Efficacy of a Novel Tapered Contrast Catheter for Endoscopic Ultrasound-Guided Hepaticogastrostomy: A Multicenter Study.

Background: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is an alternative for failed endoscopic retrograde cholangiopancreatography (ERCP), with current success rates of 65-84% considered suboptimal. A novel ERCP catheter (SHOREN, Kaneka Corporation, Osaka, Japan) with a tapered 3.3-French tip may facilitate smoother insertion, potentially improving outcomes. Methods: This retrospective analysis encompassed EUS-HGS procedures conducted from January 2021 to August 2023 at four institutions. The aim of this study was to compare the performance of conventional and novel ERCP contrast catheters regarding the success rate of single-attempt catheter insertion, failure rates, technical success rates, and incidence of adverse events. Results: The study included 48 patients; 26 underwent EUS-HGS using conventional catheters and 22 with the novel catheter. The novel catheter achieved higher success rates in single-attempt insertions (96.5% vs. 80.8%) and lower failure rates (4.6% vs. 7.7%). The occurrence of bile peritonitis was comparable between the two groups. Conclusions: The novel ERCP contrast catheter with a tapered tip appears to contribute to successful catheter insertion and is useful for EUS-HGS.

Tailor-made amino acids in the design of small-molecule blockbuster drugs.

The role of amino acids (AAs) in modern health industry is well-appreciated. Residues of individual AAs, or their chemical modifications, such as diamines and amino alcohols, are frequently found in the structures of modern pharmaceuticals. The goal of this review article, is to emphasize that, currently, tailor-made AAs serve as key structural features in many most successful pharmaceuticals, so-called blockbuster drugs. In the present article, we profile 14 small-molecule drugs, underscoring the breadth of structural variety of AAs applications in numerous therapeutic areas. For each compound, we provide spectrum of biological activity, medicinal chemistry discovery, and synthetic approaches.

Cyclic tailor-made amino acids in the design of modern pharmaceuticals.

Tailor-made AAs are indispensable components of modern medicinal chemistry and are becoming increasingly prominent in new drugs. In fact, about 30% of small-molecule pharmaceuticals contain residues of tailor-made AAs or structurally related diamines and amino-alcohols. Cyclic tailor-made AAs present a particular value to rational structural design by virtue of their local conformational constraints and are widely used in lead optimization programs. The present review article highlights 34 compounds, all of which are derived from cyclic AAs, representing recently-approved, small-molecule pharmaceuticals as well as promising drug candidates currently in various phases of clinical study. For each compound, the discussion includes the discovery, therapeutic profile and optimized synthesis, with a focus on the preparation of cyclic tailor-made AA as the principal structural feature. The present review article is intended to serve as a reference source for organic, medicinal and process chemists along with other professionals working in the fields of drug design and pharmaceutical discovery.

Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals.

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

The planocerid flatworm is a main supplier of toxin to tetrodotoxin-bearing fish juveniles.

Tetrodotoxin (TTX), a potent neurotoxin, is found in various phylogenetically diverse taxa. In marine environments, the pufferfish is at the top of the food chain among TTX-bearing organisms. The accumulation of TTX in the body of pufferfish appears to be of the food web that begins with bacteria. It is known that toxic pufferfishes possess TTX from the larval/juvenile stage. However, the source of the TTX is unknown because the maternally sourced TTX is extremely small in quantity. Therefore, the TTX has to be obtained from other organisms or directly from the environment. Here, we report evidence that the source of TTX for toxic fish juveniles including the pufferfish (Chelonodon patoca) and the goby (Yongeichthys criniger) is in the food organisms, as seen in their gut contents. Next generation sequencing analysis for the mitochondrial COI gene showed that the majority of the sequence recovered from intestinal contents of these toxic fishes belonged to the flatworm Planocera multitentaculata, a polyclad flatworm containing highly concentrated TTX from the larval stage. PCR specific to P. multitentaculata also showed that DNA encoding the planocerid COI gene was strongly detected in the intestinal contents of the goby and pufferfish juveniles. Additionally, the planocerid specific COI sequence was detected in the environmental seawater collected from the water around the sampling locations for TTX-bearing fish. These results suggest that planocerid larvae are the major TTX supplier for juveniles of TTX-bearing fish species.

Applications of fluorine-containing amino acids for drug design.

Fluorine-containing amino acids are becoming increasingly prominent in new drugs due to two general trends in the modern pharmaceutical industry. Firstly, the growing acceptance of peptides and modified peptides as drugs; and secondly, fluorine editing has become a prevalent protocol in drug-candidate optimization. Accordingly, fluorine-containing amino acids represent one of the more promising and rapidly developing areas of research in organic, bio-organic and medicinal chemistry. The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements. The compounds under discussion represent pharmaceutical drugs currently on the market, or in clinical trials as well as examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action. For each compound, we present features of biological activity, a brief history of the design principles and the development of the synthetic approach, focusing on the source of tailor-made amino acid structures and fluorination methods. General aspects of the medicinal chemistry of fluorine-containing amino acids and synthetic methodology are briefly discussed.

Optical Resolution of Rimantadine.

This work discloses a new procedure for the resolution of commercially available racemic rimantadine hydrochloride to enantiomerically pure (S)-rimantadine using (R)-phenoxypropionic acid as a recyclable resolving reagent. Good chemical yields, operational ease, and low-cost structure underscore the preparative value of this method for the production of enantiomerically pure rimantadine for medicinal or synthetic studies.

Including planocerid flatworms in the diet effectively toxifies the pufferfish, Takifugu niphobles.

Beginning with the larval stages, marine pufferfish such as Takifugu niphobles contain tetrodotoxin (TTX), an extremely potent neurotoxin. Although highly concentrated TTX has been detected in adults and juveniles of these fish, the source of the toxin has remained unclear. Here we show that TTX in the flatworm Planocera multitentaculata contributes to the toxification of the pufferfish throughout the life cycle of the flatworm. A species-specific PCR method was developed for the flatworm, and the specific DNA fragment was detected in the digesta of wild pufferfish adults. Predation experiments showed that flatworm larvae were eaten by the pufferfish juveniles, and that the two-day postprandial TTX content in these pufferfish was 20-50 µg/g. Predation experiments additionally showed flatworm adults were also eaten by pufferfish young, and after two days of feeding, TTX accumulated in the skin, liver and intestine of the pufferfish.

Second-order asymmetric transformation and its application for the practical synthesis of α-amino acids.

We report a discovery of a new rimantadine [1-(1-adamantyl)ethanamine]-derived chiral ligand and its application for the preparation of α-amino acids using the second-order asymmetric transformation approach. The operational ease of experimental procedures coupled with excellent chemical yields and stereochemical outcome suggests some potential synthetic generality of this approach.

Tandem Alkylation-Second-Order Asymmetric Transformation Protocol for the Preparation of Phenylalanine-Type Tailor-Made α-Amino Acids.

In this work, we disclose an advanced general process for the synthesis of tailor-made α-amino acids (α-AAs) via tandem alkylation-second-order asymmetric transformation. The first step is the alkylation of the chiral Ni(II) complex of glycine Schiff base, which is conducted under mild phase-transfer conditions allowing the structural construction of target α-AAs. The second step is based on the methodologically rare second-order asymmetric transformation, resulting in nearly complete precipitation of the corresponding (SC,RN,RC)-configured diastereomer, which can be collected by a simple filtration. The operational convenience and potential scalability of all experimental procedures, coupled with excellent stereochemical outcome, render this method of high synthetic value for the preparation of various tailor-made α-AAs.

The Second-generation of Highly Potent Hepatitis C Virus (HCV) NS3/4A Protease Inhibitors: Evolutionary Design Based on Tailor-made Amino Acids, Synthesis and Major Features of Bio-activity.

Hepatitis C is a current pandemic liver disease caused by the hepatitis C virus (HCV) with high morbidity and mortality. Recently, the direct-acting antiviral agents (DAAs) targeting HCV NS3/4A, NS5A and NS5B have become the most effective therapies against HCV infection in the clinical treatment. Among them, the second-generation of NS3/4A inhibitors have emerged as the mainstay of the DAA therapies, which are derived from the peptide substrate of NS3/4A protease and modified with various tailor-made amino acids in order to achieve high sustained virologic response (SVR) against HCV. This review summarizes sixteen examples of the second-generation of HCV NS3/4A inhibitors, mainly focusing on the clinical application, structure development, structure-activity relationship (SAR) and their synthesis.

Seasonal Changes in the Tetrodotoxin Content of the Flatworm Planocera multitentaculata.

Tetrodotoxin (TTX) is a potent neurotoxin that acts specifically on voltage-gated sodium channels on excitable membranes of muscle and nerve tissues. The biosynthetic process for TTX is unclear, although marine bacteria are generally thought to be the primary producers. The marine flatworm Planocera multitentaculata is a known TTX-bearing organism, and is suspected to be a TTX supplier to pufferfish. In this study, flatworm specimens were collected from an intertidal zone in Hayama, Kanagawa, Japan, the TTX content of the flatworm was measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and seasonal changes in TTX content were investigated. No significant difference in TTX concentration of the flatworm body was found between the spawning period and other periods. However, the TTX content in individual flatworms was significantly higher in the spawning period than at other times. The TTX content rose in association with an increase in the body weight of the flatworm.

Early dual drainage combining transpapillary endotherapy and percutaneous catheter drainage in patients with pancreatic fistula associated with severe acute pancreatitis.

BACKGROUND: The development of pancreatic fistula (PF) associated with pancreatic necrosis is of great concern in the management of severe acute pancreatitis (SAP). We expected that early recognition and intervention of PF combined with percutaneous catheter drainage (PCD) for pancreatic infection may improve SAP outcomes. METHODS: Fifteen consecutive patients with SAP were enrolled. Whenever feasible, fine-needle aspiration for fluid collection was performed to determine infection and amylase concentration. For infection and PF with amylase-rich fluid, PCD and transpapillary endotherapy (preferably naso-pancreatic drainage) were carried out as soon as possible. PCD was intensively managed by irrigating the sized-up and multiple large bore catheters. RESULTS: Infected fluid collection and PF were both detected in 13 (86.7%) patients. Pancreatic duct (PD) disruption (n = 6) and organ failure (n = 5) occurred exclusively in patients with amylase-rich collection ≥10,000 U/L. The median timing of PCD and endotherapy was 15.5 and 16.5 days, respectively. No serious complications or mortality resulted from intervention procedures other than stent occlusion in one (6.7%) patient. Surgical intervention due to uncontrollable infection and visceral organ injury was avoided. Fistula closure was achieved in 12 (92.3%) of 13 PF patients with a median duration of 45 days. Disease-related mortality occurred in one (6.7%) patient. CONCLUSION: Amylase-rich fluid collection ≥10,000 U/L may be an indication for further endoscopic investigation of PD disruption. Early dual drainage combining pancreatic endotherapy and PCD is feasible and safe, and may improve treatment outcome.

Advanced asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by alkylation/cyclization of newly designed axially chiral Ni(II) complex of glycine Schiff base.

Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is in extremely high demand due to the pharmaceutical importance of this tailor-made, sterically constrained α-amino acid. Here we report the development of an advanced procedure for preparation of the target amino acid via two-step SN2 and SN2' alkylation of novel axially chiral nucleophilic glycine equivalent. Excellent yields and diastereoselectivity coupled with reliable and easy scalability render this method of immediate use for practical synthesis of (1R,2S)-vinyl-ACCA.

[Endoscopic nasobiliary and nasopancreatic drainage contributing to healing of duodenal ulcer perforation: a case report].

A 75-year-old man with vomiting and right abdominal pain was admitted to the Department of Surgery in our hospital. With a diagnosis of perforated duodenal ulcer, he was treated conservatively. On the day 8 of hospitalization, his general condition worsened and he underwent surgery. During operation, the perforated duodenal ulcer and paraduodenal fluid collection was observed, and percutaneous drainage was accordingly established. After this procedure, renal dysfunction was exacerbated and he was transferred to our department for endoscopic treatment. On day 28 of hospitalization, nasobiliary and nasopancreatic drainage was administered. Renal dysfunction gradually improved, and healing of the perforated duodenal ulcer was recognized on day 93. On day 112, the patient was discharged.

Chemical dynamic kinetic resolution and S/R†interconversion of unprotected α-amino acids.

Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α-amino acids (α-AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/R interconversions of α-AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.

Copper-catalyzed enantioselective allylic alkylation of terminal alkyne pronucleophiles.

The copper-catalyzed enantioselective allylic alkylation of terminal alkynes with primary allylic phosphates was developed by the use of a new chiral N-heterocyclic carbene ligand bearing a phenolic hydroxy group at the ortho position of one of the two N-aryl groups. This reaction occurred with excellent γ-branch regioselectivity and high enantioselectivity, forming a controlled stereogenic center at the allylic/propargylic position. Various terminal alkynes, including silyl, aliphatic, and aromatic alkynes, could be used directly without premetalation of the C(sp)-H bond. On the basis of the results of experiments using an isomeric secondary allylic phosphate, which gave a branched product through an α-selective substitution reaction with retention of configuration, a reaction pathway involving 1,3-allylic migration of Cu in a ([σ + π]-allyl)copper(III) species is proposed.

Design and synthesis of (S)- and (R)-α-(phenyl)ethylamine-derived NH-type ligands and their application for the chemical resolution of α-amino acids.

This work presents the first chemical approach for the resolution of α-amino acids offering the following advantages: (1) The specially designed resolving reagent is derived from α-(phenyl)ethylamine, the most inexpensive chiral auxiliary, which can be recycled and reused, rendering the cost structure of the complete process very attractive; (2) the time-efficient two-step process can be conducted under operationally convenient conditions with virtually quantitative yields; and (3) the process can readily be adapted to large-scale use.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids.

This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-ß-hydroxy and α,ß-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations.

Alkylations of chiral or achiral Ni(II) complexes of glycine Schiff bases constitute a landmark in the development of practical methodology for asymmetric synthesis of α-amino acids. Straightforward, easy preparation as well as high reactivity of these Ni(II) complexes render them ready available and inexpensive glycine equivalents for preparing a wide variety of α-amino acids, in particular on a relatively large scale. In the case of Ni(II) complexes containing benzylproline moiety as a chiral auxiliary, their alkylation proceeds with high thermodynamically controlled diastereoselectivity. Similar type of Ni(II) complexes derived from alanine can also be used for alkylation providing convenient access to quaternary, α,α-disubstituted α-amino acids. Achiral type of Ni(II) complexes can be prepared from picolinic acid or via recently developed modular approach using simple secondary or primary amines. These Ni(II) complexes can be easily mono/bis-alkylated under homogeneous or phase-transfer catalysis conditions. Origin of diastereo-/enantioselectivity in the alkylations reactions, aspects of practicality, generality and limitations of this methodology is critically discussed.