (3), the flavonoid artonin F (4), the flavonoid cycloartobiloxanthone (5), and the xanthone artoindonesianin C (6). Compounds 1, 4, and 5 exhibited antiplasmodial activity against Plasmodium falciparum. All compounds showed antimycobacterial activity against Mycobacterium tuberculosis, with 4 being the most active compound (MIC 6.25 microg/ml). Compounds 5 and 6 were active against KB cells, whereas 2, 5, and 6 showed varying toxicity to BC cells. Compounds 1-3, 5, and 6 were active in the NCI-H187 cytotoxicity assay, with 3 being the most active compound (IC(50) 1.26 microg/ml).     

Copper(I)-catalyzed regio- and chemoselective single and double addition of nucleophilic silicon to propargylic chlorides and phosphates

Copper(I)-catalyzed propargylic substitution of linear precursors with (Me(2)PhSi)(2)Zn predominantly yields the γ isomer independent of the propargylic leaving group. The thus formed allenylic silane reacts regioselectively with another equivalent of (Me(2)PhSi)(2)Zn, yielding a bifunctional building block with allylic and vinylic silicon groups. The reaction rates of both steps are well-balanced for chloride (γ:α ≥ 99:1) where the propargylic displacement occurs quantitatively prior to the addition step. Substitutions of α-branched propargylic phosphates are also reported.     

Synthesis of pyrrolo[1,2-f]phenanthridine-annulated polycyclic heterocycles from palladium-catalyzed intramolecular direct arylation reaction

Abstract  

A concise synthesis of pyrrolo[1,2-f]phenanthridine-annulated polycyclic heterocycles has been achieved in good yields by palladium-catalyzed intramolecular direct arylation reaction.     

Oxidation of 3,4-dihydroisoquinolinium salts with DMSO/conc HCl

3,4-Dihydroisoquinolinium salts can be oxidized to the corresponding isoquinolones by DMSO in conc HCl.     

Reductive Carbocyclization of Homoallylic Alcohols to syn‐Cyclobutanes by a Boron‐Catalyzed Dual Ring‐Closing Pathway

The organoborane‐catalyzed reductive carbocyclization of homoallylic alcohols has been developed by using hydrosilanes as reducing reagents to provide a range of 1,2‐disubstituted arylcyclobutanes. The reaction proceeds in a cis‐selective manner with high efficiency under mild conditions. Mechanistic studies, including deuterium scrambling and Hammett studies, and DFT calculations, suggest a dual ring‐closing pathway.