Temporal (Dis)Assembly of Peptide Nanostructures Dictated by Native Multistep Catalytic Transformations.

Emergence of complex catalytic machinery via simple building blocks under non-equilibrium conditions can contribute toward the system level understanding of the extant biocatalytic reaction network that fuels metabolism. Herein, we report temporal (dis)assembly of peptide nanostructures in presence of a cofactor dictated by native multistep cascade transformations. The short peptide can form a dynamic covalent bond with the thermodynamically activated substrate and recruit cofactor hemin to access non-equilibrium catalytic nanostructures (positive feedback). The neighboring imidazole and hemin moieties in the assembled state rapidly converted the substrate to product(s) via a two-step cascade reaction (hydrolase-peroxidase like) that subsequently triggered the disassembly of the catalytic nanostructures (negative feedback). The feedback coupled reaction cycle involving intrinsic catalytic prowess of short peptides to realize the advanced trait of two-stage cascade degradation of a thermodynamically activated substrate foreshadows the complex non-equilibrium protometabolic networks that might have preceded the chemical emergence of life.

Photoelectrochemical Solution Gated Graphene Field-Effect Transistor Functionalized by Enzymatic Cascade Reaction for Organophosphate Detection.

Solution Gated Graphene Field-Effect Transistors (SGGT) are eagerly anticipated as an amplification platform for fabricating advanced ultra-sensitive sensors, allowing significant modulation of the drain current with minimal gate voltage. However, few studies have focused on light-matter interplay gating control for SGGT. Herein, this challenge is addressed by creating an innovative photoelectrochemical solution-gated graphene field-effect transistor (PEC-SGGT) functionalized with enzyme cascade reactions (ECR) for Organophosphorus (OPs) detection. The ECR system, consisting of acetylcholinesterase (AChE) and CuBTC nanomimetic enzymes, selectively recognizes OPs and forms o-phenylenediamine (oPD) oligomers sediment on the PEC electrode, with layer thickness related to the OPs concentration, demonstrating time-integrated amplification. Under light stimulation, the additional photovoltage generated on the PEC gate electrode is influenced by the oPD oligomers sediment layer, creating a differentiated voltage distribution along the gate path. PEC-SGGT, inherently equipped with built-in amplification circuits, sensitively captures gate voltage changes and delivers output with an impressive thousandfold current gain. The seamless integration of these three amplification modes in this advanced sensor allows a good linear range and highly sensitive detection of OPs, with a detection limit as low as 0.05 pm. This work provides a proof-of-concept for the feasibility of light-assisted functionalized gate-controlled PEC-SGGT for small molecule detection.

Hauser-Kraus Annulation Initiated Multi-Cascade Reactions for Facile Access to Functionalized and Fused Oxazepines, Carbazoles and Phenanthridinediones.

The Hauser-Kraus (H-K) annulation of N-unsubstituted 3-olefinic oxindoles with 3-nucleophilic phthalides triggers a cascade of ring expansion and ring contraction reactions through several regioselective steps in one pot. While oxazepines were isolated in the presence of stoichiometric amounts of base at room temperature, carbazoles and phenanthridinediones were the products in the presence of excess base and microwave irradiation. Mechanistic studies guided by stepwise reactions and control experiments revealed that the isolable oxazepine intermediate, formed via ring expansion of the H-K adduct, is the key precursor to carbazole and phenanthridinedione via decarboxylative regioselective cyclizations.

Poly(ferrocenylsilane)-Based Redox-Active Artificial Organelles for Biomimetic Cascade Reactions.

Artificial organelles serve as functional counterparts to natural organelles, which are primarily employed to artificially replicate, restore, or enhance cellular functions. While most artificial organelles exhibit basic functions, we diverge from this norm by utilizing poly(ferrocenylmethylethylthiocarboxypropylsilane) microcapsules (PFC MCs) to construct multifunctional artificial organelles through water/oil interfacial self-assembly. Within these PFC MCs, enzymatic cascades are induced through active molecular exchange across the membrane to mimic the functions of enzymes in mitochondria. We harness the inherent redox properties of the PFC polymer, which forms the membrane, to facilitate in-situ redox reactions similar to those supported by the inner membrane of natural mitochondria. Subsequent studies have demonstrated the interaction between PFC MCs and living cell including extended lifespans within various cell types. We anticipate that functional PFC MCs have the potential to serve as innovative platforms for organelle mimics capable of executing specific cellular functions.

An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds.

A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C-C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.

Engineering cascade biocatalysis in whole cells for syringic acid bioproduction.

BACKGROUND: Syringic acid (SA) is a high-value natural compound with diverse biological activities and wide applications, commonly found in fruits, vegetables, and herbs. SA is primarily produced through chemical synthesis, nonetheless, these chemical methods have many drawbacks, such as considerable equipment requirements, harsh reaction conditions, expensive catalysts, and numerous by-products. Therefore, in this study, a novel biotransformation route for SA production was designed and developed by using engineered whole cells. RESULTS: An O-methyltransferase from Desulfuromonas acetoxidans (DesAOMT), which preferentially catalyzes a methyl transfer reaction on the meta-hydroxyl group of catechol analogues, was identified. The whole cells expressing DesAOMT can transform gallic acid (GA) into SA when S-adenosyl methionine (SAM) is used as a methyl donor. We constructed a multi-enzyme cascade reaction in Escherichia coli, containing an endogenous shikimate kinase (AroL) and a chorismate lyase (UbiC), along with a p-hydroxybenzoate hydroxylase mutant (PobA**) from Pseudomonas fluorescens, and DesAOMT; SA was biosynthesized from shikimic acid (SHA) by using whole cells catalysis. The metabolic system of chassis cells also affected the efficiency of SA biosynthesis, blocking the chorismate metabolism pathway improved SA production. When the supply of the cofactor NADPH was optimized, the titer of SA reached 133 µM (26.2 mg/L). CONCLUSION: Overall, we designed a multi-enzyme cascade in E. coli for SA biosynthesis by using resting or growing whole cells. This work identified an O-methyltransferase (DesAOMT), which can catalyze the methylation of GA to produce SA. The multi-enzyme cascade containing four enzymes expressed in an engineered E. coli for synthesizing of SA from SHA. The metabolic system of the strain and biotransformation conditions influenced catalytic efficiency. This study provides a new green route for SA biosynthesis.

Utilizing microbial metabolite in catalytic cascade synthesis of conjugated oligomers for In-Situ regulation of biological activity.

Despite the advances of multistep enzymatic cascade reactions, their incorporation with abiotic reactions in living organisms remains challenging in synthetic biology. Herein, we combined microbial metabolic pathways and Pd-catalyzed processes for in-situ generation of bioactive conjugated oligomers. Our biocompatible one-pot coupling reaction utilized the fermentation process of engineered E. coli that converted glucose to styrene, which participated in the Pd-catalyzed Heck reaction for in-situ synthesis of conjugated oligomers. This process serves a great interest in understanding resistance evolution by utilizing the inhibitory activity of the synthesized conjugated oligomers. The approach allows for the in-situ combination of biological metabolism and CC coupling reactions, opening up new possibilities for the biosynthesis of unnatural molecules and enabling the in-situ regulation of the bioactivity of the obtained products.

Synthesis of cis-(8b,14a)-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinolin-14-ones via photo cascade reaction.

A concise method for the synthesis of cis-(8b,14a)-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinolin-14-ones 2 via photo-induced 3-([1,1'-biphenyl]-2-yl)-1-(2-hydroxyethyl)pyridin-2(1H)-ones 1 was developed. Irradiation of 1 in the solution of toluene with a 313 nm UV light in the presence of HCl gave cis-(8b,14a)-9a-α-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinoli n-14-ones and cis-(8b,14a)-9a-ß-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinolin-14-ones 2 (2-α and 2-ß) in good yields. The protocol simultaneously constructs dearomatized phenanthrene ring and oxindolizidinones ring by photo cascade reaction to achieve high bonding efficiency and high atomic efficiency. Additionally, the antitumor activities of 2 was evaluated and compounds 2b-α, 2b-ß, 2j-ß and 2 k-α showed similar or better activity compared to the cisplatin against tumor cell lines of Leukemia HL-60, lung cancer A594, liver cancer SMMC-7721 and breast cancer MDA-MB-231.

A Smartphone-Enabled Colorimetric Platform Based on Enzyme Cascade Amplification Strategy for Detection of Staphylococcus aureus in Milk.

Staphylococcus aureus (S. aureus) is a pathogenic bacterium-contaminating milk and dairy foods causing food poisoning and foodborne pathogens. In this work, a smartphone-enabled enzyme cascade-triggered colorimetric platform was constructed using cascade bio-nanozyme formed by immobilized glucose oxidase (GOx) on the Fe3O4@Ag for rapid detection of S. aureus. Benefiting from reasonable experimental design, a bio-nanozyme cascade-triggered reaction was achieved through H2O2 produced by GOx oxidation of glucose, followed by in situ catalysis of 3,3',5,5'-tetramethylbenzidine (TMB) by the inherent peroxidase-like activity of Fe3O4@Ag to produce color signals. S. aureus detection could be performed through naked-eye observation and smartphone measurement, the developed assay can achieve quantitative and qualitative detection of S. aureus. The on-site nanoplatform had satisfactory specificity and sensitivity with a low detection limit of 6.9 cfu·mL-1 in 50 min. Moreover, the nanoplatform has good practicality in the detection of S. aureus in milk samples. Therefore, the assay has potential application prospects in food safety inspection.

Bioinspired Total Synthesis of (+)-Kopsiyunnanine B.

The first enantioselective total synthesis of kopsiyunnanine B, which has a unique folded and complex pentacyclic structure containing six contiguous chiral centers, has been achieved along our originally proposed biosynthetic pathway. The key reaction of this synthesis includes a bioinspired cascade that builds three ring structures and three chiral centers in one step and features the stereoselective reduction of a ß-acrylate and oxidation to an oxindole.

Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization-Coupling of Trisubstituted Allenamides with Arylboronic Acids.

1,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported. Recently, we reported a facile synthesis of trisubstituted allenamides via N-acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized from readily available propargylamines with high efficiency. In light of this research background, we focused on the utility of this methodology for the synthesis of substituted 1,2-dihydroisoquinolines. In this study, a palladium-catalyzed cascade cyclization-coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids is described. When N-acetyl diphenyl-substituted trisubstituted allenamide and phenylboronic acid were treated with 10 mol% of Pd(OAc)2, 20 mol% of P(o-tolyl)3, and 5 equivalents of NaOH in dioxane/H2O (4/1) at 80 °C, the reaction proceeded to afford a substituted 1,2-dihydroisoquinoline. The reaction proceeded via intramolecular cyclization, followed by transmetallation with the arylboronic acid of the resulting allylpalladium intermediate. A variety of highly substituted 1,2-dihydroisoquinolines were concisely obtained using this methodology because the allenamides, as reaction substrates, were prepared from readily available propargylamines in one step.

Designing Degradable Polymers from Tricycloalkenes via Complete Cascade Metathesis Polymerization.

Cascade metathesis polymerization has been developed as a promising method to synthesize complex but well-defined polymers from monomers containing multiple reactive functional groups. However, this approach has been limited to the monomers involving simple alkene/alkyne moieties or produced mainly non-degradable polymers. In this study, we demonstrate a complete cascade ring-opening/ring-closing metathesis polymerization (RORCMP) using various tricycloalkenes and two strategies for the efficient degradation. Through rational design of tricycloalkene monomers, the structure and reactivity relationship was explored. For example, tricycloalkenes with trans configuration in the central ring enabled faster and better selective cascade RORCMP than the corresponding cis isomers. Also, a 4-substituted cyclopentene moiety in the monomers significantly enhanced the overall cascade RORCMP performance, with the maximum turnover number (TON) reaching almost 10,000 and molecular weight up to 170 kg/mol using an amide-containing monomer. Furthermore, we achieved one-shot cascade multiple olefin metathesis polymerization using tricycloalkenes and a diacrylate, to produce new highly A,B-alternating copolymers with full degradability. Lastly, we successfully designed xylose-based tricycloalkenes to give well-defined polymers that underwent ultra-fast and complete degradation under mild conditions.

An Electrocatalytic Cascade Reaction for the Synthesis of Ketones Using CO2 as a CO Surrogate.

The construction of carbonyl compounds via carbonylation reactions using safe CO sources remains a long-standing challenge to synthetic chemists. Herein, we propose a catalyst cascade Scheme in which CO2 is used as a CO surrogate in the carbonylation of benzyl chlorides. Our approach is based on the cooperation between two coexisting catalytic cycles: the CO2-to-CO electroreduction cycle promoted by [Fe(TPP)Cl] (TPP=meso-tetraphenylporphyrin) and an electrochemical carbonylation cycle catalyzed by [Ni(bpy)Br2] (2,2'-bipyridine). As a proof of concept, this protocol allows for the synthesis of symmetric ketones from good to excellent yields in an undivided cell with non-sacrificial electrodes. The reaction can be directly scaled up to gram-scale and operates effectively at a CO2 concentration of 10 %, demonstrating its robustness. Our mechanistic studies based on cyclic voltammetry, IR spectroelectrochemistry and Density Functional Theory calculations suggest a synergistic effect between the two catalysts. The CO produced from CO2 reduction is key in the formation of the [Ni(bpy)(CO)2], which is proposed as the catalytic intermediate responsible for the C-C bond formation in the carbonylation steps.

Diastereo- and Enantioselective Synthesis of Tetracyclic Cycloheptanols through (4+3) Annulation via C-C/C-H Activation Cascade.

Transition metal-catalyzed annulations of four-membered rings via C-C activation are powerful tools to construct complex fused and bridged ring systems. Despite significant progress in (4+1), (4+2) and (4+4) annulations, the (4+3) annulation remains unexplored. Herein, we develop an asymmetric Rh-catalyzed intramolecular (4+3) annulation of α-arylalkene-tethered benzocyclobutenols for the synthesis of dihydrofuran-annulated dibenzocycloheptanols with two discontinuous chiral carbon centers via a C-C and C-H activation cascade. The reaction features excellent diastereo- and enantioselectivities and 100 % atom economy, and is applicable to late-stage modification of complex molecules.

Stereodivergent Construction of 1,5/1,7-Nonadjacent Tetrasubstituted Stereocenters Enabled by Pd/Cu-Cocatalyzed Asymmetric Heck Cascade Reaction.

The construction of chiral motifs containing nonadjacent stereocenters in an enantio- and diastereoselective manner has long been a challenging task in synthetic chemistry, especially with respect to their stereodivergent synthesis. Herein, we describe a protocol that enables the enantio- and diastereoselective construction of 1,5/1,7-nonadjacent tetrasubstituted stereocenters through a Pd/Cu-cocatalyzed Heck cascade reaction. Notably, a C=C bond relay strategy involving the shift of the π-allyl palladium intermediate was successfully applied in the asymmetric construction of 1,7-nonadjacent stereocenters. The current method allows for the efficient preparation of chiral molecules bearing two privileged scaffolds, oxindoles and non-natural α-amino acids, with good functional group tolerance. The full complement of the four stereoisomers of products bearing 1,5/1,7-nonadjacent stereocenters could be readily accessed by a simple combination of two chiral metal catalysts with different enantiomers.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles.

A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method enables a rapid access to heterocycles containing a trifluoromethyl group.

Renal Clearable Catalytic 2D Au-Porphyrin Coordination Polymer Augmented Photothermal-Gas Synergistic Cancer Therapy.

As a gasotransmitter, carbon monoxide (CO) possesses antitumor activity by reversing the Warburg effect at higher concentrations. The targeted delivery of carbon monoxide-releasing molecules (CORMs) using nanomaterials is an appealing option for CO administration, but how to maintain CO above the threshold concentration in tumor tissue remains a challenge. Herein, a nanozyme-catalyzed cascade reaction is proposed to promote CO release for high-efficacy photothermal therapy (PTT)-combined CO therapy of cancer. A gold-based porphyrinic coordination polymer nanosheet (Au0 -Por) is synthesized to serve as a carrier for CORM. It also possesses excellent glucose oxygenase-like activity owing to ultrasmall zero-valent gold atoms on the nanosheet. The catalytically generated H2 O2 can efficiently catalyze CORM decomposition, which enables in situ generation of sufficient CO for gas therapy. In vivo, the Au0 -Por nanosheets-enhanced photoacoustic imaging (PAI) and fluorescence imaging collectively demonstrate high tumor-targeting efficiency and nanomaterial retention. Proven to have augmented therapeutic efficacy, the nanoplatform can also be easily degraded and excreted through the kidney, indicating good biocompatibility. Thus, the application of rational designed Au0 -Por nanosheet with facile approach and biodegradable property to PAI-guided synergistic gas therapy can provide a strategy for the development of biocompatible and highly effective gaseous nanomedicine.

Integrating Dual-Single-Atom Moieties with N, S Co-Coordination Configurations for Oxidative Cascaded Catalysis.

Oxidation reaction is of critical importance in chemical industry, in which the primary O2 activation step still calls for high-performance catalysts. Here, a newly developed precise locating carbonization strategy for the fabrication of 21 kinds of dual-metal single-atom catalysts with N, S co-coordinated configurations is reported. As is exemplified by CoN3 S1 /CuN4 @NC, systematical characterizations and in situ observations imply the atomic CoN3 S1 and CuN4 sites immobilized on N-doped carbon, over which the remarkable electron redistribution originating from their unsymmetrical coordination configurations. Impressively, the obtained CoN3 S1 /CuN4 @NC exhibits unprecedented capability in O2 activation and enables a spontaneous process through its dynamic configuration, significantly outperforming the CoN4 /CuN4 @NC and CoN3 S1 @NC counterparts. Hence, the CoN3 S1 /CuN4 @NC shows attractive performance in domino synthesis of natural flavone and 19 kinds of derivatives from benzyl alcohol, 2'-hydroxyacetophenone, and corresponding substituted substrates via aerobic oxidative coupling-dehydrogenation. Detailed reaction mechanisms and molecule behaviors over CoN3 S1 /CuN4 @NC are also investigated through in situ experiments and simulations.

Chiral Ruthenium Nanozymes with Self-Cascade Reaction Driven the NO Generation Induced Macrophage M1 Polarization Realizing the Lung Cancer "Cocktail Therapy".

Macrophages as the main cause of cancer immunosuppression, how to effectively induce macrophage M1 polarization remain the major challenge in lung cancer therapy. Herein, inspired by endogenous reactions, a strategy is proposed to coactivate macrophage M1 polarization by reactive oxygen species (ROS) and nitric oxide (NO) with self-autocatalytic cascade reaction. To enhance the generation of NO and ROS, NO Precursor-Arginine as capping agents for inducing synthesis two kinds of chiral ruthenium nanozyme (D/L-Arginine@Ru). Under the properties of Ru nanozymes through synchronously mimicking the activity of oxidase and nitric oxide synthase (NOS), chiral Ru nanozyme can rapidly generate 1 O2 and O2 at first stage, and then catalyze Arginine to produce sufficient NO, thus enhance macrophage M1 polarization to reverse tumor immunosuppression. Moreover, combination the antitumor activity of 1 O2 , NO, the chiral Ru nanozymes realize the "cocktail therapy" by inducing tumor cell apoptosis as well as ferroptosis. In addition, the chirality influences the bioactivity of Ru nanozymes that L-Arginine@Ru shows the better therapeutic effect with stronger catalytic activity and natural homology. It is hoped the high performance of chiral Ru nanozyme with "cocktail therapy" is an effective therapeutic reagent and can provide a feasible treatment strategy for tumor catalytic therapy.