Associations between intraoperative nociceptive response index and early postoperative acute kidney injury in patients undergoing non-cardiac surgery under general anesthesia: a single-center retrospective cohort study.

Both tissue hypoperfusion and elevated surgical stress during surgery are involved in the pathogenesis of postoperative acute kidney injury (AKI). Although intraoperative hypotension, which evokes renal hypoperfusion, has been reported to be associated with the development of postoperative AKI, there is no consensus on the association between surgical stress responses (e.g., hypertension and inflammation) and postoperative AKI. Given that intraoperative values of nociceptive response (NR) index are reportedly associated with surgical stress responses, the present study was performed to assess associations between intraoperative NR index and postoperative AKI in patients undergoing non-cardiac surgery. In this single-institutional retrospective cohort study, data of the highest and lowest values of NR index during surgery were obtained in consecutive adult patients undergoing non-cardiac surgery under general anesthesia from February 2022 to August 2023. Data on highest and lowest mean blood pressure (MBP) during surgery were also obtained. In 5,765 patients enrolled, multivariate regression analysis revealed that the development of early postoperative AKI was significantly associated with highest NR during surgery ≥ 0.920, lowest MBP during surgery < 54 mmHg, age ≥ 48 years, male sex, ASA-PS ≥ III, emergency, and duration of surgery ≥ 226 min. In addition to intraoperative hypotension, a higher level of intraoperative NR index is likely associated with higher incidence of early postoperative AKI in adult patients undergoing non-cardiac surgery under general anesthesia.

Age-related changes in intraoperative mean values of nociceptive response in patients undergoing non-cardiac surgery under general anesthesia: A retrospective cohort study.

Intraoperative nociception is affected by preoperative factors, surgical invasiveness, and anesthesia. Although age-related changes in nociception in conscious humans have been well examined, those in intraoperative nociception in unconscious patients under general anesthesia are unknown. To clarify associations between age and intraoperative nociception under general anesthesia, we performed a retrospective cohort study in consecutive patients of all ages undergoing non-cardiac surgery under general anesthesia from January 2019 to July 2023. The intraoperative nociception value in each surgery was assessed by the averaged value of nociceptive response (mean NR) index during surgery. Patient characteristics, including age, sex, body mass index (BMI), emergent surgery, preoperative serum C-reactive protein (CRP) level, and comorbidities were also collected. After excluding patients with missing data of CRP and mean NR index, 22,061 patients were enrolled, and were divided into low, intermediate, and high surgical risk groups. Multivariable regression analysis showed a significant association between age and mean NR index in all three surgical procedure risk groups. The preoperative variables of CRP levels, BMI, emergent surgery, atrial fibrillation, renal failure, and long-term steroid use also showed significant associations with mean NR index in all three groups. Sensitivity analysis showed that intraoperative mean NR index was higher in younger children than that in both older children and younger adults, and it gradually increased again in older adults to the same level as in younger children. In conclusion, there is likely an association between age and intraoperative mean NR index in patients under general anesthesia.

Structural and Mechanistic Insights into the C-C Bond-Forming Rearrangement Reaction Catalyzed by Heterodimeric Hinokiresinol Synthase.

Hinokiresinol synthase (HRS) from Asparagus officinalis consists of two subunits, α and ß, and catalyzes an unusual decarboxylative rearrangement reaction of 4-coumaryl 4-coumarate to generate (Z)-hinokiresinol with complete stereoselectivity. Herein, we describe the mechanism of rearrangement catalysis and the role played by the heterodimeric HRS, through structural and computational analyses. Our results suggest that the HRS reaction is unlikely to proceed via the previously hypothesized Claisen rearrangement mechanism. Instead, we propose that the 4-coumaryl 4-coumarate substrate is first cleaved into coumarate and an extended p-quinone methide, which then recombine to generate a new C-C bond. These processes are facilitated by proton transfers mediated by the basic residues (α-Lys164, α-Arg169, ß-Lys168, and ß-Arg173) in the cavity at the heterodimer interface. The active site residues, α-Asp165, ß-Asp169, ß-Trp17, ß-Met136, and ß-Ala171, play crucial roles in controlling the regioselectivity of the coupling between the fragmented intermediates as well as the stereoselectivity of the decarboxylation step, leading to the formation of the (Z)-hinokiresinol product.

Mechanistic Analysis of Stereodivergent Nitroalkane Cyclopropanation Catalyzed by Nonheme Iron Enzymes.

BelL and HrmJ are α-ketoglutarate-dependent nonheme iron enzymes that catalyze the oxidative cyclization of 6-nitronorleucine, resulting in the formation of two diastereomeric 3-(2-nitrocyclopropyl)alanine (Ncpa) products containing trans-cyclopropane rings with (1'R,2'R) and (1'S,2'S) configurations, respectively. Herein, we investigate the catalytic mechanism and stereodivergency of the cyclopropanases. The results suggest that the nitroalkane moiety of the substrate is first deprotonated to produce the nitronate form. Spectroscopic analyses and biochemical assays with substrates and analogues indicate that an iron(IV)-oxo species abstracts proS-H from C4 to initiate intramolecular C-C bond formation. A hydroxylation intermediate is unlikely to be involved in the cyclopropanation reaction. Additionally, a genome mining approach is employed to discover new homologues that perform the cyclopropanation of 6-nitronorleucine to generate cis-configured Ncpa products with (1'R,2'S) or (1'S,2'R) stereochemistries. Sequence and structure comparisons of these cyclopropanases enable us to determine the amino acid residues critical for controlling the stereoselectivity of cyclopropanation.

Mechanistic Investigation of the Degradation Pathways of α-ß/α-α Bridged Epipolythiodioxopiperazines (ETPs).

Epipolythiodioxopiperazines (ETPs) make up a class of biologically active fungal metabolites with a transannular disulfide bridge. In this work, we used DFT calculations to examine in detail the degradation (desulfurization) pathways of α-ß/α-α bridged ETPs. The chemical stability of ETPs is influenced by the type of sulfur bridge, the structural features, and the storage conditions. Our results suggest appropriate protection of the phenolic OH of ETPs would improve various pharmaceutically relevant properties, including bioavailability.

A Switchable Near-Infrared-Absorbing Dye Based on Redox-Bistable Benzitetraazaporphyrin.

Activatable near-infrared (NIR) dyes responsive to external stimuli are used in medical and other applications. Here, we describe the design and synthesis of bench-stable 18π- and 20π-electron benzitetraazaporphyrins (BzTAPs) possessing redox-switchable NIR properties. X-Ray, NMR, and UV/Visible-NIR analyses revealed that 20π-electron BzTAP 1 exhibits NIR absorption and antiaromaticity with a paratropic ring-current, while 18π-electron BzTAP 2 shows weakly aromatic character with NIR inertness. Notably, the NIR-silent BzTAP 2 was readily converted to the NIR-active BzTAP 1 in the presence of mild reducing agents such as amine. The intense NIR absorption band of BzTAP 1 is in sharp contrast to the very weak absorption bands of previously reported antiaromatic porphyrinoids. Molecular orbital analysis revealed that symmetry-lowering perturbation of the 20π-electron porphyrinoid skeleton enables the HOMO-LUMO transition of 1 to be electric-dipole-allowed. BzTAPs are expected to be useful for constructing activatable NIR probes working in reductive environments.

Total Biosynthesis of Melleolides from Basidiomycota Fungi: Mechanistic Analysis of the Multifunctional GMC Oxidase Mld7.

Mushroom terpenoids are biologically and chemically diverse fungal metabolites. Among them, melleolides are representative sesquiterpenoids with a characteristic protoilludane skeleton. In this study, we applied a recently established hot spot knock-in method to elucidate the biosynthetic pathway leading to 1α-hydroxymelleolide. The biosynthesis of the sesquiterpene core involves the cytochrome P450 catalyzing stepwise hydroxylation of the Δ6 -protoilludene framework and a stereochemical inversion process at the C5 position catalyzed by short-chain dehydrogenase/reductase family proteins. The highlight of the biosynthesis is that the flavoprotein Mld7 catalyzes an oxidation-triggered double-bond shift accompanying dehydration and acyl-group-assisted substitution with two different nucleophiles at the C6 position to afford the Δ7 -protoilludene derivatives, such as melleolide and armillarivin. The complex reaction mechanism was proposed by DFT calculations. Of particular importance is that product distribution is regulated by interaction with the cell membrane.

Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes.

There is increasing interest in replacement of the planar aromatic rings of drug candidates with three-dimensional caged scaffolds in order to improve the physical properties, but bioisosteres of meta-substituted benzenes have remained elusive. We focused on the bicyclo[3.1.1]heptane (BCH) scaffold as a novel bioisostere of meta-substituted benzenes, anticipating that [3.1.1]propellane (2) would be a versatile precursor of diversely functionalized BCHs. Here, we describe a practical preparative method for [3.1.1]propellane from newly developed 1,5-diiodobicyclo[3.1.1]heptane (1), as well as difunctionalization reactions of 2 leading to functionalized BCHs. We also report postfunctionalization reactions of these products.

A combined DFT-predictive and experimental exploration of the sensitivity towards nucleofuge variation in zwitterionic intermediates relating to mechanistic models for unimolecular chemical generation and trapping of free C2 and alternative bimolecular pathways involving no free C2.

Following the recent report of the chemical generation and trapping at room temperatures of C2, generated from an alkynyl phenyl iodonium salt, a computational analysis had indicated that both unimolecular fragmentation and bimolecular substitution mechanisms for the process could be envisaged. Here a combined theoretical and experimental analysis explores how the energetics of these mechanisms and resulting experimental products respond to variation in the nucleofuge. When the phenyl iodonium nucleofuge is replaced by pyridinium, trapping products are again obtained, which we conclude favours a bimolecular mechanism involving no free C2. Trapped products in greater yield were also observed using dibenzothiophenium as the nucleofuge in both condensed solution phase and most significantly in a two-flask room temperature experiment in which a volatile species, presumed to be C2, is transferred and trapped in a second flask. The energetics of the unimolecular fragmentation process producing C2 are predicted to be too high to correspond to a facile thermal reaction, which means that an experimental/theoretical dichotomy remains to be explained.

Synthesis of Cyclophenacene- and Chiral-Type Cyclophenylene-Naphthylene Belts.

We report the synthesis of a [20]cyclophenacene-type cyclophenylene-naphthylene (CPN) belt and the enantioselective synthesis of chiral-type CPN belts (up to >99 % ee) by the cationic rhodium(I)-catalyzed intramolecular [2+2+2] cycloaddition of naphthalene-embedded cyclic polyynes. The synthesis of a depth-expanded CPN belt was also attempted, but the final intramolecular [2+2+2] cycloaddition was unsuccessful. Theoretical calculations clarified that the reactivity depends on the stability of the transition state in the initial oxidative cycloaddition step which is subject to molecular strain. The cylindrical structures of these CPN belts were confirmed by X-ray crystallographic analyses. As a result of π-extension through the introduction of naphthalenes in the chiral-type CPN belts, the anisotropy dissymmetry factors of electronic circular dichroism and circularly polarized luminescence are amplified compared with the corresponding zigzag-type chiral cyclophenylene belts.

Illuminating Stannylation.

We have developed photoboosted stannylation reactions of terminal alkynes (linear-selective hydrostannylation) and fluoroarenes (defluorostannylation), in which the stannyl anion is photoexcited to an excited triplet (T1) stannyl diradical species. This unprecedented T1-stannyl diradical species shows completely different reactivity and selectivity from those of stannyl anions and stannyl radicals. This methodology is operationally simple, has broad functional group tolerance, and proceeds in high yield without the need for any catalyst.

Molecular and Computational Bases for Spirofuranone Formation in Setosusin Biosynthesis.

The 3(2H)-furanone unit is observed in many biologically active natural products, as represented by the antifungal medication griseofulvin. Setosusin (1) is a fungal meroditerpenoid featuring a unique spiro-fused 3(2H)-furanone moiety; however, the biosynthetic basis for spirofuranone formation has not been investigated since its isolation. Therefore, in this study we identified the biosynthetic gene cluster of 1 in the fungus Aspergillus duricaulis CBS 481.65 and elucidated its biosynthetic pathway by heterologous reconstitution of related enzyme activities in Aspergillus oryzae. To understand the reaction mechanism to afford spirofuranone, we subsequently performed a series of in vivo and in vitro isotope-incorporation experiments and theoretical calculations. The results indicated that SetF, the cytochrome P450 enzyme that is critical for spirofuranone synthesis, not only performs the epoxidation of the polyketide portion of the substrate but also facilitates the protonation-initiated structural rearrangement to yield 1. Finally, a mutagenesis experiment using SetF identified Lys303 as one of the potential catalytic residues that are important for spirofuranone synthesis.

Benchtop-Stable Hypervalent Bromine(III) Compounds: Versatile Strategy and Platform for Air- and Moisture-Stable λ3-Bromanes.

We present the first synthesis of air/moisture-stable λ3-bromanes (9 and 10) by using a cyclic 1,2-benzbromoxol-3-one (BBX) strategy. X-ray crystallography and NMR and IR spectroscopy of N-triflylimino-λ3-bromane (12) revealed that the bromine(III) center is effectively stabilized by intramolecular R-Br-O hypervalent bonding. This strategy enables the synthesis of a variety of air-, moisture-, and benchtop-stable Br-hydroxy, -acetoxy, -alkynyl, -aryl, and bis[(trifluoromethyl)sulfonyl]methylide λ3-bromane derivatives.

Stereodivergent Nitrocyclopropane Formation during Biosynthesis of Belactosins and Hormaomycins.

Belactosins and hormaomycins are peptide natural products containing 3-(2-aminocyclopropyl)alanine and 3-(2-nitrocyclopropyl)alanine residues, respectively, with opposite stereoconfigurations of the cyclopropane ring. Herein we demonstrate that the heme oxygenase-like enzymes BelK and HrmI catalyze the N-oxygenation of l-lysine to generate 6-nitronorleucine. The nonheme iron enzymes BelL and HrmJ then cyclize the nitroalkane moiety to the nitrocyclopropane ring with the desired stereochemistry found in the corresponding natural products. We also show that both cyclopropanases remove the 4-proS-H of 6-nitronorleucine during the cyclization, establishing the inversion and retention of the configuration at C4 during the BelL and HrmJ reactions, respectively. This study reveals the unique strategy for stereocontrolled cyclopropane synthesis in nature.

Rhodium-Catalyzed Enantioselective Synthesis, Structures, and Properties of Single and Double Azahelicene-Like Molecules.

The enantioselective synthesis of aza[6] and [7]helicene-like molecules have been achieved by the cationic rhodium(I)/axially chiral biaryl bisphosphine complex-catalyzed intramolecular [2+2+2] cycloaddition of cyanodiynes. This protocol was successfully applied to the diastereo- and enantioselective synthesis of an S-shaped double aza[6]helicene-like molecule with a high ee value of 89 %. Although no epimerization and racemization were observed in the double carbo[6]helicene-like molecule at 80 °C, epimerization and racemization of the double aza[6]helicene-like molecule proceeded at 80 °C. This double aza[6]helicene-like molecule showed good fluorescent quantum yields and chiroptical responses under both neutral and acidic conditions.

Synthetic Access to gem-Difluoropropargyl Vinyl Ethers and Their Application to Propargyl Claisen Rearrangement.

With the increasing importance of fluorine to medicinal chemistry and other areas, methods to access various fluorinated compounds are needed. Herein, we report the synthesis of difluoropropargyl vinyl ethers from ketones and aldehydes using difluoropropargyl bromide dicobalt complexes. We applied difluoropropargyl vinyl ethers to the synthesis of difluorodienone or difluoroallene under thermal conditions and trifluoro-pyran under acid-catalyzed conditions.

Theoretical Study on the Mechanism of Spirocyclization in Spiroviolene Biosynthesis.

Spiroviolene is a spirocyclic triquinane diterpene produced by Streptomyces violens. Recently, a biosynthetic pathway that includes secondary carbocation intermediates and a complicated concerted skeletal rearrangement was proposed for spiroviolene, based upon careful labeling experiments. On the basis of density functional theory (DFT) calculations, we propose a revised pathway for spiroviolene biosynthesis, involving a multistep carbocation cascade that bypasses the formation of unstable secondary carbocations by breaking the adjacent C-C bond to form a more stable tertiary carbocation (IM3) and by Wagner-Meerwein 1,2-methyl rearrangement (IM7).

α-Cyclodextrin Encapsulation of Bicyclo[1.1.1]pentane Derivatives: A Storable Feedstock for Preparation of [1.1.1]Propellane.

The bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α-cyclodextrin (α-CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3-diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non-polar solvents. The combination of these methodologies enables simple, on-demand preparation of [1.1.1]propellane in various solvents under mild conditions from α-CD capsules containing 1,3-diiodo BCP.

DFT Study of a Missing Piece in Brasilane-Type Structure Biosynthesis: An Unusual Skeletal Rearrangement.

Brasilane-type sesquiterpenes have been known for a long time, but their biosynthetic pathways and mechanisms remain elusive. Recently, two groups independently characterized a Trichoderma terpene cyclase that produces trichobrasilenol, a brasilane-type sesquiterpene, and a plausible biosynthetic pathway was proposed based on isotopic labeling experiments. In the proposed mechanism, the characteristic brasilane-type 5/6 bicyclic skeleton is synthesized from a 5/7/3 tricyclic intermediate via a complicated concerted reaction, including six chemical events of C-C σ bond metathesis and rearrangements, ring-contraction, π bond formation, and regioselective hydroxylation. However, our density functional theory (DFT) calculations do not support this mechanism. On the basis of DFT calculations, we propose a new pathway for trichobrasilenol biosynthesis, involving a multistep carbocation cascade in which cyclopropylcarbinyl cations in equilibrium with homoallyl cations play a pivotal role. This pathway and mechanism is in good agreement with previous biosynthetic studies on brasilane-type compounds and related terpenoids, including isotope-labeling experiments and byproducts analysis.

Nucleophilic Diboration Strategy Targeting Diversified 1-Boraphenarene Architectures.

1-Boraphenalenes, a class of boron-doped polyaromatic hydrocarbons, were synthesized by nucleophilic diboration reaction of alkynes. Activation of diboron reagents with a highly basic sp2 -carbanion results in very fast successive C-B bond formations to construct the boracycle. This methodology is characterized by high chemoselectivity, affording a wide variety of 1-boraphenarenes with diverse polar substituents. The endocyclic boron can be arylated conveniently in one pot, and the peripheral boron is available for various chemical transformations. Highly diastereoselective diboration gives pseudo-enantio-enriched boraphenarene, which emits circularly polarized fluorescence (CPL).