Cascade Reaction Research Articles

A review of the Bovis Calculus’s intervention mechanism and clinical application in ischemic stroke

BackgroundBovis Calculus (BC), also named Niuhuang in Chinese, is utilized as a resuscitation drug in Traditional Chinese Medicine (TCM) for the treatment of neurological disorders. Ischemic stroke (IS) is a significant global public health issue that currently lacks safe and effective therapeutic drugs. Ongoing efforts are focused on identifying effective treatment strategies from Traditional, Complementary, and Integrative Medicine. Noticeably, BC has been used in TCM for thousands of years to prevent or treat IS-related diseases.MethodsThe historical origins of BC in the treatment of IS were investigated through the examination of ancient Chinese medical texts. Furthermore, the chemical components of BC were analyzed, and its mechanisms of action against IS were summarized using literature sourced from databases such as Web of Science, PubMed, and China National Knowledge Infrastructure. Information on Chinese medicine preparations and clinical reports was also integrated to provide an overview of modern applications and safety considerations.ResultsBC mainly includes chemical components such as bile pigments, bile acids, cholesterol, proteins amino acids, and trace elements. Additionally, the efficacy of BC in treating cerebral ischemia/reperfusion injury (CI/RI) is certain, particularly due to the components of bile pigments, bile acids, and amino acids that can interfere with the enzymatic cascade reaction of CI/RI through multiple components, targets, and pathways. The active components of BC exert neuroprotective effects by reducing microcirculation disturbance, excitatory amino acid toxicity, and oxidative stress injury in the acute stage; inhibiting inflammatory injury, apoptosis, and blood-brain barrier (BBB) disruption in the subacute stage; and promoting angiogenesis and neurogenesis in the restoration stage. Furthermore, as a crude drug, BC appears in many Chinese patent medicine (CPM) preparations for the treatment of IS, and clinical and preclinical studies have proved its safety.ConclusionThe use of BC in the treatment of IS has a long history, proven efficacy, and widespread application. Future efforts should focus on elucidating its mechanisms of action and exploring its applications.

Efficient Synthesis of l-Asparagine by an Immobilized Three-Enzyme Cascade Reaction System

Efficient Synthesis of <scp>l</scp>-Asparagine by an Immobilized Three-Enzyme Cascade Reaction System

Enzyme cascade nanozyme based colorimetric sensor for detection of uric acid as a biomarker of hyperuricemia.

ACr-doped VO2 nanobelt (Cr/VO2) with remarkable peroxidase-like activity was synthesized and coupled with uricase to catalyze the cascade reaction for detection of uric acid. Notably, the affinity of Cr/VO2 for 3,3',5,5'-tetramethylbenzidine dihydrochloride hydrate (TMB) and hydrogen peroxide (H2O2) is tenfold and 20-fold higher, respectively, than that of horseradish peroxidase (HRP). The Cr/VO2 exhibits highly reactive and stable peroxidase activity at temperatures of 20-60 ℃. Thus, the reaction catalyzed by Cr/VO2 can be carried out at room temperature, greatly simplifying the testing process. This enzyme cascade nanozyme based colorimetric assay enables the selective and simple detection of uric acid within 30 min with a detection limit of only 0.34μM, and has an observable potential in clinical applications.

Ionic Strength-Induced Compartmentalization for Nanogel-in-Microgel Colloids.

Compartmentalization is crucial for control over complex biological cascade reactions. In microgels, the formation of discrete compartments allows for simultaneous uptake and orthogonal release of physicochemically distinct drugs, among others. However, many state-of-the-art approaches yielding compartmentalized microgels require the use of specific, though not always biocompatible, components and temperatures well above the physiological range, which may damage possible biological cargo. Therefore, a novel technique to fabricate compartmentalized microgels by exploiting ionic strength-induced precipitation as a mechanism for compartmentalization is developed. For this, a droplet-based microfluidic approach in which preformed nanogels are incorporated into poly(N-isopropylacrylamide)- or poly(acrylamide)-based microgels is employed. Allowing contact between the nanogel-monomer mixture and a salt solution only at the cross junction inhibits premature precipitation of the nanogels and aggregates form on the chip. It is demonstrated that this method is applicable to a variety of nanogel species in both stimuli-responsive and non-stimuli-responsive microgel networks. For temperature-responsive nanogel compartments in non-responsive microgels, anisotropic shape change is investigated by adjusting temperature or salt concentration or changing the solvent. Lastly, an exemplary uptake and release experiment demonstrates highly selective drug absorption, paving the way for more advanced biomimetic polymer structures.

Formal [3+1+1+1] annulation of 2‐isocyanophenyl propargylic esters and 4‐hydroxy‐2H‐chromen‐2‐ones: an access to quinoline‐fused polycyclic skeletons

A cascade reaction involving 2‐isocyanophenyl propargylic ester and 4‐hydroxy‐2H‐chromen‐2‐one has been documented. This reaction leads to the formation of a highly strained cyclopropen‐imine species, thereby offering an efficient route to synthesize quinoline‐fused polycyclic skeletons.

What Factors Determine the Brevione B Desaturation Mechanism in the Nonheme Iron Dioxygenase BrvJ?

The natural product synthesis of brevione J undergoes a cascade of reactions including an oxidative desaturation and a ring-expansion. The C1-C2 desaturation of brevione B is catalyzed by the nonheme iron dioxygenase BrvJ using one molecule of O2 and a-ketoglutarate (aKG). However, whether the subsequent oxidative ring expansion reaction is also catalyzed by the same enzyme is unknown and remains controversial. To gain insight into the mechanism of brevione J biosynthesis a computational study is reported here using molecular dynamics and density functional theory approaches. The work predicts that both cycles can proceed in the same protein structure on an iron center with O2 and aKG for each cycle. The rate-determining step is a hydrogen atom abstraction step in both reaction cycles. Interestingly, the OH rebound barriers are high in energy in cycle 1 due to stereochemical interactions and substrate positioning that enable an efficient desaturation reaction.

Ion-molecule reactions in CO2 clusters induced by low-energy electron attachment

Abstract Dissociative electron attachment (DEA) process in molecular clusters is inherently complex, and elucidating the underlying mechanisms presents significant challenges. This study builds upon our previous research by investigating DEA in the larger and more numerous CO2 clusters, and extending the electron attachment energy to 15 eV. This enhanced approach allows for the detection of anionic species such as O 2 − and (CO2)nO 2 − . We recorded the production efficiency curves and kinetic energy distributions of the fragment anions, revealing that the O 2 − anions can be formed via the DEA process of CO2 monomers, consistent with previously reported observations. Additionally, O 2 − may also be produced through a cascade reaction process involving ion-molecule/atom interactions within the clusters, even when the attachment energy exceeds the DEA threshold of O 2 − production from CO2 monomers. Furthermore, the stabilization of these detected anions (CO2)nO 2 − is attributed to energy dissipation via molecular evaporative cooling, as previously proposed. This study offers new insights into the underlying mechanisms of DEA in molecular clusters, thereby enhancing our understanding of electron-induced reactions in atmospheric and astrochemical contexts.

Palladium-Catalyzed Cascade Reactions for Synthesis of Heterocycles Initiated by C(sp3)–H Functionalization

Heterocycles are widely present in natural products, pharmaceuticals, and organic functional materials. In heterocycle synthesis, Pd-catalyzed cascade C–H functionalization has been regarded as one of the most powerful approaches due to its advantages in terms of high atom efficiency and readily available starting materials. In this review, we will briefly introduce the major advances in palladium-catalyzed cascade C(sp3)–H activation and annulation for constructing different types of heterocycles through inter- and intramolecular pathways from 2010 to 2023.

Photomediated One-Pot Multicomponent Cascade Reaction for the Synthesis of N-Acyl/Sulfonyl-α-Phosphonated-1,2,3,4-Tetrahydroisoquinoline via Twice Acyl/Sulfonyl IminiumFormation.

N-acyl/sulfonyl-α-phosphonated 1,2,3,4-tetrahydroiso-quinolines (THIQs) are highly important structural motifs in organic synthesis and drug discovery. However, the one-pot approach enabling direct difunctionalization of THIQs remains challenging. Herein we report a photomediated one-pot multicomponent cascade reaction to access N-acyl/sulfonyl-α-phosphonated THIQs via twice acyl/sulfonyl iminium. This method features air as an oxidant, high atom and step economy, and mild conditions.

Aptamer proximal enzyme cascade reactions for ultrafast detection of glucose in human blood serum.

Aninnovative colorimetric sensing strategy was developedfor the detection of glucose by the integration of glucose aptamer, glucose oxidase (GOx), and horseradish peroxidase (HRP), termed aptamer proximal enzyme cascade reactions (APECR). In the presence of glucose, aptamer binding enables GOx to catalyze glucose oxidation into H2O2 efficiently. Subsequently, the adjacent HRP catalyzes the oxidation of the peroxidase substrate, 2,2'-biazobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS2-), utilizing the generated H2O2, resulting in a distinct color change. In comparison to the free enzymes and the HRP-GOx system, APECR exhibited higher colorimetric signal. This approach achieved glucose detection within three minutes, which was significantly faster than previous methods. This method showed good sensitivity and selectivity with a limit of detection of 0.013mM. Moreover, the practical utility of this strategy was verified by achieving rapid detection of glucose in clinical serum samples. Hence, the developed strategy has the advantages of simple operation and rapid analysis time for the detection of glucose in human serum.

Correction: Hu et al. Dynamics of Nanomotors Propelled by Enzyme Cascade Reactions. Int. J. Mol. Sci. 2024, 25, 12586

There was an error in the original publication [...]

Discovery and Total Synthesis of a New Class of Minor Immunosuppressive Plant Sesterterpenoids

Plant sesterterpenoids are an extremely rare family of natural products that generally possess novel chemical structures and diverse biological activities. Here, we report the discovery of an unprecedented group of minor plant sesterterpenoids, gracilisoids B‐E (2‐5), which feature two types of highly functionalized bicyclo[3.2.0]heptane carbon skeletons, along with their biogenetically‐related precursor gracilisoid A (1), from a Lamiaceae ethnomedicinal plant, Eurysolen gracilis. To confirm their structures and obtain adequate materials for biological research, the asymmetric total syntheses of gracilisoids A‐E (1‐5) and four new biogenetically‐related congeners gracilisoids F‐I (6‐9) were achieved from commercially available (−)‐citronellal via a bioinspired approach that involves a Norrish‐Yang photocyclization/α‐hydroxy ketone rearrangement tandem reaction and a late‐stage biomimetic photo‐oxidation as key steps. Biological investigations revealed that gracilisoids A‐I (1‐9) significantly inhibited IFN‐γ production and/or T cell proliferation probably via inhibition of the STAT pathway. The findings herald the potential of these gracilisoids as novel immunosuppressive agents, and the efficient synthetic approaches will facilitate a comprehensive evaluation of their value in future drug development.

Discovery and Total Synthesis of a New Class of Minor Immunosuppressive Plant Sesterterpenoids.

Plant sesterterpenoids are an extremely rare family of natural products that generally possess novel chemical structures and diverse biological activities. Here, we report the discovery of an unprecedented group of minor plant sesterterpenoids, gracilisoids B-E (2-5), which feature two types of highly functionalized bicyclo[3.2.0]heptane carbon skeletons, along with their biogenetically-related precursor gracilisoid A (1), from a Lamiaceae ethnomedicinal plant, Eurysolen gracilis. To confirm their structures and obtain adequate materials for biological research, the asymmetric total syntheses of gracilisoids A-E (1-5) and four new biogenetically-related congeners gracilisoids F-I (6-9) were achieved from commercially available (-)-citronellal via a bioinspired approach that involves a Norrish-Yang photocyclization/α-hydroxy ketone rearrangement tandem reaction and a late-stage biomimetic photo-oxidation as key steps. Biological investigations revealed that gracilisoids A-I (1-9) significantly inhibited IFN-γ production and/or T cell proliferation probably via inhibition of the STAT pathway. The findings herald the potential of these gracilisoids as novel immunosuppressive agents, and the efficient synthetic approaches will facilitate a comprehensive evaluation of their value in future drug development.

Copper-Catalyzed Domino Annulation of Isoselenocyanates: A Pathway to Structurally Diverse N, Se-Bis-Heterocyclic, and Fused Heterocyclic Compounds.

A copper-catalyzed domino addition/cyclization reaction was developed to synthesize novel benzoselenazole-linked 1,2,3-triazole and tetracyclic fused 12H-benzo[4,5]selenazole[2,3-b]quinazolin-12-one derivatives from isoselenocyanates. This domino reaction efficiently constructed multiple new chemical bonds in a single step, forming either four (one C-Se and three C-N) or three (one C-Se and two C-N) bonds. The reaction offers several key advantages, including mild conditions, broad substrate compatibility, and straightforward and safe operation. It presents a new method for synthesizing N, Se-containing polycyclic compounds, which have potential interest in medicinal chemistry. Notably, some of the synthesized compounds exhibited anticancer activity with IC50 values below 20 μmol L-1 against T24 human bladder cancer cells.

Enzymatic Cascades for Stereoselective and Regioselective Amide Bond Assembly.

Amide bond formation is fundamental in nature and is widely used in the synthesis of pharmaceuticals and other valuable products. Current methods for amide synthesis are often step and atom inefficient, requiring the use of protecting groups, deleterious reagents and organic solvents that create significant waste. The development of cleaner and more efficient catalytic methods for amide synthesis remains an urgent unmet need. Herein, we present novel biocatalytic cascade reactions for synthesising various amides under mild aqueous conditions from readily available organic nitriles combining nitrile hydrolysing enzymes and amide bond synthetase enzymes. These cooperative biocatalytic cascades enable kinetic resolution of racemic nitriles and provide a highly enantioselective biocatalytic extension of the Strecker reaction. The regioselective non-directed C-H bond amidation of simple arenes was demonstrated through the incorporation of photoredox catalysis to the front end of the cascade. C-H bond amidation of simple aromatic precursors was also achieved via a CO2 fixation cascade combining enzymatic carboxylation and amide bond synthesis in one-pot.

Fabrication of Compartmentalized Multienzyme Reactor for Colorimetric Biosensing of Glucose and Phenol with High Sensitivity.

Enzymatic cascade reactions are widely utilized in food security, environmental monitoring, and disease diagnostics, whereas their practical application was hindered due to their limited catalytic efficiency and intrinsic fragility to environmental influences. Herein, a compartmentalized dual-enzyme cascade nanoreactor was constructed in metal-organic frameworks (ZIF-8) by a shell-by-shell growth method. ZIF-8 provided a good microenvironment to maintain the activity of enzymes and protected them against harsh conditions. Importantly, experimental results revealed that the encapsulation order and enzyme ratio affected the cascade catalytic activity. When the cascade enzyme ratio was 1:1 and horseradish peroxidase (HRP) was encapsulated in the inner layer with glucose oxidase (GOx) in the outer layer (H@ZIF-8@G@ZIF-8), the nanoreactor facilitated the mass transfer process of substrates and showed the highest cascade catalytic efficiency. The maximum reaction rate (Vmax) of H@ZIF-8@G@ZIF-8 was 294.96 nM s-1, which was 1.6 times greater than G@ZIF-8@H@ZIF-8 (182.84 nM s-1). Therefore, H@ZIF-8@G@ZIF-8 was effectively applied in glucose monitoring and phenol sensing. The glucose biosensor showed a low detection limit of 0.76 μM and a broad linear range of 5-300 μM. The phenol biosensor demonstrated a wide linear range (20-300 μM) with a detection limit of 0.60 μM. In addition, the spiked recovery experiments for glucose and phenol were carried out in serum (recovery: 95.26-100.04%) and tap water (recovery: 97.05-106.50%), respectively. The high accuracy demonstrated potential applications of the cascade system in biosensing and environmental detection.

Improving Photocatalytic Hydrogen Generation via Polycitric Acid-based Carbon Nanodots.

Bottom-up syntheses of carbon nanodots (CND) using solvothermal treatment of citric acid are known to afford nanometer-sized, amorphous polycitric acid-based materials. The addition of suitable co-reactants in the form of in-situ synthesized N-hetero-π-conjugated chromophores facilitates hereby the overall functionalization. Our incentive was to design a CND model that features phenazine (P-CND) - a well-known N-hetero-π-conjugated chromophore - to investigate the influence of the CND matrix on its redox chemistry as well as photochemistry. The scope of our work was to go beyond investigating the electrochemical properties of the resulting P-CND by shedding light onto differences relative to nano-aggregates of phenazine (PNZNA), which served as reference. In particular, chemical as well as electrochemical reduction of PNZNA initiated a reaction cascade that affords the primary reduction intermediate, that is, the reduced and protonated (PNZ-H)•. In accordance with literature, the final product of a bimolecular disproportionation was 5,10-dihydrophenazine (PNZ-H2). Reducing P-CND also resulted in the formation of (PNZ-H)•. But, no evidence for a subsequent bimolecular disproportionation was gathered. Instead, (PNZ-H)• as an integrative part of P-CND was found to be actively involved in a H2 generation reaction. A more than twofold increase in efficiency compared to PNZNA under identical conditions was the consequence.

Electrosynthesis of Organonitrogen Compounds via Hydroxylamine-Mediated Cascade Reactions.

Hydroxylamine (NH2OH) is a key intermediate in the formation of numerous high value-added organonitrogen compounds. The traditional synthesis of NH2OH requires the use of precious metals under high temperature conditions, which leads to high cost, high energy consumption, and environmental pollution. The NH2OH-mediated cascade reaction integrates the electrochemical synthesis of NH2OH and the chemical synthesis of organonitrogen compounds, offering a facile, green, and efficient alternative. This review presents the recent advances on electrosynthesis of high value-added organonitrogen compounds by NH2OH-mediated cascade reactions. We present key concepts and the transformation process of different N-species to NH2OH, discuss suitable substrates and electrocatalysts, and elucidate the reaction mechanisms involved in generating compounds such as amino acids, cyclohexanone oxime, urea, amine, etc.. Finally, we address current challenges and future directions in this emerging field to encourage further research effort and the development of NH2OH-mediated cascade reaction.

Electrosynthesis of Organonitrogen Compounds via Hydroxylamine−Mediated Cascade Reactions

Electrosynthesis of Organonitrogen Compounds via Hydroxylamine−Mediated Cascade Reactions

Palladium-Catalyzed Tandem Reaction of β-Ketonitriles with Arylboronic Acids and Dimethyl Sulfoxide: Application to Multicomponent Synthesis of Poly-Substituted Pyridines.

The Pd-catalyzed multicomponent tandem reaction of β-ketonitriles, arylboronic acids and DMSO was efficiently developed, enabling access to a variety of poly substituted pyridines. The protocol shows excellent chemoselectivity, generating nicotinonitriles or symmetrical tetrasubstituted pyridines under different conditions by tandem cyclization of enaminone intermediates with β-ketonitriles or enolates, respectively, and does not require extra ammonias. This method boasts notable advantages, such as the use of commercially available or easily prepared substrates, simple conditions, a broad substrate scope, and good functional group tolerance.