Pathophysiology and surgical outcomes of patients with fungal peritonitis from upper gastrointestinal tract perforation: a retrospective study.

PURPOSE: To compare the pathophysiology and surgical outcomes of emergency surgery for upper gastrointestinal tract perforation with and without fungal peritonitis and identify the risk factors for fungal peritonitis. METHODS: The subjects of this retrospective study were patients with upper gastrointestinal perforation and peritonitis who underwent emergency surgery at a single medical center in Japan. The patients were allocated to two groups according to the presence or absence of fungal peritonitis: group F and group N, respectively. RESULTS: At the time of surgery, ascitic fluid culture or serum ß-D glucan levels were available for 54 patients: 29 from group F and 25 from group N, respectively. The stomach was perforated in 14 patients (25.9%) and the duodenum was perforated in 40 patients (74.1%). Group F had a higher proportion of patients with low preoperative prognostic nutritional index scores (≤ 40) and C-reactive protein levels and a higher postoperative complication rate. The time to initiate food intake and the postoperative hospital stay were also significantly longer in group F. Multivariate analysis identified that the perforation site of the stomach was a risk factor for fungal peritonitis. CONCLUSION: Patients with fungal peritonitis from upper gastrointestinal tract perforation had higher postoperative complication rates, delayed postoperative recovery, and a longer hospital stay. Gastric perforation was a risk factor for fungal peritonitis.

Effect of 1,4-Dioxane Solvent on ß-Glucuronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-ß-D-glucuronate as the Glycosyl Donor.

A facile and selective ß-D-glucuronidation of alcohols, such as (-)-menthol, cholestanol, (+)- and (-)-borneols, and 2-adamantanol, using commercially available methyl 1,2,3,4-tetra-O-acetyl-ß-D-glucuronate as the glycosyl donor and trimethylsilyl bis(trifluoromethanesulfonyl)imide (Tf2NTMS) (0.5 equivalent) as the activator in 1,4-dioxane at 60 °C gave products in moderate yields. The addition of MS4A increased the ß : α ratios of D-glucuronides when cholestanol, (+)-borneol, and 2-adamantanol were used as the acceptor substrate.

Facile Preparation of L-Iduronic Acid and α-L-Iduronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-α-L-iduronate as Glycosyl Donor.

Methyl 1,2,3,4-tetra-O-acetyl-α-L-iduronate was prepared from methyl 1,2,3,4-tetra-O-ß-D-glucuronate in two steps: Ferrier's photobromination and subsequent radical reduction with tris(trimethylsilyl)silane. The obtained methyl 1,2,3,4-tetra-O-acetyl-α-L-iduronate was a good glycosyl donor for the L-iduronidation when bis(trifluoromethanesulfonic)imide was employed as the activator. The reaction afforded the α-isomer as the major product, the configuration of which is the same as that of the L-iduronic acid unit in heparin and heparan sulfate.

A Facile α-Glucuronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-D-glucuronate as Glycosyl Donor.

Some terpenyl 2,3,4-tri-O-acetyl-α-D-glucuronide methyl esters were facilely synthesized from commercially available methyl 1,2,3,4-tetra-O-acetyl-ß-D-glucuronate and terpenoid alcohols in the presence of bis(trifluoromethanesulfonyl)imide (Tf2NH) in dichloromethane (DCM) in good yields. The predominant α-selectivity at the anomer position is caused via transition state in which the neighboring group participation of the methoxycarbonyl group at C-6 stabilizes the oxonium intermediate by forming 1C4 conformation. The intermediate accelerates the glucuronidation reaction despite the use of the acetyl group, which is not a good activating group in general glycosylation reactions, as the activating group.

Construction of Acyclic All-Carbon Quaternary Stereocenter Based on Asymmetric Michael Addition of Chiral Amine.

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,ß-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the ß-amino ester derivative.

A Facile and Convenient Synthesis of Trisubstituted (E)-α,ß-Unsaturated Esters by Tandem Acetylation-E1cB Reaction.

A facile and convenient synthesis of trisubstituted (E)-α,ß-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in ß-hydroxy esters, furnishing α,ß-unsaturated esters in shorter steps than the previous method: an acetylation of ß-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,ß-unsaturated esters.

Elucidation of the Relationship between CD Cotton Effects and the Absolute Configuration of Sixteen Stereoisomers of Spiroheterocyclic-Lactams.

As part of research to search for antitumor agents in fungi originating from marine organisms, cephalimysins E⁻L were isolated from a culture broth of Aspergillus fumigatus that was separated from the marine fish Mugil cephalus. One- and two-dimensional nuclear magnetic resonance spectra revealed their planar structures, which are diastereomers of each other. Their absolute stereostructures were established by epimerization at C-8 with acidic methanol, nuclear Overhauser effect spectroscopy (NOESY), and circular dichroism (CD) spectroscopy. These demonstrated the detailed relationships between absolute configuration and CD Cotton effects. Additionally, in the growth inhibition assay against P388, HL-60, L1210, and KB cell lines, some of the fungal metabolites or reaction products exhibited moderate activities.

Glycosylation Reaction of Thioglycosides by Using Hypervalent Iodine(III) Reagent as an Excellent Promoter.

Thioglycosides are available donors in glycosylation due to the stability of the anomeric C-S bond under general reaction conditions of protection and deprotection, and offer orthogonality in their activation. We report now that the hypervalent iodine effectively induced glycosylation reaction of thioglycosides with various alcohols. This method features a high efficiency, completion in a short time, and proceeding under very mild conditions.

The synthesis of [18F]pitavastatin as a tracer for hOATP using the Suzuki coupling.

Fluorine-18 labeled radiotracers, such as [(18)F]fluorodeoxyglucose, can be used as practical diagnostic agents in positron emission tomography (PET). Furthermore, the properties of pharmaceuticals can be enhanced significantly by the introduction of fluorine groups into their original structures, and significant progress has been made during the last three decades towards the development of practical procedures for the introduction of fluorine. The replacement of the fluorine atoms present in pharmaceuticals with radioactive (18)F atoms is a rational approach for designing novel PET tracers. As a fluorine-containing pharmaceutical agent, pitavastatin has attracted considerable interest from researchers working in the life sciences because it can act as an antihyperlipidemic agent as well as a substrate for hepatic organic anion transporting polypeptides (hOATP). With this in mind, it was envisaged that [(18)F]pitavastatin would be used as an excellent imaging agent for hOATP, which prompted us to investigate the synthesis of this agent. Herein, we report a practical method for the synthesis of [(18)F]pitavastatin by the Suzuki coupling reaction of p-iodofluorobenzene and a quinoline boronate derivative, with the desired product being formed in a radiochemical yield of 12 ± 3% (decay corrected from [(18)F]fluoride ions, n = 3).

Synthesis and evaluation of (-)- and (+)-[¹¹C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging.

Improved radiopharmaceuticals for imaging cerebral acetylcholinesterase (AChE) are needed for the diagnosis of Alzheimer's disease (AD). Thus, (11)C-labeled (-)-galanthamine and its enantiomers were synthesized as novel agents for imaging the localization and activity of AChE by positron emission tomography (PET). C-11 was incorporated into (-)- and (+)-[(11)C]galanthamine by N-methylation of norgalanthamines with [(11)C]methyl triflate. Simple accumulation of (11)C in the brain was measured in an in vivo biodistribution study using mice, whilst donepezil was used as a blocking agent in analogous in vivo blocking studies. In vitro autoradiography of rat brain tissue was performed to investigate the distribution of (-)-[(11)C]galanthamine, and confirmed the results of PET studies in mice. The radiochemical yields of N-methylation of (-)- and (+)-norgalanthamines were 13.7% and 14.4%, respectively. The highest level of accumulation of (11)C in the brains of mice was observed at 10 min after administration (2.1% ID/g). Intravenous pretreatment with donepezil resulted in a 30% decrease in accumulation of (-)-[(11)C]galanthamine in the striatum; however, levels in the cerebellum were unchanged. In contrast, use of (+)-[(11)C]galanthamine led to accumulation of radioactivity in the striatum equal to that in the cerebellum, and these levels were unaffected by pretreatment with donepezil. In in vitro autoradiography of regional radioactive signals of brain sections showed that pretreatment with either (-)-galanthamine or donepezil blocked the binding of (-)-[(11)C]galanthamine to the striatum, while sagittal PET imaging revealed accumulation of (-)-[(11)C]galanthamine in the brain. These results indicate that (-)-[(11)C]galanthamine showed specific binding to AChE, whereas (+)-[(11)C]-galanthamine accumulated in brain tissue by non-specific binding. Thus, optically pure (-)-[(11)C]galanthamine could be a useful PET tracer for imaging cerebral AChE.

Isolation and characterization of new onionins A2 and A3 from Allium cepa, and of onionins A1, A2, and A3 from Allium fistulosum.

In this study, the new stable sulfur-containing compounds onionins A2 (1) and A3 (2) were isolated from the acetone extracts of the bulbs of Allium cepa L. and identified as the stereoisomers of onionin A1 discovered in our previous study. Their chemical structures, 3,4-dimethyl-5-(1E-propenyl)-tetrahydrothiophene-2-sulfenic acid-S-oxides, were characterized using various spectroscopic techniques. In addition, 1 and 2 together with onionin A1 were successfully isolated from the leaves of the Welsh onion, Allium fistulosum L. The onion-extracted fractions showed good potential to inhibit the polarization of M2 activated macrophages, indicating their possible ability to inhibit tumor cell proliferation.

Conversion of tomato saponins to pregnane derivatives.

Here reports new conversions methods of tomato saponins, esculeoside A (1) and a mixture of esculeosides B-1 (2) and B-2 (3), (the latter two were obtained from tomato cans) into pregnane derivative (5) by an alkal treatment followed by acid treatment. Compound 1 or a mixture of 2 and 3 were each refluxed with 1 N KOH to afford a characteristic pyridine steroidal glycoside (4), which was then treated with 2 N HCl-MeOH to afford a pregnane derivative, 3ß-hydroxy-5α-pregn-16-en-20-one (5). The results of the above two reactions indicated that tomato saponins are chemically closely related to pregnane hormones. We assume that the assimilated tomato saponins via the small intestine are metabolized into pregnane derivatives, demonstrating various bioactivities such as anti-cancer, anti-osteoporosis, and anti-menopausal disorder activities.

Novel design and synthesis of a radioiodinated glycolipid analog as an acceptor substrate for N-acetylglucosaminyltransferase V.

Guided by the known molecular recognition interactions between N-acetylglucosaminyltransferase V (GnT-V) and certain synthetic substrates, we synthesized a radiolabeled double-stranded glycolipid composed of a long-chain alkyl unit and a radioiodinated phenylalkyl unit, [(125)I]-2-[N-(2-hydroxy-3-hexadecyloxy)propyl-15-(4-iodophenyl)pentadecanecarboxamido]ethyl 2-acetamido-2-deoxy-ß-D-glucopyranosyl-(1→2)-α-D-mannopyranosyl-(1→6)-ß-D-glucopyranoside ([(125)I]2), as a novel intravital glycolipid mimic substrate of GnT-V. The radioactive iodine ((125)I) was incorporated via iododestannylation of the phenyltributyltin derivative, 2-[N-(2-acetoxy-3-hexadecyloxy)propyl-15-(4-tributylstannylphenyl)pentadecanecarboxamido]ethyl 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-ß-D-glucopyranosyl-(1→2)-3,4,6-O-acetyl-α-D-mannopyranosyl-(1→6)-2,3,4-tri-O-acetyl-ß-D-glucopyranoside (26). Subsequent deacetylation at the final step afforded [(125)I]2.

Prognostic significance of preoperative osteopenia on outcomes after gastrectomy for gastric cancer.

Aim: Osteopenia, characterized by low bone mineral density, is a potential prognostic factor for patients with cancer. The aim of this study was to clarify the impact of preoperative osteopenia in patients with gastric cancer (GC) after gastrectomy. Methods: We included 224 patients with GC who underwent gastrectomy between August 2013 and May 2022. Osteopenia was evaluated by measuring the pixel density in the mid-vertebral core of the 11th thoracic vertebra using computed tomography. Results: Osteopenia was identified in 68 patients (30%). The osteopenia group had significantly worse overall survival (OS) and disease-free survival (DFS) than the non-osteopenia group (P < .01, P < .01, respectively). The postoperative hospital stay was significantly longer, and the occurrence of postoperative complications (Clavien-Dindo grade ≥ III) was significantly higher in the osteopenia group (P = .04, P < .01, respectively). In multivariate analysis, osteopenia (P < .01), stage ≥II (P < .01), and R1 or R2 curability (P < .01) were independent and significant predictors of DFS. Additionally, osteopenia (P < .01), intraoperative blood loss (P = .04), stage ≥II (P < .01), and R1 or R2 curability (P < .01) were independent and significant predictors of OS. Conclusion: Preoperative osteopenia was independently associated with a poor prognosis and recurrence in patients who underwent gastrectomy for GC.

Microwave-assisted synthesis of organometallic complexes of 99mTc(CO)3 and Re(CO)3: its application to radiopharmaceuticals.

(99m)Tc-tricarbonyl [(99m)Tc(CO)(3)] complexes have been conventionally synthesized by heating [(99m)Tc(CO)(3)(H(2)O)(3)](+) and a tridentate chelating ligand under atmospheric pressure; however, this method is poor in terms of chemical yield and reproducibility. Moreover, since the half-life of (99m)Tc is very short (6 h), the development of facile and rapid methods of synthesizing (99m)Tc-labeled compounds, which could be used as radioactive tracers for single photon emission computed tomography (SPECT), is required. Thus, we initiated a study on the application of a microwave reaction to the synthesis of (99m)Tc(CO)(3)-2-picolylamine monoacetic acid (PAMA) [(99m)Tc(CO)(3)-PAMA] complexes on the basis of the fact that synthesis of metal complexes proceeds rapidly by microwave irradiation owing to an efficient exothermic phenomenon and heat conduction effect. Formation of by-products could be markedly suppressed by comparison with that in conventional methods. In the present study, rhenium (Re), an element belonging to the same group in the periodic table as technetium (Tc), and which also forms bipyramidal complexes, was first used to investigate the synthetic reaction because no stable isotopes exist for Tc. As a result, when water was used as the solvent under the irradiation of microwaves within 1 min, the Re(CO)(3)-PAMA complex could be directly synthesized from ethyl ester of PAMA (PAMAEE) and [Re(CO)(3)(H(2)O)(3)]Br in one step and with a high yield (94%). Finally, the (99m)Tc(CO)(3)-PAMA complex was successfully synthesized at a high radiochemical yield (>99%) within 1 min of reaction using (99m)Tc instead of Re under the same conditions.

Metal-Free Synthesis of Acyl Glycosides and Application to Oligosaccharide Synthesis.

Oligosaccharides are involved in numerous biological processes. Achieving optimal anomeric selectivity and regioselectivity remains challenging. Herein, we present a method for the oxidative glycosylation of thioglycosides with hypervalent iodine reagents derived from carboxylic acid to form C-O bonds. The reaction of thioglycosides with various hypervalent iodine carboxylates afforded acyl O-glycosyl compounds. These acyl O-glycosyl compounds could react with thioglycoside acceptors to produce disaccharides; trisaccharides and tetrasaccharides could be synthesized by repeating this method.

New class azaphilone produced by a marine fish-derived Chaetomium globosum. The stereochemistry and biological activities.

Four new metabolites, chaetomugilins P-R and 11-epi-chaetomugilin I, were isolated from a strain of Chaetomium globosum originally obtained from the marine fish Mugil cephalus, and their absolute stereostructures were elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR techniques and various chemical transformations. Particularly, the skeleton of chaetomugilin P is different from that of other azaphilones isolated from this fungal strain to date. In addition, these compounds significantly inhibited the growth of cultured P388, HL-60, L1210 and KB cell lines.

Synthesis and evaluation of a radioiodinated trisaccharide derivative as a synthetic substrate for a sensitive N-acetylglucosaminyltransferase V radioassay.

N-acetylglucosaminyltransferase V (GnT-V) is one of the most relevant glycosyltransferases to tumor invasion and metastasis. Based on previous findings of molecular recognition between GnT-V and synthetic substrates, we designed and synthesized a p-iodophenyl-derivatized trisaccharide, 2-(4-iodophenyl)ethyl 6-O-[2-O-(2-acetamido-2-deoxy-ß-D-glucopyranosyl)-α-d-mannopyranosyl]-ß-D-glucopyranoside (IPGMG, 1) and its radiolabeled form, [(125)I]IPGMG ([(125)I]1), for use in assays of GnT-V activity in vitro. The tributyltin derivative, 2-[4-(n-tributylstannyl)phenyl]ethyl 6-O-[2-O-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-ß-D-glucopyranosyl)-3,4,6-tri-O-acetyl-α-D-mannopyranosyl]-2,3,4-tri-O-acetyl-ß-D-glucopyranoside (21), was synthesized as a precursor for the preparation of [(125)I]1. The iododestannylation of 21 using hydrogen peroxide as an oxidant followed by deacetylation yielded [(125)I]1. When [(125)I]1 was incubated in GnT-V-expressing cells with a UDP-GlcNAc donor, the production of ß1-6GlcNAc-bearing IPGMG (IPGGMG, 2) was confirmed by radio-HPLC. In kinetic analysis, 1 was found to be a good substrate with a K(m) of 23.7 µM and a V(max) of 159 pmol/h. µg protein. [(125)I]1 would therefore be a useful synthetic substrate for the quantitative determination of GnT-V activity.

The relationship between the CD Cotton effect and the absolute configuration of FD-838 and its seven stereoisomers.

Three new metabolites having a spiro-heterocyclic gamma-lactam core, cephalimysins B-D (1-3), as well as FD-838 (4) were isolated from a culture broth of Aspergillus fumigatus that was originally separated from the marine fish Mugil cephalus. Compounds 1-3 are the diastereomers of 4. Compounds 2 and 3 exhibit an opposite absolute configuration at a spiro carbon to that of other known naturally occurring spiro-heterocyclic gamma-lactams. In addition, we succeeded in the chemical transformation of the four natural products (1-4) into their epimers (1'-4') at C-8 to afford all the stereoisomers of FD-838 (4) with three stereogenic centers. Consequently, the relationship between the absolute configuration at stereogenic centers and the CD Cotton effects for these compounds could be unambiguously established. All of the compounds except 1 moderately inhibited the growth of cultured P388 and HL-60 cell lines.

One-pot construction of multiple contiguous chiral centers using Michael addition of chiral amine.

Multiple contiguous chiral centers were constructed in one pot using three types of multistep reactions initiated with the Michael addition of N-benzyl-2(R)-methoxy-(+)-10-bornylamide to alpha,beta-unsaturated esters, i.e., asymmetric Michael-aldol reaction, double Michael addition, and double Michael-aldol reaction. The chiral 2-methoxy-10-bornyl group as well as the benzyl group on the amino group of the products in the Michael-aldol reaction could be easily cleaved by treatment with NIS (4 equiv), and beta-amino esters with multiple contiguous chiral centers were obtained in good yield. As an application, the beta-amino-beta'-hydroxy ester obtained in the asymmetric Michael-aldol reaction was converted to the beta-lactam derivative in good yield.