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.

The Impact of Nociception Monitor-Guided Multimodal General Anesthesia on Postoperative Outcomes in Patients Undergoing Laparoscopic Bowel Surgery: A Randomized Controlled Trial.

BACKGROUND: Excess surgical stress responses, caused by heightened nociception, can lead to elevated levels of postoperative inflammation, resulting in an increased incidence of complications after surgery. We hypothesized that utilizing nociception monitor-guided multimodal general anesthesia would exert effects on postoperative outcomes (e.g., serum concentrations of C-reactive protein (CRP) after surgery, postoperative complications). METHODS: This single-center, double-blinded, randomized trial enrolled ASA class I/II adult patients with normal preoperative CRP levels, scheduled for laparoscopic bowel surgery. Patients were randomized to receive either standard care (control group) or nociception monitor-guided multimodal general anesthesia using the nociceptive response (NR) index (NR group), where NR index was kept below 0.85 as possible. The co-primary endpoint was serum concentrations of CRP after surgery or rates of 30-day postoperative complications (defined as Clavien-Dindo grades ≥ II). MAIN RESULTS: One hundred and four patients (control group, n = 52; NR group, n = 52) were enrolled for analysis. The serum CRP level on postoperative day (POD) 1 was significantly lower in the NR group (2.70 mg·dL-1 [95% confidence interval (CI), 2.19-3.20]) than in the control group (3.66 mg·dL-1 [95% CI, 2.98-4.34], p = 0.024). The postoperative complication rate was also significantly lower in the NR group (11.5% [95% CI, 5.4-23.0]) than in the control group (38.5% [95% CI, 26.5-52.0], p = 0.002). CONCLUSIONS: Nociception monitor-guided multimodal general anesthesia, which suppressed intraoperative nociception, mitigated serum concentrations of CRP level, and decreased postoperative complications after laparoscopic bowel surgery.

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.

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.

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.

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.

Dearomative triple elementalization of quinolines driven by visible light.

Organoboron and organosilicon compounds are used not only as synthetic building blocks but also as functional materials and pharmaceuticals, and compounds with multiple boryl and silyl groups are beginning to be used for these purposes. Especially in drug discovery, methodology providing easy stereoselective access to aliphatic nitrogen heterocycles bearing multiple boryl or silyl groups from readily available aromatic nitrogen heterocycles would be attractive. However, such transformations remain challenging, and available reactions have been mostly limited to dearomative hydroboration or hydrosilylation reactions. Here, we report the dearomative triple elementalization (carbo-sila-boration) of quinolines via the addition of organolithium followed by photo-boosted silaboration, affording the desired products with complete chemo-, regio-, and stereoselectivity. The reaction proceeds via the formation of silyl radicals instead of silyl anions. We also present preliminary studies to illustrate the potential of silaboration products as synthetic platforms.

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.

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.

Diamond-rich crystalline nanosheets seeded with a Langmuir monolayer of arachidic acid on water.

The enigmatic self-assembling ability of nanodiamond (ND) particles has been discovered herein. Diamond-rich crystalline nanosheets with thickness of approximately ∼25 nm were grown from a Langmuir monolayer of arachidic acid (AA) at the interface between air and a dilute aqueous ND solution. Their fine rectangular shapes with uniform uniaxial birefringence indicate appreciable crystallinity, thus supporting that they are hydrated colloidal crystals of homogeneous ND particles.

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.

In Situ Generation of N-Triflylimino-λ3-iodanes: Application to Imidation of Phosphines and Catalytic α-Amidation of 1,3-Dicarbonyl Compounds.

We describe the imidation of phosphines and α-amidation of 1,3-dicarbonyl compounds using N-triflylimino-λ3-iodane, which is generated in situ from iodosylarene and triflylamide without any other additives. Furthermore, the imino-λ3-iodane catalytically generated from an iodoarene precatalyst with oxone and triflylamide promotes α-amidation of 1,3-dicarbonyl compounds, representing the first method catalyzed by imino-λ3-iodane.

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.

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.

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.

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).

DFT Study on the Biosynthesis of Verrucosane Diterpenoids and Mangicol Sesterterpenoids: Involvement of Secondary-Carbocation-Free Reaction Cascades.

Some experimental observations indicate that a sequential formation of secondary (2°) carbocations might be involved in some biosynthetic pathways, including those of verrucosane-type diterpenoids and mangicol-type sesterterpenoids, but it remains controversial whether or not such 2° cations are viable intermediates. Here, we performed comprehensive density functional theory calculations of these biosynthetic pathways. The results do not support previously proposed pathways/mechanisms: in particular, we find that none of the putative 2° carbocation intermediates is involved in either of the biosynthetic pathways. In verrucosane biosynthesis, the proposed 2° carbocations (II and IV) in the early stage are bypassed by the formation of the adjacent 3° carbocations and by unusual skeletal rearrangement reactions, and in the later stage, the putative 2° carbocation intermediates (VI, VII, and VIII) are not present as the proposed forms but as nonclassical structures between homoallyl and cyclopropylcarbinyl cations. In the mangicol biosynthesis, one of the two proposed 2° carbocations (X) is bypassed by a C-C bond-breaking reaction to generate a 3° carbocation with a C=C bond, while the other (XI) is bypassed by a strong hyperconjugative interaction leading to a nonclassical carbocation. We propose new biosynthetic pathways/mechanisms for the verrucosane-type diterpenoids and mangicol-type sesterterpenoids. These pathways are in good agreement with the findings of previous biosynthetic studies, including isotope-labeling experiments and byproducts analysis, and moreover can account for the biosynthesis of related terpenes.

Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog.

Decreasing the partition coefficient (LogP) by the introduction of a hydrophilic group is the conventional approach for improving the aqueous solubility of drug candidates, but is not always effective. Since melting point is related to aqueous solubility, we and other groups have developed alternative strategies to improve solubility by means of chemical modification to weaken intermolecular interaction in the solid state, thereby lowering the melting point and increasing the solubility. Here, we show that converting the symmetrical molecular structure of the clinically used estrogen receptor (ER) antagonist cyclofenil (1) into asymmetrical form by introducing an alkyl group enhances the aqueous solubility. Among the synthesized analogs, the chiral methylated analog (R)-4c shows the highest solubility, being 3.6-fold more soluble than 1 even though its hydrophobicity is increased by the methylation. Furthermore, (R)-4c also showed higher membrane permeability than 1, while retaining a comparable metabolic rate, and equivalent biological activity of the active forms (R)-13a to 2. Further validation of this strategy using lead compounds having symmetric structures is expected.

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.