Precursor-directed biosynthesis and biological activity of tripropeptin Cpip, a new tripropeptin C analog containing pipecolic acid.

Tripropeptin C, a non-ribosomal cyclic lipopeptide containing three proline residues, exhibits excellent efficacy in the mouse-methicillin-resistant Staphylococcus aureus septicemia model. Since tripropeptins contain L-prolyl-D-proline and, as a result, are known to form a hairpin structure in proteins, it was of interest to determine whether this substructure contributes to their antibacterial activity. In this study, prolines in tripropeptin C were replaced with pipecolic acid(s) using precursor-directed biosynthesis. Only a new tripropeptin analog, tripropeptin Cpip, which has one L-pipecolic acid in place of L-proline, was isolated. The in vitro antimicrobial activity of the new analog was approximately two to four times weaker activity against Gram-positive bacteria, including drug-resistant species, compared with that of tripropeptin C. These results suggest that the L-prolyl-D-proline substructure plays an important role in the observed potency of tripropeptins.

Enantioselective Total Syntheses of (+)-Ganocin A and (-)-Cochlearol B.

Herein, we report the total syntheses of (+)-ganocin A and (-)-cochlearol B, featuring pentacyclic skeletons, in optically active forms. We utilized asymmetric Corey-Bakshi-Shibata reduction, phenolic oxidative cyclization, the intramolecular radical cyclization-benzylic oxidative cyclization sequence, and intramolecular [2 + 2] photocycloaddition. These key steps enabled enantioselective access with the longest linear sequence of 17 steps and 9% overall yield for (+)-ganocin A and with 16 steps and 9% overall yield for (-)-cohlearol B.

Oxygen-Fueled Iterative Hydride Transfer Driven by a Rigid Planar Architecture.

An iterative hydride reduction/oxidation process was promoted under ambient conditions by a quasi-planar iminium cation rigidified by two concatenated quinoline units. The iminium proton was fixed by hydrogen bonding from neighboring quinoline nitrogen atoms, rendering the imine highly susceptible to hydride reduction with weak reductants, e.g., 1,4-dihydropyridines. The thus-formed amine was readily oxidized by molecular oxygen to regenerate the quasi-planar iminium cation under ambient conditions. This process was exploited for catalytic oxidation of 1,4-dihydropyridines as well as 9,10-dihydroacridine to highlight an intriguing rigidity-driven catalysis.

Diastereoselective Direct Catalytic Asymmetric Mannich-Type Reactions of Alkylnitriles with a Ni(II)-Carbene Complex.

Despite recent advances in reactions using alkylnitriles as carbon nucleophiles, diastereoselective direct catalytic asymmetric reactions, in which two consecutive chiral centers could be controlled, remain largely unexplored. Herein, we report the addition of alkylnitriles (such as propionitrile) to imines in the presence of a catalytic amount of a chiral pincer-type Ni-carbene complex and potassium 2,6-di-tert-butyl-4-methylphenoxide (KBHT). BHT and molecular sieves were used as additives to improve the yields, diastereoselectivity, and enantiomeric ratio up to >99%, 90:10 anti/syn, and 97.5:2.5 er, respectively. The Mannich adducts can be readily converted to the corresponding ß-amino acids.

Total Synthesis of Cochlearol†B via Intramolecular [2+2] Photocycloaddition.

Herein, we describe the first total synthesis of cochlearol B, a meroterpenoid natural product featuring a 4/5/6/6/6-fused pentacyclic structure. Key steps, oxidative cyclization and subsequent intramolecular [2+2] photocycloaddition, which constructed the pentacyclic structure in highly stereoselective manner, allowed efficient access to cochlearol B with the longest linear sequence of 16 steps, and in 9 % overall yield. Single-crystal X-ray crystallographic analysis clearly confirmed the stereochemistry of cochlearol B.

Convergent total synthesis of corallocin A.

The first total synthesis of corallocin A is described herein. The Suzuki coupling reaction as a key step proceeded with high stereoselectivity and in good yield. Robust transformations, including Vilsmeier-Haack formylation and Wittig reaction, allowed for effective access to corallocin A.

Direct Catalytic Asymmetric Addition of Alkylnitriles to Aldehydes with Designed Nickel-Carbene Complexes.

A direct catalytic asymmetric addition of acetonitrile to aldehydes that realizes over 90 % ee is the ultimate challenge in alkylnitrile addition chemistry. Herein, we report achieving high enantioselectivity by the strategic use of a sterically demanding NiII pincer carbene complex, which afforded highly enantioenriched ß-hydroxynitriles. This highly atom-economical process paves the way for exploiting inexpensive acetonitrile as a promising C2 building block in a practical synthetic toolbox for asymmetric catalysis.

Author Correction: TriQuinoline.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

TriQuinoline.

The bottom-up synthesis of structurally well-defined motifs of graphitic materials is crucial to understanding their physicochemical properties and to elicit new functions. Herein, we report the design and synthesis of TriQuinoline (TQ) as a molecular model for pyridinic-nitrogen defects in graphene sheets. TQ is a trimer of quinoline units concatenated at the 2- and 8-positions in a head-to-tail fashion, whose structure leads to unusual aromatisation behaviour at the final stage of the synthesis. The central atomic-sized void endows TQ with high proton affinity, which was confirmed empirically and computationally. TQ•H+ is a two-dimensional cationic molecule that displays both π-π and CH-π contact modes, culminating in the formation of the ternary complex ([12]cycloparaphenylene(CPP) ⊃ (TQ•H+/coronene)) that consists of TQ•H+, coronene (flat), and [12]cycloparaphenylene ([12]CPP) (ring). The water-miscibility of TQ•H+ allows it to serve as an efficient DNA intercalator for e.g. the inhibition of topoisomerase I activity.

Anteroposterior molecular registries in ectoderm of the echinus rudiment.

BACKGROUND: Echinoderms and hemichordates are sister taxa that both have larvae with tripartite coeloms. Hemichordates inherit the coelom plan and ectoderm from larvae, whereas echinoderms form the adult rudiment comprising rearranged coeloms and a vestibule that then develops into adult oral ectoderm. Molecular networks that control patterns of the ectoderm and the central nervous system along the anteroposterior (AP) axis are highly conserved between hemichordates and chordates, respectively. In echinoderms, however, little is known about the AP registry in the ectoderm. RESULTS: We isolated ectodermal AP map genes from the sand dollar Peronella japonica and examined their expression. Comparative expression analyses showed that (1) P. japonica orthologs of hemichordate anterior markers are expressed in the larval apical plate, which degenerates during metamorphosis; (2) P. japonica orthologs of the medial markers are expressed in the ambulacral ectoderm of the rudiment; and (3) few P. japonica orthologs of the posterior markers are expressed in ectoderm. CONCLUSIONS: We suggest that echinoids only inherit the ambulacral ectoderm from a common ambulacrarian ancestor, which largely corresponds to the collar ectoderm in hemichordates. The ectodermal AP registry provides insights into the AP axis and evolutionary processes of echinoderms from a common ambulacrarian ancestor. Developmental Dynamics 247:1297-1307, 2018. © 2018 Wiley Periodicals, Inc.

Synthesis of α-Borylated Ketones by Regioselective Wacker Oxidation of Alkenylboronates.

As part of a program aimed at metal-catalyzed oxidative transformations of molecules with carbon-metalloid bonds, the synthesis of α-borylated ketones is reported via regioselective TBHP-mediated Wacker-type oxidation of N-methyliminodiacetic acid (MIDA)-protected alkenylboronates. The observed regioselectivity correlates with the hemilabile nature of the B-N dative bond in the MIDA boronate functional group, which allows boron to guide selectivity through a neighboring group effect.

The neutrophil-to-lymphocyte ratio (NLR) predicts short-term and long-term outcomes in gastric cancer patients.

BACKGROUND: The preoperative neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic marker for gastric cancer patients. However, the utility of the NLR in predicting short-term outcomes in gastric cancer patients remains unclear. Here, we investigated whether the preoperative NLR is a predictor of short-term outcomes in gastric cancer patients. METHODS: We retrospectively evaluated 154 consecutive gastric cancer patients. We compared the perioperative outcomes and median survival times (MSTs). In particular, for stage II/III (UICC, 7th edition) gastric cancer patients, we compared median disease-free survival time (MDFST) between the low- and high-NLR groups. RESULTS: Between the low-NLR group (n = 110) and the high-NLR group (n = 44), significant differences were observed in perioperative outcomes, including postoperative complications (3 (2.7%) vs. 5 (11.3%); p = 0.015), intraoperative blood loss (158 ± 168 g vs. 232 ± 433 g; p = 0.022), and intraoperative blood transfusions (0 vs. 3 (6.8%); p = 0.042). MSTs and MDFSTs were also significantly different (812 vs. 594 days, p = 0.04; and 848 vs. 475 days, p = 0.03, respectively). Multivariate analysis identified the NLR (hazard ratio [HR], 2.015; p = 0.004), Glasgow Prognostic Score (GPS) (HR, 1.533; p = 0.012), and presence of stage III/IV disease (HR, 5.488; p < 0.001), preoperative symptoms (HR, 3.412; p = 0.008), or postoperative complications (HR, 2.698; p < 0.001) as independent prognostic factors. CONCLUSIONS: We suggest that the preoperative NLR is an additional useful predictor of both long-term and short-term outcomes in gastric cancer patients.

Collision tumor consisting of a colorectal adenocarcinoma and dissemination of a gastric adenocarcinoma.

BACKGROUND: Collision tumors, composed of histologically distinct tumor types, are rare entities, especially in the colorectum, and corresponding evidence-based clinical management or treatment strategies are poorly defined. This is the first report of a collision tumor composed of two histologically distinct adenocarcinomas. CASE PRESENTATION: A 78-year-old male showed severe anemia and a 10% body weight loss over 1 month. Preoperative examination revealed T3N1M0 stage IIIA gastric cancer and T3N0M0 stage IIA rectal cancer. Distal gastrectomy and rectectomy with regional lymph node dissection were performed. Immunohistochemistry revealed two distinct adenocarcinomas with gland duct structures - a colorectal adenocarcinoma and a disseminated gastric adenocarcinoma - that had collided to form an invasive tumor on the serosal surface of the anterior rectum wall. CONCLUSION: This extremely rare case of a collision tumor supports that precise immunohistochemical identification of all tumor components is needed for guiding decisions affecting overall prognosis, adjuvant treatment and survival.

Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors.

Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. Driven by the unmet need to develop chemoselective access to boron chemotypes, we report herein the synthesis of α- and ß-aminocyano(MIDA)boronates from borylated carbonyl compounds. Activity-based protein profiling of the resulting ß-aminoboronic acids furnishes selective and cell-active inhibitors of the (ox)lipid-metabolizing enzyme α/ß-hydrolase domain 3 (ABHD3). The most potent compound displays nanomolar in vitro and in situ IC50 values and fully inhibits ABHD3 activity in human cells with no detectable cross-reactivity against other serine hydrolases. These findings demonstrate that synthetic methods that enhance the heteroatom diversity of boron-containing molecules within a limited set of scaffolds accelerate the discovery of chemical probes of human enzymes.

Hepatic sarcoidosis mimicking cholangiocellular carcinoma: A case report and literature review.

INTRODUCTION: Sarcoidosis is a multisystem disease characterized by the presence of non-caseating granulomas in affected organs. Almost 70% of patients with a sarcoidosis reaction have hepatic involvement. However, evidence-based clinical management or treatment strategies for hepatic sarcoidosis are poorly defined. Here, we present a case of a resected hepatic sarcoidosis patient. Additionally, we review the relevant hepatic sarcoidosis literature and discuss the clinical management of hepatic sarcoidosis. PRESENTATION OF CASE: A 20-mm liver tumor of segment 8 was incidentally detected in a 64-year-old female. Radiological images resembled the enhancement pattern of cholangiocellular carcinoma. Thus, this lesion was assigned a preoperative classification of pT1N0M0 stage I according to the 7th Union for International Cancer Control guidelines. The patient underwent a partial liver resection. Histologically, the tumor contained sarcoidosis lesions indicated by a conglomerate of epithelioid granulomas with giant cells. These histopathological findings were consistent with the diagnosis of hepatic sarcoidosis. DISCUSSION: Histopathological examination has been established as the definitive diagnostic tool for hepatic sarcoidosis. Therefore, liver biopsy or surgical resection of a liver tumor should be considered in cases that are difficult to preoperatively distinguish from malignant tumors. CONCLUSION: We present the case of a patient with surgically resected hepatic sarcoidosis that was difficult to preoperatively distinguish from cholangiocellular carcinoma.

The impact of three-dimensional reconstruction on laparoscopic-assisted surgery for right-sided colon cancer.

INTRODUCTION: During laparoscopic-assisted colorectal surgery (LACS) for right-sided colon cancer patients, we performed three-dimensional (3D) surgical simulation to investigate vascular anatomy, including the ileocolic artery (ICA), right colic artery (RCA) and superior mesenteric vein (SMV). AIM: We also used 3D imaging to examine the shortest distance from the root of the ileocolic vein (ICV) to the gastrocolic trunk (GCT). MATERIAL AND METHODS: We analyzed 46 right-sided colon cancer patients who underwent 3D-simulated LACS. We also examined a control group of 20 right-sided colon cancer patients who underwent LACS without 3D imaging. Patients who received such assessments were classified into the following two groups based on the vessel arrangement patterns of the ICA and SMV: the type A group, in which the ICA crosses anterior to the SMV, and the type B group, in which the ICA crosses posterior to the SMV. The shortest length from the root of the ICV to the GCT (D mm) was measured via 3D imaging. Patient characteristics and perioperative outcomes for these three groups were compared. RESULTS: The mean D mm for all cases was 29.2 ±5.21 mm. Mean D mm values for the type A and type B groups were 27.8 ±4.21 and 30.5 ±5.53 mm, respectively. Intraoperative blood loss was lower in the type A group (41.8 ±27.5 g) and the type B group (44.5 ±31.6 g) than that in the control group (86.8 ±27.5 g) (p = 0.013). CONCLUSIONS: 3D imaging was useful for understanding anatomical relationships during LACS.

Cyclols Revisited: Facile Synthesis of Medium-Sized Cyclic Peptides.

Medium-sized rings, particularly the corresponding cyclic peptides, are challenging synthetic targets. In the present study, we report an approach to medium-sized cyclic peptides through targeted formation and collapse of cyclol intermediates. This methodology operates on ß-amino imides derived from 2,5-diketopiperazines and offers a straightforward transition from frequently examined scaffolds in drug discovery to a rarely visited class of medium-sized rings.

Pyramidalization/twisting of the amide functional group via remote steric congestion triggered by metal coordination.

For decades, the planarity of the amide functional group has garnered sustained interest in organic chemistry, enticing chemists to deform its usually characteristic high-fidelity plane. As opposed to the construction of amides that are distorted by imposing rigid covalent bond assemblies, we demonstrate herein the deformation of the amide plane through increased steric bulk in the periphery of the amide moiety, which is induced by coordination to metal cations. A crystallographic analysis revealed that the thus obtained amides exhibit significant pyramidalization and twisting upon coordination to the metals, while the amide functional group remained intact. The observed deformation, which should be attributed to through-space interactions, substantially enhanced the solvolytic cleavage of the amide, providing compelling evidence that temporary crowding in the periphery of the amide functional group may be used to control the reactivity of amides.

Oxalyl Boronates Enable Modular Synthesis of Bioactive Imidazoles.

Described herein is the preparation of oxalyl boronate building blocks and their application for the construction of heterocycles. The oxalyl unit, readily accessible through commercially available starting materials, enables a modular approach for the synthesis of imidazoles. A variety of aromatic, heteroaromatic, and alkyl carboxaldehydes were condensed with oxalyl boronates to afford substituted boryl imidazoles in a regiocontrolled fashion. Subsequent palladium-catalyzed cross-coupling with haloarenes furnished the desired trisubstituted imidazole scaffolds. To demonstrate the utility of these scaffolds, potent inhibitors of the serine/threonine-protein kinase STK10 were synthesized.

Synthesis of Aminoboronic Acid Derivatives from Amines and Amphoteric Boryl Carbonyl Compounds.

Herein, we demonstrate the use of α-boryl aldehydes and acyl boronates in the synthesis of aminoboronic acid derivatives. This work highlights the untapped potential of boron-substituted iminium ions and offers insights into the behavior of N-methyliminodiacetyl (MIDA) boronates during condensation and tautomerization processes. The preparative value of this contribution lies in the demonstration that various amines, including linear and cyclic peptides, can be readily conjugated with boron-containing fragments. A mild deprotection of amino MIDA-boronates enables access to α- and ß-aminoboronic acids in high chemical yields. This simple process should be applicable to the synthesis of a wide range of bioactive molecules as well as precursors for cross-coupling reactions.