Dithioacetal Research Articles

Reactive Oxygen Species-Responsive Pillararene-Embedded Covalent Organic Frameworks with Amplified Antimicrobial Photodynamic Therapy for the Targeted Elimination of Periodontitis Pathogens.

Reactive oxygen species (ROS)-responsive drug delivery systems possess immense potential for targeted delivery and controlled release of therapeutics. However, the rapid responsiveness to ROS and sustained release of antibacterial drugs are often limited by the challenging microenvironment of periodontitis. Integrating ROS-responsive drug delivery systems with photocatalytic technologies presents a strategic approach to overcome these limitations. Herein, a pillararene-embedded covalent organic framework (PCOF) incorporating the antibacterial prodrug thioacetal (TA) has been developed to treat periodontitis. This drug-loaded nanoplatform, namely TA-loaded PCOF, utilizes the self-amplifying ROS property to enhance therapeutic efficacy. PCOFs demonstrate exceptional photosensitivity and ROS generation capabilities when employed as drug carriers. When exposed to ROS, TA within the nanoplatform was activated and cleaved into cinnamaldehyde (CA), a highly potent antibacterial compound. By leveraging visible light to activate the site-specific infection targeting, TA-loaded PCOF effectively alleviated periodontitis, thereby advancing the field of antibacterial drug delivery systems.

A Thioether‐Bridging Surface Modification of Polymeric Microspheres Offers Nonbiological Protein A‐Mimetic Affinity for IgG

AbstractSurface modification of polymeric materials to control their interaction with proteins has been studied extensively, leading to widespread bio‐applications. However, the development of nonbiological, smart polymer surfaces, mimicking the recognition ability of biomolecules, remains a challenge. The present study presents a thioether‐bridging surface modification of polymeric microspheres as a new approach for mimicking protein A affinity for immunoglobulin G (IgG). The bridge‐modified surface is created through an epoxide linking reaction of porous polymeric microspheres with potassium thioacetate in a 2:1 molar ratio, acting as a protein A ligand, which is essential for industrial IgG purification. This surface exhibits buffer responsiveness and selective high‐affinity binding to the IgG Fc region. Remarkably, a comparison among the binding behaviors of a series of thioether‐modified microspheres indicates that bridging structures composed of β,β′‐dihydroxysulfide play a predominant role in IgG recognition. This straightforward approach can lead to the development of economical and practical nonbiological alternatives to protein A‐conjugated materials, providing solutions for various applications such as biosensors and site‐specific reagents utilizing the affinity of the IgG Fc region. The improved understanding of protein interactions at bridged/non‐bridged interfaces can be valuable in various applications such as implant materials and biomaterials.

PH-Responsive Micellar Nanoparticles for the Delivery of a Self-Amplifying ROS-Activatable Prodrug.

The objective of this study is to enhance the therapeutic efficacy of the anticancer drug, camptothecin (CPT) via a nanoparticle (NP) formulation using a novel amphiphilic biopolymer. We have designed a dimeric prodrug of CPT with the ability to self-amplify and respond to reactive oxygen species (ROS). For this, we incorporated the intracellular ROS generator cinnamaldehyde into a ROS-cleavable thioacetal (TA) linker to obtain the dimeric prodrug of CPT (DCPT(TA)). For its efficient NP delivery, a pH-responsive block copolymer of acetalated dextran and poly(2-ethyl-2-oxazoline) (AcDex-b-PEOz) was synthesized. The amphiphilic feature of the block copolymer enables its self-assembly into micellar NPs and results in high prodrug loading capacity and a rapid release of the prodrug under acidic conditions. Upon cellular uptake by HeLa cells, DCPT(TA)-loaded micellar NPs induce intracellular ROS generation, resulting in accelerated prodrug activation and enhanced cytotoxicity. These results indicate that this system holds significant potential as an effective prodrug delivery strategy in anticancer treatment.

A Comparative Kinetic and Computational Investigation of the Carbon‐Sulfur Cross Coupling of Potassium Thioacetate and 2‐Bromo Thiophene Using Palladium/Bisphosphine Complexes

AbstractWe conducted an investigation into the palladium‐catalyzed carbon‐sulfur cross‐coupling reaction involving a 2‐bromothiophene derivative and potassium thioacetate as a substitute for hydrogen sulfide. This investigation utilized kinetic and computational methods. We synthesized two palladium complexes supported by the bisphosphane ligands bis(diphenylphosphino)ferrocene (DPPF) and bis(diisopropylphosphino)ferrocene (DiPPF), as well as their tentative intermediates in the catalytic cycle. Reaction rates were measured and then compared to computational predictions.

N-Terminal Proline Editing for the Synthesis of Peptides with Mercaptoproline and Selenoproline: Mechanistic Insights Lead to Greater Efficiency in Proline Native Chemical Ligation.

Native chemical ligation (NCL) at proline has been limited by cost and synthetic access. In addition, prior examples of NCL using mercaptoproline have exhibited stalling of the reaction after thioester exchange, due to inefficient S → N acyl transfer. Herein, we develop methods, using inexpensive Boc-4R-hydroxyproline, for the solid-phase synthesis of peptides containing N-terminal 4R-mercaptoproline and 4R-selenoproline. The synthesis proceeds via proline editing on the N-terminus of fully synthesized peptides on the solid phase, converting an N-terminal Boc-4R-hydroxyproline to the 4S-bromoproline, followed by an SN2 reaction with potassium thioacetate or selenobenzoic acid. After cleavage from the resin and deprotection, peptides with functionalized N-terminal proline amino acids were obtained. NCL reactions with mercaptoproline proceeded slowly under standard NCL conditions, with the S-acyl transthioesterification intermediate observed as a major species. Computational investigations indicated that the bicyclic intermediates and transition states for S → N acyl transfer are sufficiently low in energy (10-15 kcal mol-1 above starting material) that ring strain cannot explain the slow S → N acyl transfer. Instead, the bicyclic zwitterionic tetrahedral intermediate has a low barrier for reversion to the S-acyl intermediate, causing reversion to the thioester (reverse reaction) to occur preferentially over elimination to generate the amide (forward reaction). We hypothesized that a buffer capable of general acid and/or general base catalysis could promote S → N acyl transfer and thus achieve greater efficiency in proline NCL. In the presence of 2 M imidazole at pH 6.8, NCL with mercaptoproline proceeded efficiently to generate the peptide with a native amide bond. NCL with selenoproline also proceeded efficiently to generate the desired products when a thiophenol thioester was employed as a ligation partner. After desulfurization or deselenization, the products obtained were identical to those synthesized directly, confirming that the solid-phase proline editing reactions proceeded stereospecifically and without epimerization.

New synthetic strategy to create intricate thiaoxacyclophanes via ring‐closing metathesis

AbstractThis study explores a thiol‐free, two‐step synthetic strategy to intricate thiacyclophanes from bromoaryl precursors. Our methodology involves a one‐pot substitution reaction of aryl bromides with potassium thioacetate (PTA) followed by ring‐closing metathesis (RCM). Potassium thioacetate is advantageous over other sulfur‐containing reagents like sodium sulfide, sodium hydrosulfide, and sodium hydroxymethylsulfinate (rongalite), etc., as it generates a stable and odorless thioacetate intermediate which allows access to a variety of symmetrical and unsymmetrical sulfides. These sulfides undergo RCM to generate new thiacyclophanes. Applying this methodology, we have created 24 new oxa‐thiacyclophanes and aza‐oxa‐thiacyclophanes containing different aromatic and aliphatic units. The structures and stereochemistry of these cyclophanes are confirmed by NMR data and further supported by single‐crystal X‐ray diffraction data.

Thiol-free multicomponent synthesis of non-racemic β-acyloxy thioethers from biocatalytically obtained chiral halohydrins.

A novel multicomponent chemoenzymatic strategy for the preparation of enantioenriched β-acyloxy thioethers has been developed. This robust methodology employs mild bases, air atmosphere, room temperature and avoids the use of foul-smelling thiols. Instead, potassium thioacetate is employed as a universal sulfur source. This chemoselective strategy tolerates aromatic and aliphatic components and diverse functional groups. The chirality is enzymatically defined by ADH-catalyzed bioreduction of α-haloketones delivering an enantioenriched halohydrin which is one of the three components, and the optical purity remains untouched in the final product. Semipreparative scale multicomponent reaction affords high yield of the products (up to 96%).

Metal‐Free Regioselective 1,6‐Conjugate Addition of Sulfide to para‐Quinone Methides: Simple Access to E‐Selective Thiaoxacyclophanes

AbstractWe realized a simple approach involving the 1,6‐conjugate addition (regioselective thiolation) of para‐quinone methides (p‐QMs) with easily available thio‐based nucleophiles. Through ring‐closing metathesis (RCM), this procedure delivered a variety of para‐ and meta‐thiaoxacyclophanes as E‐isomers in good yields. A simple thiol‐free one‐pot approach is reported for the direct synthesis of sulfides and sulfones under green reaction conditions without the use of any metal catalysts. Low‐cost and easily accessible compounds such as p‐QMs and benzyl bromides are used as starting materials in the presence of potassium thioacetate (PTA) and Oxone®. Novel thiaoxacyclophanes were assembled in three simple steps including conjugate addition of PTA, Grignard addition, and RCM sequence.

Multicomponent Selective Thioetherification of KSAc: Easy Access to Symmetrical/Unsymmetrical 4‐Alkylthio‐3‐halo‐2(5H)‐furanones

AbstractAn easy two‐/three‐component selective thioetherification of KSAc for the synthesis of a series of symmetrical/unsymmetrical 4‐alkylthio‐3‐halo‐2(5H)‐furanones has been described. The reaction without any metal catalyst or additive is carried out in air atmosphere at room temperature for 5 h, only using potassium thioacetate as an odourless sulfur source and a base simultaneously. The broad substrate scope and high yield make it important for the studies on both constructing C−S bond based on non‐aryl Csp2−X bond and synthesizing new 2(5H)‐furanone functional molecules.

Thiol‐Free E‐Selective Approach to Dithiacyclophanes via Ring‐Closing Metathesis

AbstractApplication of cyclophanes is well‐established in molecular recognition, supramolecular chemistry and material science. Here, we assembled novel [6,6], [8,6] and [6,3,3] dithiacyclophanes by using three facile steps involving potassium thioacetate, Grignard reagent and ring‐closing metathesis (RCM). This strategy provides E‐isomers of orthometa‐, orthopara‐, meta‐ and paradithiacyclophane derivatives selectively by RCM. Sulfur‐based precursors (dithiadiformyl compound) are prepared from bromomethyl benzaldehydes instead of thiols as starting materials. The structure of dithiacyclophanes are confirmed unambiguously by single‐crystal X‐ray diffraction studies and the distinguishing structural features in isomers of cyclophanes are discussed.

Engineering doping and defect in graphitic carbon nitride by one-pot method for enhanced photocatalytic hydrogen evolution

Hydrogen energy, as one clean energy, is one of the important ways to decarbonize in the future. The advancement of doping and constructing defect engineering in graphitic carbon nitride (g-C3N4) show promise for artificial photosynthesis for H2 evolution using solar energy. Unfortunately, it is still difficult to generate g-C3N4 that has been co-modified by doping and defect and investigate their synergistic effects. In this study, potassium thioacetate was used first-time as a potassium source and dehydrogenation agent to prepare g-C3N4 decorated by K+ ions and cyano groups with enhanced H2 evolution by a one-step method in an air atmosphere. The presence of K+ ions can increase the density of electron clouds in the delocalized π bond of the heptazine ring. The cyano group may successfully delocalize the solitary valence electrons in conjugated heterocycles since it is a potent electron-withdrawing group. These outcomes allow the modified catalysts to achieve improved H2 evolution activity, reduced interfacial transfer resistance, and increased light absorption and photocurrent. Finally, K(0.05)-CN's photocatalytic hydrogen evolution rate (HER) rose to 1319 μmol h−1 g−1, which is five-fold better than that of CN, and the normalized HER reached 118 μmol h−1 m−2, which was much higher than other reports. This research not only offers a fresh approach to creating photocatalysts with good H2 evolution efficiency but also advances a deep understanding of how structural defects and alkali metal doping affect photocatalytic activity.

Self-amplified chain-shattering cinnamaldehyde-based poly(thioacetal) boosts cancer chemo-immunotherapy

The selective activation of stimuli-responsive polymers in the tumor microenvironment is a great concern to achieve intelligent cancer therapy, but most of them show inadequate response due to insufficient endogenous triggering agents. Herein, we rationally designed a reactive oxygen species (ROS)-responsive cinnamaldehyde (CA)-based poly(thioacetal), consisting of ROS-responsive thioacetal (TA) and ROS-generating agent CA, with self-amplified chain-shattering polymer degradation. The mechanism of self-amplified chain-shattering is that endogenous ROS as a triggering agent facilitates chain cleavage of TA with the release of CA, which in turn produces more ROS through mitochondrial dysfunction, resulting in an exponential polymer degradation cascade. The polymer can be further modified with anticancer drug doxorubicin (DOX) for cooperative amplification of oxidative stress and immunogenic cell death (ICD) of tumor cells, thereby boosting the effect of chemo-immunotherapy. The self-amplified chain-shattering polymer designed in this work holds great promise in developing stimuli-responsive polymers for efficient drug delivery. Statement of significanceThis study presented an approach to utilize self-amplified chain-shattering cinnamaldehyde-based poly (thioacetal) as a drug delivery system to restrain tumor growth and boost chemo-immunotherapy. The endogenous ROS as a triggering agent initiates the chain cleavage with the release of CA, which in turn produces ROS through mitochondria dysfunction, resulting in an exponential polymer degradation cascade and rapid drug release.

Cinnamaldehyde-based poly(thioacetal): A ROS-awakened self-amplifying degradable polymer for enhanced cancer immunotherapy

Although stimuli-responsive polymers have emerged as promising strategies for intelligent cancer therapy, limited polymer degradation and insufficient drug release remain a challenge. Here, we report a novel reactive oxygen species (ROS)-awakened self-amplifying degradable cinnamaldehyde (CA)-based poly(thioacetal) polymer. The polymer consists of ROS responsive thioacetal (TA) group and CA as the ROS generation agent. The self-amplified polymer degradation process is triggered by endogenous ROS-induced cleavage of the TA group to release CA. The CA released then promotes the generation of more ROS through mitochondrial dysfunction, resulting in amplified polymer degradation. More importantly, poly(thioacetal) itself can trigger immunogenic cell death (ICD) of the tumor cells and its side chains can be conjugated with indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor to reverse the immunosuppressive tumor microenvironment for synergistic cancer immunotherapy. The self-amplified degradable poly(thioacetal) developed in this work provides insights into the development of novel stimulus-responsive polymers for enhanced cancer immunotherapy.

CO2 -Promoted Direct Acylation of Amines and Phenols by the Activation of Inert Thioacid Salts.

Herein a carbon dioxide-promoted synthetic approach for the direct amidation between unactivated thioacid salts and amines under mild conditions was developed for a wide range of substrates. The method afforded amides in good to excellent yields under transition-metal-free and activation-reagent-free conditions, in sharp contrast to early methodologies on amide synthesis based on transition-metal catalysis. The method offered a greener and transition metal-free protocol applicable to pharmaceuticals preparations. Phenolic compounds were also found to be suitable acylation substrates with potassium thiosulfide KHS as the only byproduct. Moreover, this approach was applied to amide synthesis of valuable bio-active molecules such as moclobemide, melatonin, and a fungicide. Insights into the reaction mechanism involving carbon dioxide were provided through NMR spectroscopy and computational calculations. A plausible mechanism was proposed that involves weak interactions between carbon dioxide and potassium thioacetate in a dynamic equilibrium state formation of a six-membered ring.

Establishing the Reaction Pathways of the Catalytic Conversion of Erythrulose to Sulphides of Alpha‐Hydroxy Thioesters and Esters

AbstractSulphides of alpha‐hydroxy thioesters and esters (SAH(T)Es) are important fine chemicals and have great potential as platform molecules. SAH(T)Es are typically synthesized from fossil sources while little is known regarding their synthesis from carbohydrates. We report our findings about the one‐pot chemocatalytic conversion of erythrulose (ERU) to SAH(T)Es. Sn, Mo and W chlorides were the most selective catalysts towards the synthesis of S‐butyl‐4‐butylthio‐2‐hydroxybutanethioate (BBTHBT) in 1‐BuSH. The selectivity towards BBTHBT was impacted by the formation of different thioacetals (TAs). The addition of either KOH, H2O or MeOH was effective to decrease TAs formation and increase selectivity towards BBTHBT (or its ester). A kinetic profile, in situ 13C NMR measurements and experiments at different temperatures complement our studies to unravel the complicated reaction network involved in the conversion of ERU to SAH(T)Es. This insight provides a solid foundation for future improvements in the sustainable synthesis of SAH(T)Es.

Efficient linking of two epoxides using potassium thioacetate in water and its use in polymerization.

Here, we show that two epoxides can be efficiently linked using potassium thioacetate (AcSK) in water even at their imbalanced stoichiometric ratios. We found that the first reaction between epoxide and AcSK gave rise to an intermediate that underwent the second reaction with another epoxide with a reactivity much higher than that of AcSK. Time-dependent 1H NMR measurements revealed that the rate constant of the second reaction was 31 times larger than that of the first reaction. Using this reaction, we succeeded in nonstoichiometric polymerization of a bifunctional epoxide. Furthermore, in the presence of a multifunctional epoxide, we obtained hydrogels and self-standing films. We expect that this straightforward and efficient reaction of versatile reagents, epoxide and AcSK, in water would lead to new applications of epoxides.

Improved Synthesis of 1‐Glycosyl Thioacetates and Its Application in the Synthesis of Thioglucoside Gliflozin Analogues

AbstractAn improved method to synthesize 1‐glycosyl thioacetates was developed, where per‐O‐acetylated glycoses were allowed to directly react with potassium thioacetate (KSAc) in the presence of BF3 ⋅ Et2O in ethyl acetate under mild conditions. This method not only overcomes the disadvantage of the traditional one‐step method, which is that the odorous and toxic thioacetic acid has to be used, but also overcomes the disadvantage of the traditional two‐step method, which is that the unstable intermediate, glycosyl halide, has to be synthesized from the per‐O‐acetylated glycose in advance. Based on this, the per‐O‐acetylated glucosyl disulfide and the per‐O‐acetylated glucosyl 1‐thiol were efficiently synthesized in high yields (91 % and 90 % respectively) starting from per‐O‐acetylated glycoses in two‐step without the need to isolate intermediate products. Through metal‐catalyzed cross‐coupling of per‐O‐acetylated glucosyl 1‐thiol with aryl‐iodide under very mild conditions, two thioglucoside gliflozin analogues were efficiently synthesized in high yields for the first time. These two thioglucoside gliflozin analogues were further confirmed to be stable to hydrolysis of β‐glucosidase.

Porous [Ru(bpy)3]2+-Cored Metallosupramolecular Polymers: Preparation and Recyclable Photocatalysis for the Formation of Amides and 2-Diazo-2-phenylacetates

A covalently bonded three-dimensional [Ru(bpy)3]2+-cored metallosupramolecular polymer (MSP-CB[8]-c) has been prepared from a noncovalently bonded metallosupramolecular polymer (MSP-CB[8]-nc) through cucurbit[8]uril (CB[8])-promoted [2 + 2] photodimerization of the ethylene units. Both MSPs function well as heterogeneous photocatalysts for visible light-induced amidation of aromatic amines with potassium thioacetate and the C–H diazomethylation of arenes with a benziodoxolone, and MSP-CB[8]-c exhibits increased catalytic activity than MSP-CB[8]-nc or a CB[8]-free metallosupramolecular polymer (MSP-c). For both kinds of reactions, the catalytic activity of the [Ru(bpy)3]2+ unit of MSP is comparable with that obtained by homogeneous prototypic Ru(bpy)3Cl2 or Ru(bpy)3(PF6)2 due to its porosity but allows for remarkable recyclability and can be reused 12 times while maintaining a considerable activity.

S‐doped 3D porous carbons derived from potassium thioacetate activation strategy for zinc‐ion hybrid supercapacitor applications

Aqueous zinc-ion hybrid supercapacitors (ZHSCs) emerge as a promising option for green energy storage in recent years. However, development of reliable carbon-based cathodes remains a challenge. Herein, an effective potassium thioacetate activation technique has been promoted for the producing of S-doped 3D porous carbons (S-3DPCs) by employing sustainable pine needles as the carbon source without any additives. Different from the previously reported routes, the potassium thioacetate can serve as the activator as well as the S source. The resulting S-3DPCs display a unique 3D architecture with a large specific surface area, a certain amount of sulfur (~0.88-3.60 at%), which enables S-3DPCs to exhibit excellent electrochemical performance as the cathodes for ZHSCs. Particularly, S-3DPC-800 (pyrolysis at 800) can deliver a large specific capacity of 203.3 mAh g−1 (the volumetric capacity is 123.8 mAh cm−3) in 2 M ZnSO4 at 0.2 A g−1, high rate performance, and outstanding cyclic durability. Moreover, S-3DPC-800-based ZHSCs can possess the maximum energy density up to 162.6 Wh kg−1 (99.0 Wh L−1) at a power density of 160 W kg−1 (97.4 W L−1), which suggests the significant potential of S-3DPCs as the robust cathodes for ZHSCs. This facile potassium thioacetate activation strategy points toward a new way to develop S-doped 3D porous carbon cathodes for high performances ZHSCs applications.

A Facile and Highly Efficient Route to Amphiphilic Star-Like Rod-Coil Block Copolymer via a Combination of Atom Transfer Radical Polymerization with Thiol-Ene Click Chemistry.

With a combination of atom transfer radical polymerization (ATRP), quasi-living Grignard metathesis method, and thiol-ene click reaction, an amphiphilic star-like rod-coil diblock copolymer poly(acrylic acid)-block-poly(3-hexylthiophene) comprising 21-arm inner coil-like PAA blocks and outer rod-like conjugated polymer poly(3-hexylthiophene) (P3HT) blocks with well-defined molecular structures and narrow molecular weight distribution is synthesized. First, the bromide end-groups of 21-arm star-like ATRP coil polymers PtBA-Br are converted successfully into reactive thioacetate end groups by post-functionalization using potassium thioacetate. Subsequently, 21-arm star-like coil polymers PtBA-SCOCH3 react with rod-like vinyl-functionalized P3HT to yield functional star-like rod-coil diblock copolymers PtBA-b-P3HT via thiol-ene click reaction, followed by selective hydrolysis of inner PtBA block into PAA block. The present synthetic approach enables the construction of well-defined star-like conformation with few structural limitations in a facile and highly efficient manner due to the robust and orthogonal nature of the thiol-ene click reaction. It may be extended to produce block copolymers with other topologies, such as cylindrical, hyperbranched, and dendritic structures.