Hirokazu Arimoto

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Protein silencing represents an essential tool in biomedical research. Targeted protein degradation (TPD) strategies exemplified by PROTACs are rapidly emerging as modalities in drug discovery. However, the scope of current TPD techniques is limited because many intracellular materials are not substrates of proteasomal clearance. Here, we described a novel targeted-clearance strategy (autophagy-targeting chimera [AUTAC]) that contains a degradation tag (guanine derivatives) and a warhead to provide target specificity. As expected from the substrate scope of autophagy, AUTAC degraded fragmented mitochondria as well as proteins. Mitochondria-targeted AUTAC accelerated both the removal of dysfunctional fragmented mitochondria and the biogenesis of functionally normal mitochondria in patient-derived fibroblast cells. Cytoprotective effects against acute mitochondrial injuries were also seen. Canonical autophagy is viewed as a nonselective bulk decomposition system, and none of the available autophagy-inducing agents exhibit useful cargo selectivity. With its target specificity, AUTAC provides a new modality for research on autophagy-based drugs.

The signaling pathway of nitric oxide (NO) depends mainly on guanosine 3',5'-cyclic monophosphate (cGMP). Here we report the formation and chemical biology of a nitrated derivative of cGMP, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), in NO-mediated signal transduction. Immunocytochemistry demonstrated marked 8-nitro-cGMP production in various cultured cells in an NO-dependent manner. This finding was confirmed by HPLC plus electrochemical detection and tandem mass spectrometry. 8-Nitro-cGMP activated cGMP-dependent protein kinase and showed unique redox-active properties independent of cGMP activity. Formation of protein Cys-cGMP adducts by 8-nitro-cGMP was identified as a new post-translational modification, which we call protein S-guanylation. 8-Nitro-cGMP seems to regulate the redox-sensor signaling protein Keap1, via S-guanylation of the highly nucleophilic cysteine sulfhydryls of Keap1. This study reveals 8-nitro-cGMP to be a second messenger of NO and sheds light on new areas of the physiology and chemical biology of signal transduction by NO.

An efficient, highly convergent, stereocontrolled total synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on gram scale. Key elements of the successful strategy include (1) elaboration of three advanced fragments from a common precursor (CP) which embodies the repeating stereochemical triad of the discodermolide backbone, (2) σ-bond installation of the Z trisubstituted olefin, exploiting a modified Negishi cross-coupling reaction, (3) synthesis of a late-stage phosphonium salt utilizing high pressure, and (4) Wittig installation of the Z disubstituted olefin and the terminal (Z)-diene.

Autophagy is a cellular self-catabolic process wherein organelles, macromolecules, and invading microbes are sequestered in autophagosomes that fuse with lysosomes. In this study, we uncover the role of nitric oxide (NO) as a signaling molecule for autophagy induction via its downstream mediator, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP). We found that 8-nitro-cGMP-induced autophagy is mediated by Lys63-linked polyubiquitination and that endogenous 8-nitro-cGMP promotes autophagic exclusion of invading group A Streptococcus (GAS) from cells. 8-nitro-cGMP can modify Cys residues by S-guanylation of proteins. We showed that intracellular GAS is modified with S-guanylation extensively in autophagosomes-like vacuoles, suggesting the role of S-guanylation as a marker for selective autophagic degradation. This finding is supported by the fact that S-guanylated bacteria were selectively marked with polyubiquitin, a known molecular tag for selective transport to autophagosomes. These results collectively indicate that 8-nitro-cGMP plays a crucial role in cytoprotection during bacterial infections or inflammations via autophagy upregulation.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTADDITION / CORRECTIONThis article has been corrected. View the notice.Gram-Scale Synthesis of (+)-DiscodermolideAmos B. Smith, Michael D. Kaufman, Thomas J. Beauchamp, Matthew J. LaMarche, and Hirokazu ArimotoView Author Information Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Pennsylvania 19104 Cite this: Org. Lett. 1999, 1, 11, 1823–1826Publication Date (Web):October 29, 1999Publication History Received24 September 1999Published online29 October 1999Published inissue 1 December 1999https://doi.org/10.1021/ol9910870Copyright © 1999 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1610Altmetric-Citations112LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (72 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Anions,Cross coupling reaction,Ethers,Pharmaceuticals,Salts Get e-Alerts

Targeted degradation is a promising new modality in drug discovery that makes it possible to reduce intracellular protein levels with small molecules. It is a complementary approach to the conventional protein knockdown typically used in laboratories and may offer a way to approach the currently undruggable human proteome. Recently, the first autophagy-mediated degraders, called AUTACs, were developed based on observations in a xenophagy study.

A multivalent polymer of vancomycin, synthesized via ring-opening metathesis polymerization (ROMP), exhibited significant enhancement of antibacterial activity against vancomycin-resistant enterococi (VRE).

Novel semisynthetic vancomycin derivatives with antibacterial activity against vancomycin-resistant S. aureus (VRSA) were prepared. Replacement of Cl groups of vancomycin by Suzuki−Miyaura cross-coupling reaction, which gave the title compounds, is described for the first time. Introduction of a carbon substituent at the amino acid residue 2 of vancomycin led to an enhancement of antibacterial activity against vancomycin-resistant strains, whereas the additional introduction at the amino acid residue 6 resulted in a reduction in activity even against vancomycin-susceptible strains.

The absolute stereochemistry of a marine alkaloid halichlorine, which significantly inhibits VCAM-1 induction in HUVE cells, was established by synthesis of a degradation product of natural product.

Novel macrolides, haterumalides NA (1), NB (2), NC (3), ND (4), and NE (5), were isolated from an Okinawan sponge Ircinia sp. The absolute stereostructure of 1 was determined by spectroscopic analysis and modified Mosher's method. Haterumalide NA (1) showed cytotoxicity against P388 cells and acute toxicity against mice.

To evaluate the protective activity of fruits against liver injury, 22 different fruits were fed to rats with liver damage caused by D-galactosamine, a powerful liver toxin. As measured by changes in the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), avocado showed extraordinarily potent liver injury suppressing activity. Five active compounds were isolated and their structures determined. These were all fatty acid derivatives, of which three, namely, (2E,5E,12Z,15Z)-1-hydroxyheneicosa-2,5,12,15-tetraen-4-one, (2E,12Z,15Z)-1-hydroxyheneicosa-2,12,15-trien-4-one, and (5E,12Z)-2-hydroxy-4-oxoheneicosa-5,12-dien-1-yl acetate, were novel.

In our ongoing search for bioactive substances from marine organisms, novel alkaloids have been isolated. Pinnatoxins and pinnamine, potent shellfish poisons, were purified from the Okinawan bivalve Pinna muricata. Pinnatoxins activate Ca2+ channels. Halichlorine was isolated from the marine sponge Halichondria okadai. This compound inhibits the induction of VCAM-1. Drugs that block VCAM-1 may be useful for treating coronary artery diseases, angina, and noncardiovascular inflammatory diseases. Pinnaic acids, which are cPLA2 inhibitors, were also obtained from P. muricata. Interestingly, the structures of pinnaic acids are closely related to that of halichlorine. Norzoanthamine hydrochloride, isolated from the colonial zoanthid Zoanthus sp., suppresses decreases in bone weight and strength in ovariectomized mice, and could be a good candidate for an osteoporotic drug. Ircinamine, purified from the marine sponge Ircinia sp., has a reactive thioester. Aburatubolactams, inhibitors of superoxide anion generation, were isolated from Streptomyces sp. This article covers the bioactive marine alkaloids that have been recently isolated by this research group.

Degrader technologies, which enable the chemical knockdown of disease-causing proteins, are promising for drug discovery. After two decades of research, degraders using the ubiquitin-proteasome system (UPS) are currently in clinical trials. However, the UPS substrates are mainly limited to soluble proteins. Autophagy-targeting chimeras and autophagosome-tethering compounds are degraders that use autophagy, which has functions complementary to the UPS. They can degrade organelles and aggregate-prone proteins, making them promising treatments against age-related conditions such as mitochondrial dysfunction and neurodegenerative diseases. The molecular mechanism of selective autophagy is an ongoing research topic, which explains why autophagy-based degraders were not available until recently. In this review, we introduce four classifications of selective autophagy mechanisms to facilitate the understanding of the degrader design.

Recently, three natural products have been identified, the epothilones, eleutherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitotic phase of the cell cycle. In this report, we have compared and contrasted the effects of these new agents in Taxol-sensitive and -resistant cell lines. We also have taken advantage of a human lung carcinoma cell line, A549-T12, that was isolated as a Taxol-resistant cell line and found to require low concentrations of Taxol (2-6 nM) for normal cell division. This study then examined the ability of these new compounds to substitute for Taxol in sustaining the growth of A549-T12 cells. Immunofluorescence and flow cytometry have both indicated that the epothilones and eleutherobin, but not discodermolide, can substitute for Taxol in this Taxol-dependent cell line. In A549-T12 cells, the presence of Taxol significantly amplified the cytotoxicity of discodermolide, and this phenomenon was not observed in combinations of Taxol with either the epothilones or eleutherobin. Median effect analysis using the combination index method revealed a schedule-independent synergistic interaction between Taxol and discodermolide in four human carcinoma cell lines, an effect that was not observed between Taxol and epothilone B. Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increase in the hypodiploid population, thereby indicating that a possible mechanism for the observed synergy is the potentiation of apoptosis. Our results suggest that Taxol and discodermolide may constitute a promising chemotherapeutic combination.

Two new cytotoxic compounds, nakiterpiosin (1) and nakiterpiosinone (2), were isolated from the Okinawan sponge Terpios hoshinota. Their structures were determined by spectroscopic analysis. The absolute stereostructure of 1 was also determined by a modified Mosher's method. Nakiterpiosin (1) and nakiterpiosinone (2) showed potent cytotoxicity against mouse lymphocytic leukemia cell (P388).

Nitric oxide (NO), a gaseous free radical that is biologically synthesized by nitric oxide synthases, participates in a critical fashion in the regulation of diverse physiological functions including vascular and neuronal signal transduction, host defense, and cell death regulation. This article reviews the chemical and biochemical mechanisms of protein thiol modifications caused by NO and by electrophiles derived from NO metabolism. The classical NO signaling pathway involves formation of the second messenger guanosine 3',5'-cyclic monophosphate (cGMP). Post-translational modifications of redox-sensitive protein thiols have also been shown to be important in this signaling pathway. For instance, redox-sensitive thiols are targets for NO conjugation and formation of S-nitrosothiols. Electrophiles generated by reactions of NO or reactive nitrogen oxide species and biomolecules (i.e., fatty acids) effect thiol conjugations through S-alkylation. Among this class of reactions, S-guanylation is particularly emphasized. S-Guanylation is a novel type of S-alkylation with nitrated cGMP that contributes to the cytoprotective effects of NO. Post-translational modifications of thiols affect protein structures and functions: allosteric effects may alter protein structure, modification of active centers of enzymes may suppress enzyme actions, and modifications may modulate protein-protein interactions. Better understanding of protein modification by NO-derived electrophiles and the molecular basis of NO signaling would be useful in the development of new diagnostic methods and treatment of diseases related to NO metabolism.

Abstract The enantioselective total synthesis of the bioactive marine natural products pinnaic acid and halichlorine is reported in detail. Our total synthesis features the construction of the five‐membered ring and C9 and C13 stereogenic centers through a palladium‐catalyzed trimethylenemethane [3+2] cyclization; the installation of the nitrogen atom through a regioselective Beckmann rearrangement of a poorly reactive ketone; the stereoselective cyclization of the spiro ring through a four‐step, one‐pot hydrogenation–cyclization; and efficient connection of the sterically hindered lower chain through a reduced‐pressure cross olefin metathesis reaction.

Related to synthetic study on γ-pyrone-containing natural products, conversions of β-triketides having unstable substituents to the corresponding γ-pyrones have successfully been accomplished by the new methods under conditions using (CH3)2S+Cl or Ph3P+CX3 (or Ph3P+X, X Cl, Br) as the oxygen acceptors.

Pinned together: Asymmetric total synthesis of pinnaic acid was accomplished through a stereospecific route that features as key steps a Pd-catalyzed trimethylenemethane (TMM) [3+2] cyclization, a four-step tandem hydrogenation–cyclization, and cross-olefin-metathesis reactions (see scheme). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z701581_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The solitary spider wasp Cyphononyx dorsalis is well known to hunt spiders: it uses its stinger to paralyze its prey to feed its larva. This wasp venom was fractionated by bioassay-guided chromatography. Cation-exchange chromatography indicated that the pI value of the active principle was >6.5. 2D-PAGE analysis of the active fraction obtained by gel permeation chromatography showed three major spots of proteins. Two that appeared at pI of >6.5 were analyzed by in-gel digestion and protein sequencing. Three proteins were identified: an arginine kinase-like protein that was highly homologous to that of honeybee, an elastase like-protein that was homologous to that of fire ant, and an unknown protein that was not homologous to any protein in the database. Recombinant proteins expressed in E. coli were purified and used for bioassay. The results showed that the arginine kinase-like protein exhibited paralytic activity against spiders with the same characteristic symptoms as the crude venom.

Group A Streptococcus (GAS) is deleterious pathogenic bacteria whose interaction with blood vessels leads to life-threatening bacteremia. Although xenophagy, a special form of autophagy, eliminates invading GAS in epithelial cells, we found that GAS could survive and multiply in endothelial cells. Endothelial cells were competent in starvation-induced autophagy, but failed to form double-membrane structures surrounding GAS, an essential step in xenophagy. This deficiency stemmed from reduced recruitment of ubiquitin and several core autophagy proteins in endothelial cells, as demonstrated by the fact that it could be rescued by exogenous coating of GAS with ubiquitin. The defect was associated with reduced NO-mediated ubiquitin signaling. Therefore, we propose that the lack of efficient clearance of GAS in endothelial cells is caused by their intrinsic inability to target GAS with ubiquitin to promote autophagosome biogenesis for xenophagy.

Abstract Because of the scanty pipeline of antibiotics newly obtained from nature, chemical modification of established drugs is one of the major streams of current antibacterial research. Intuitive and easy-to-use assays are critical for identifying drug candidates with novel modes of action. In this study, we demonstrated that metabolic fluorescent staining of growing cell walls is a powerful tool for mode-of-action analyses of antibiotics using Streptococcus pyogenes . A set of major cell-wall-inhibiting antibiotics (bacitracin, d -cycloserine, flavomycin, oxacillin, ramoplanin, and vancomycin) was employed to validate the potential of the assay. The mechanistic differences of these antibiotics were successfully observed. For instance, d -cycloserine treatment induced fluorescently stained, excessive peripheral cell wall growth. This may indicate that the switch from the peripheral growth stage to the succeeding septal growth was disturbed by the treatment. We then applied this assay to analyze a series of vancomycin derivatives. The assay was sufficiently sensitive to detect the effects of single-site chemical modification of vancomycin on its modes of action. This metabolic fluorescent labeling method is easy to perform, especially because it does not require radiolabeled substrates. Thus, it is suitable for the preliminary evaluation of antibacterial mechanisms during antibacterial research.

Abstract Tanzawaic acids have been isolated from Penicillium citrinum and their structures were elucidated by spectroscopic analysis. Their relative stereochemistries were also clarified by detailed analyses of 1H–1H coupling constants and NOE data. Tanzawaic acid B (GS-1302-1) significantly inhibits superoxide anion production in human neutrophils.

An asymmetric synthesis of the spirocyclic core of pinnaic acid, a cPLA2 inhibitor, is described. A key transformation in the sequence involves an asymmetric Michael-initiated ring closure.

A one-pot exo-olefin reductive cleavage was for the first time developed. The reaction could proceed under a mild condition avoiding the use of hazardous and expensive reagents. Meanwhile, a TMSCl-mediated Clemmensen reduction in alcoholic solvent was also examined.

“TADA!” is not the trumpet fanfare but the transannular Diels–Alder reaction concluding the synthesis of the tetracyclic core of the mangicols, a family of marine sesterterpenes. Further highlights in the synthesis include a novel chlorination and an intramolecular Nozaki–Hiyama–Kishi coupling reaction. Bn=benzyl.

Conformational features of palytoxin and acetylated palytoxin were investigated by detailed analyses of NOESY spectra. The conformational differences between palytoxin and acetylated palytoxin may account for the difference in the assembly state of palytoxin, which exists as an associated dimer, and the acetylated derivative, which exists as a monomer in aqueous solution. Two palytoxin units in the dimer may come in contact with each other at the hydrophobic region (C21–40) and the region around two conjugated double bonds (C60–84). The amino group of palytoxin is important for biological activities via Na/K ATPase, but it was not found to be involved in the contact faces of the two palytoxin units. This information should aid in revealing how palytoxin interacts with Na/K ATPase.

(′)-Pinnaic acid (1) was synthesized via the catalytic hydrogenation of an a, β-unsaturated ketone (12) as the key step to construct an aza-spiro skeleton.

A novel and efficient avenue for the preparation of dimeric vancomycins is described, and the dimers exhibited excellent antibacterial activities in the murine infection model.

Azido- and fluoro- derivatives of 8-nitroguanosine were developed, and will contribute to the exploration of protein S-guanylation by endogenous nitrated nucleosides.

An approach to the macrocyclic core of kendomycin is described in which the Nozaki–Hiyama–Kishi coupling and a ring-closing olefin metathesis are the key reactions.

Abstract The discovery of new ecologically active compounds often triggers the development of basic scientific concepts in the field of biological sciences, since such compounds have direct physiological and behavioral effects on other living organisms. We have focused on the identification of natural key compounds that control biologically and physiologically intriguing phenomena. We describe three recent aspects of chemical ecology that we have investigated: natural toxins, coral communities, and symbiotic relationships. Blarina toxin (BLTX) is a lethal mammalian venom that was isolated from the short-tailed shrew. Duck-billed platypus venom shows potent Ca2+ influx in neuroblastoma cells. The venom of the solitary wasp contains arginine kinase-like protein and is used to paralyze its prey to feed its larva. The ecological behaviors of corals are controlled by combinations of small molecules. The polyol compound symbiodinolide may serve as a defense substance for symbiotic dinoflagellates to prevent digestion of their host animals. These compounds reveal the wonder of nature, in both terrestrial and marine ecological systems.

A highly stereocontrolled, convergent total synthesis of kendomycin [(-)-TAN2162], an ansa-macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji-Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18-membered carbocyclic framework. The oxa-six- and five-membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one-pot epoxidation/5-exo-tet epoxide opening.

IBX affords a novel, highly selective dehomologation of alcohols to their corresponding one-carbon shorter carboxylic acids.

Mild cyclization method [DMSO - (COCl)2 or Ph3P - CCl4] of triketides bearing optically active functional groups to the corresponding γ-pyrones provided determination of the absolute configurations of ilikonapyrone and peroniatriols I and II isolated from the marine molluscs Onchidium verruculatum and Peronia peronii.

Synthesis of the C13-C19 C-glycoside portion of kendomycin was achieved via oxidative pyran cyclization and Claisen rearrangement to construct the fully functionalized aromatic ring.

Abstract The transannular Diels–Alder (TADA) reaction was applied to the synthesis of the CDE ring system of nakiterpiosin (1). Tetracyclic compound 25 may be a key intermediate in the total synthesis of 1.

We have developed an accurate and traceable quantitation method of proteins and peptides by isotope-dilution mass spectrometry with the precolumn derivatization for hydrolyzed amino acid. This method utilized N-butylnicotinic acid N-hydroxysuccinimide ester iodide as the derivatization reagent and C-30 reversed phase column for the separation. Quantitative results of porcine insulin and human serum albumin obtained from the hydrolyzed six or seven amino acids showed a good agreement, with less than 3% of the expanded uncertainties. This method allows more accurate and more robust amino acid analysis in comparison with non-labeled methods.

The emergence of vancomycin-resistant bacteria has created an urgent need for new active analogues of vancomycin. We previously reported vancomycin dimers with in vivo antibacterial activity. Here, we provide the first experimental insights into their inhibitory actions in bacterial cell wall synthesis.

Synthesis of the tricyclic core of halichlorine, a VCAM-1 expression suppressor, was achieved using ene-yne metathesis cyclization as a key step.

A scalable synthetic route for 15N-labeled 4-oxo-2,2,6,6-tetraethylpiperidine nitroxide (15N-TEEPONE) is described. This 15N-labeled nitroxide is suitable for electron paramagnetic resonance imaging of brain, and its higher sensitivity compared with that of its 14N-counterpart is an important advantage of the labeled derivative.

A novel blood–brain barrier (BBB)-permeable compound 10 was discovered, wherein the nitroxide moiety was linked to a nicotine acetylcholine receptor ligand. It was applied as a probe for electron paramagnetic resonance (EPR) imaging of the mouse brain. The results demonstrated that the newly synthesized compound 10 exhibited BBB permeability. These findings provide an essential discovery for in vivo EPR imaging.

Reaction of iodo Wittig ylide 1 with aldehyde 2 affords moderate yields of cis epoxides 6a and 7a, in addition to the expected olefin 3. A mechanism is proposed to account for both the high Z selectivity and the modest yield of olefin observed with this reagent.

The first total synthesis of onchitriol II, a cytotoxic metabolite of mollusc Onchidium sp., is described. It employs mild cyclization method [DMSO - (COCl)2 or Ph3P - CCl4] of triketides bearing optically active functional groups to the corresponding γ-pyrones as a key step. Additional synthesis of some diastereoisomers provided a possibility to revise the structure of closely related onchitriol I.

In connection with the two γ-pyrones obtained by decomposition reactions of peroniatriols I and II, γ-pyrone derivatives have been synthesized by newly developed mild cyclization methods, and this result revised the partial structures of these natural products.

Abstract Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin‐resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC‐VV‐linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin‐resistant Staphylococcus aureus in vitro. In addition, double‐disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin‐resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin‐resistant strains.

Palytoxin, one of the most toxic non-peptide substances, formed an associated dimer of 5 nm length in aqueous solution.

ABSTRACT Van-M-02, a novel glycopeptide, was revealed to exert potent activities against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA). A crude assay system was then used to study the mode of action of Van-M-02 as a peptidoglycan synthesis model of both vancomycin-susceptible and -resistant strains. The results suggested that Van-M-02 inhibits the synthesis of lipid intermediates irrespective of their termini. This inhibitory activity may contribute to the anti-VRE and anti-VRSA activities observed.

Kendomycin, an ansamycin-type natural product first reported in 1996, possesses a series of attractive bioactivities and a unique all-carbon macrocyclic skeleton. To the date, seven total syntheses, two formal total syntheses and a number of synthetic studies on this hot molecule have been reported. In this short review article, we mainly survey and comment on these efforts regarding the difficult macrocyclization strategies.

Targeted protein degradation via the ubiquitin-proteasome system has emerged as one of the most promising drug discovery modalities. Autophagy, another intracellular degradation system, can target a wide range of nonproteinous substrates as well as proteins, but its application to targeted degradation is still in its infancy. Our previous work revealed a relationship between guanine modification of cysteine residues on intracellular proteins and selective autophagy, resulting in the first autophagy-based degraders, autophagy-targeted chimeras (AUTACs). Based on the research background, all the reported AUTACs compounds contain cysteine as a substructure. Here, we examine the importance of this substructure by conducting SAR studies and report significant improvements in the degrader's activity by replacing cysteine with other moieties. Several derivatives showed sub-μM range degrading activity, demonstrating the increased practical value of AUTACs.

The chemiluminescence of gallic acid by hydrogen peroxide had completely inhibited by the presence of ascorbate. After ascorbate had disappeared by oxidation, chemiluminescence returned. The concentration of gallic acid was virtually unchanged by presence of ascorbate, but started to decrease after the disappearance of ascorbate. This might be attributable to the rapid reduction of quinone, which was the first product of the chemiluminescence reactions, to gallic acid by ascorbate or the donation of proton to the phenoxy radical from ascorbate to stop the chemiluminescence reaction at the first stage. The effects of ascorbate on the chemiluminescence of other polyphenols depended on their oxidation rate.

The transannular Diels-Alder (TADA) reaction was applied to the synthesis of the CDE ring system of nakiterpiosin (1). TADA product 28 is a key intermediate toward the total synthesis of 1.

8-Nitro-cGMP is an endogenous nucleotide discovered under inflammation conditions as an important mediator of nitric oxide (NO) signaling. Besides cGMP-like behaviour, 8-nitro-cGMP exerts unique cytoprotective effects against oxidative stress. Although the formation of 8-nitro-cGMP from 8-nitro-GTP has previously been proposed, the mechanism by which excess or unused 8-nitro-cGMP is removed from cells remains unknown. In this study, we report a nitric oxide-dependent cellular conversion of 8-nitro-cGMP to intact cGMP in RAW 264.7 macrophage cells. In our experiments, we synthesized isotopically labeled 8-nitro-cGMP as a tool for metabolites analysis and identified 8-amino-cGMP as an initial metabolite of 8-nitro-cGMP using a LC-MS/MS technique. We also proved that endogenous 8-nitro-cGMP can be converted into 8-amino-cGMP by immunocytochemical staining with an antibody that specifically recognizes 8-amino-cGMP. Moreover, we showed that isotopically labeled 8-amino-cGMP is metabolized into cGMP under inflammation conditions. We propose that nitrosylation of 8-amino-cGMP occurs by NO formation under stress conditions and gives putative 8-diazonium-cGMP, which subsequently decomposes into cGMP. To the best of our knowledge, this study is the first to report reductive deamination of aminoguanine nucleotide at the C-8 position. The findings of this study collectively indicate that NO plays a crucial role not only in the production of 8-nitro-cGMP but also in its elimination under oxidative stress or inflammation.

Pinnarine (1), a new macrocyclic alkaloid, was isolated from the black marine sponge Halichondria okadai. The structure was elucidated on the basis of 2D NMR and comparison with the spectra of the co-isolated known halichlorine. Further confirmation of the structure and the absolute configuration was validated by a synthetic method from authentic pinnaic acid and CD analysis. The isolation of pinnarine also suggested a biogenetic pathway from pinnaic acid to halichlorine.

We developed a surface plasmon resonance (SPR) assay to estimate the interactions of antimicrobial agents with the dipeptide terminal of lipid II (D-alanyl-D-alanine) and its analogous dipeptides (L-alanyl-L-alanine and D-alanyl-D-lactate) as ligands. The established SPR method showed the reproducible immobilization of ligands on sensor chip and analysis of binding kinetics of antimicrobial agents to ligands. The ligand-immobilized chip could be used repeatedly for at least 200 times for the binding assay of antimicrobial agents, indicating that the ligand-immobilized chip is sufficiently robust for the analysis of binding kinetics. In this SPR system, the selective and specific binding characteristics of vancomycin and its analogs to the ligands were estimated and the kinetic parameters were calculated. The kinetic parameters revealed that one of the remarkable binding characteristics was the specific interaction of vancomycin to only the D-alanyl-D-alanine ligand. In addition, the kinetic binding data of SPR showed close correlation with the antimicrobial activity. The SPR data of other antimicrobial agents (e.g., teicoplanin) to the ligands showed correlation with the antimicrobial activity on the basis of the therapeutic mechanism. Our SPR method could be a valuable tool for predicting the binding characteristics of antimicrobial agents to the dipeptide terminal of lipid II.

Abstract Vancomycin‐resistant Staphylococcus aureus ( S. aureus ) (VRSA) uses depsipeptide‐containing modified cell‐wall precursors for the biosynthesis of peptidoglycan. Transglycosylase is responsible for the polymerization of the peptidoglycan, and the penicillin‐binding protein 2 (PBP2) plays a major role in the polymerization among several transglycosylases of wild‐type S. aureus. However, it is unclear whether VRSA processes the depsipeptide‐containing peptidoglycan precursor by using PBP2. Here, we describe the total synthesis of depsi‐lipid I, a cell‐wall precursor of VRSA. By using this chemistry, we prepared a depsi‐lipid II analogue as substrate for a cell‐free transglycosylation system. The reconstituted system revealed that the PBP2 of S. aureus is able to process a depsi‐lipid II intermediate as efficiently as its normal substrate. Moreover, the system was successfully used to demonstrate the difference in the mode of action of the two antibiotics moenomycin and vancomycin.

Total synthesis and structural revision of onchitriol I, a γ-pyrone-containing polypropionate, are described. Comparison of onchitriols with peroniatriols indicated the striking similarities related to both C3-10 and C13-16 segments.

The synthesis of vallartanone B, a γ-pyrone-containing polypropionate from the marine mollusc Siphonaria maura, is described. A γ-pyrone moiety, which was constructed by PPh3-CCl4 cyclization of a β-triketone, and a C1-C6 segment were joined by a Sn(OTf)2 aldol reaction and converted to vallartanone B. This synthesis allows for revision of the stereochemistry at C8. A conformational analysis was performed using PM3 to examine the proposed interpretation of its CD spectrum.

A novel avenue for oxazoles via Beckmann rearrangement of alpha-formyl ketoxime dimethyl acetals is described that indicates the possibility of a non-amino acid biosynthetic pathway in marine natural products.

Zusammengebastelt: Die asymmetrische Totalsynthese von Pinnasäure gelang auf einem stereospezifischen Weg, wobei Schlüsselschritte eine Pd-katalysierte Trimethylenmethan(TMM)-[3+2]-Cyclisierung, eine vierstufige Tandem-Hydrierung-Cyclisierung und Kreuz-Olefinmetathesereaktionen waren (siehe Schema). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2007/z701581_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Nitric oxide (NO) raises the intracellular 3′,5′-cyclic guanosine monophosphate (cGMP) level through the activation of soluble guanylate cyclase and, in the presence of reactive oxygen species (ROS), reacts with biomolecules to produce nitrated cGMP derivatives. 8-Nitro-cGMP was the first endogenous cGMP derivative discovered in mammalian cells (2007) and was later found in plant cells. Among the six nitrogen atoms in this molecule, the one in the nitro group (NO2) comes from NO. This chapter asserts that this newly found cGMP is undoubtedly one of the major physiological cNMPs. Multiple studies suggest that its intracellular abundance might exceed that of unmodified cGMP. The characteristic chemical feature of 8-nitro-cGMP is its ability to modify proteinous cysteine residues via a stable sulfide bond. In this posttranslational modification, the nitro group is detached from the guanine base. This modification, termed “protein S-guanylation,” is known to regulate the physiological functions of several important proteins. Furthermore, 8-nitro-cGMP participates in the regulation of autophagy. For example, in antibacterial autophagy (xenophagy), S-guanylation accumulates around invading bacterial cells and functions as a “tag” for subsequent clearance of the organism via ubiquitin modifications. This finding suggests the existence of a system for recognizing the cGMP structure on proteins. Autophagy induction by 8-nitro-cGMP is mechanistically distinct from the well-described starvation-induced autophagy and is independent of the action of mTOR, the master regulator of canonical autophagy.

Abstract The first total synthesis of tanzawaic acid A(GS-1302-3) is described. The stereocontrolled synthetic route allowes the absolute stereochemistry to be determined. One key transformation in the sequence involves a Stille coupling with a highly hindered aryl triflate. Examples and results of several coupling reactions are also included.

The affinity between a vancomycin polymer (3) and cell wall intermediate mimics of vancomycin resistant bacteria (VRE) was determined by use of surface plasmon resonance (SPR). The increased affinity of 3 over monomeric vancomycin derivatives 1 and 2 suggests the importance of tighter binding to VRE surfaces in the enhanced antibacterial activities of 3.

The effects of Soto's 'beta-sheet breaker peptide' and its polymer on PrPSc formation in ScN2a cells were investigated. Surface plasmon resonance study indicated that direct binding between PrP(81-145) and the 'beta-sheet breaker peptide' is not specific and may not play a major role in the inhibition of PrPSc formation.

A plant growth regulator, theobroxide, which produces potato tubers under noninduced long-day conditions, was synthesized in four steps from dihydrotoluene. Keywords: Plant growth regulator; theobroxide; practical synthesis

Samarium-mediated 7-endo-trig radical cyclization afforded excellent stereocontrol of the four contiguous asymmetric centers present in the 6-7-6 tricyclic cores of the (sugar-fused) erinacines E, F, and G.

This Article describes the simultaneous imaging of chiral nitroxyl radicals using electron paramagnetic resonance (EPR). Chiral nitroxyl radicals could be simultaneously visualized with the labeling of isotopic nitrogen. Chiral nitroxyl radicals, hydroxylmethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl, were visualized using the method of simultaneous EPR imaging, which refers to the visualization of two kinds of molecules with unpaired electrons in a single image scan. EPR spectra of a racemic mixture of chiral nitroxyl radicals and those of the respective R and S configurations confirmed labeling by isotopic nitrogen. 1H nuclear magnetic resonance (NMR) imaging and simultaneous imaging of solutions of chiral nitroxyl radicals were performed. The advantages and limitations of simultaneous imaging using EPR are also discussed. Simultaneous imaging with chiral-labeled nitroxyl radicals is a new application of EPR imaging and may be useful for biological studies involving biologically active chiral molecules.

Abstract Two new 7-geranyloxycoumarins, chloromarmin and aeglin, were isolated from the bark of Aegle marmelos, and their structures were assigned to be 7-(7-chloro-6R-hydroxy-3,7-dimethyl-2-octenyloxy)coumarin (1) and 7-[6R-(β-d-glucopyranosyloxy)-4R,7-dihydroxy-3,7-dimethyl-2-octenyloxy]coumarin (2), respectively.

Seeing is believing: S-guanylation is a novel key mechanism by which signal transduction under oxidative stress is regulated. A chemical probe whose fluorescent intensity increases after the reaction with proteinous cysteine (S-guanylation) is described. The use of this probe revealed that S-guanylation products localized in lysosomes. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

In the present study, we examined the interaction of antimicrobial agents with four model lipid membranes that mimicked mammalian cell membranes and Gram-positive and -negative bacterial membranes and analyzed the binding kinetics using our surface plasmon resonance (SPR) technique. The selective and specific binding characteristics of antimicrobial agents to the lipid membranes were estimated, and the kinetic parameters were analyzed by application of a two-state reaction model. Reproducible analysis of binding kinetics was observed. Vancomyicn, teicoplanin, erythromycin, and linezolid showed little interaction with the four lipid membranes in the SPR system. On the other hand, vancomycin analogues showed interaction with the model lipid membranes in the SPR system. The selective and specific binding characteristics of vancomycin analogues to the lipid membranes are discussed based on data for in vitro antibacterial activities and our data on the binding affinity of the D-alanyl-D-alanine terminus of a pentapeptide cell wall obtained by SPR. The mechanism of antibacterial activity against Staphylococcus aureus and vancomycin-resistant enterococci could be evaluated using the binding affinity obtained with our SPR techniques. The results indicate that the SPR method could be widely applied to predict binding characteristics, such as selectivity and specificity, of many antimicrobial agents to lipid membranes.

Abstract The synthesis and revised structure of vallartanone B, a γ-pyrone-containing polypropionate from a marine mollusc, are described.

ADVERTISEMENT RETURN TO ISSUEPREVAdditions & Corr...Additions & CorrectionsNEXTORIGINAL ARTICLEThis notice is a correctionGram-Scale Synthesis of (+)-DiscodermolideAmos B. Smith, Michael D. Kaufman, Thomas J. Beachamp, Matthew J. LaMarche, and Hirokazu ArimotoCite this: Org. Lett. 2000, 2, 13, 1983Publication Date (Web):June 22, 2000Publication History Published online22 June 2000Published inissue 1 June 2000https://doi.org/10.1021/ol006090uCopyright © 2000 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views556Altmetric-Citations10LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (37 KB) Get e-Alerts Get e-Alerts

The first synthesis of allixin, an anti-tumor promoter from garlic Allium sativum L., is described. The highly oxidized γ-pyrone moiety was synthesized via a 2-methylene tetrahydropyran derivative.

Abstract The structural revision of the product of the tandem aldol - Swern oxidation process to β—triketones is reported. Further oxidation of products leading to the corresponding diketones (ex. 4, 5) was observed. The properties of the β—triketone are also described.

„TADA“ klingt wie der Beginn eines Orchesterstücks, doch verbirgt sich nur eine transannulare Diels-Alder-Reaktion hinter diesem Akronym. Durch eine solche Reaktion wurde das tetracyclische Mangicol-Gerüst erhalten. Weitere wichtige Syntheseschritte waren eine neuartige Chlorierung und eine intramolekulare Nozaki-Hiyama-Kishi-Kupplung. Bn=Benzyl.

Toxic substances that occur in nature have various structures and functions. In fact, the very novelty of their structures and functions sometimes extends far beyond the realm of human imagination, and the capabilities of these compounds are still largely untapped despite the major advances of modern science. In this report we focus on the most recent developments in this field, with a particular emphasis on natural venoms, marine sunscreen, and marine huge molecules.

Abstract A highly stereocontrolled, convergent total synthesis of kendomycin [(−)‐TAN2162], an ansa‐macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji–Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18‐membered carbocyclic framework. The oxa‐six‐ and five‐membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one‐pot epoxidation/5‐ exo ‐tet epoxide opening.

The increasing incidence of vancomycin resistance in clinical settings has prompted research into new antibiotics against vancomycin–resistant strains. Recent efforts toward the development of novel glycopeptide antibiotics including our works are reviewed. Introduction of a carbon substituent at the amino acid residue 2 of vancomycin by Suzuki–Miyaura cross–coupling reaction led to an enhancement of antibacterial activity against vancomycin–resistant Staphylococcus aureus (VRSA). The potent activities of Van–M–02 against the Gram–positive bacteria including vancomycin–resistant enterococci (VRE) and VRSA are also described, and its mode of action was investigated with an assay system employing cell–membrane fraction of S.aureus as a crude enzyme mixture.

The Pauson-Khand reaction (PKR) is a powerful means for the construction of cyclopentenones. However, its applications have been limited to the intramolecular version of this reaction because poor yield and regioselectivity are often the major problems in intermolecular PKR. Here we describe that a carbamate moiety in alkene substrate accelerates this intermolecular PKR. The reaction of N-4-dimethylaminophenyl O-allyl carbamate with alkyne-cobalt complex gave cyclopentenones in high yield (up to 90%) and regioselectivity (>9:1).

Intercellular cleaning via autophagy is crucial for maintaining cellular homeostasis, and impaired autophagy has been associated with the accumulation of protein aggregates that can contribute to neurological diseases. Specifically, the loss-of-function mutation in the human autophagy-related gene 5 (ATG5) at E122D has been linked to the pathogenesis of spinocerebellar ataxia in humans. In this study, we generated two homozygous C. elegans strains with mutations (E121D and E121A) at positions corresponding to the human ATG5 ataxia mutation to investigate the effects of ATG5 mutations on autophagy and motility. Our results showed that both mutants exhibited a reduction in autophagy activity and impaired motility, suggesting that the conserved mechanism of autophagy-mediated regulation of motility extends from C. elegans to humans.

Vancomycin-resistance is one of the most important problems in public health. This review survey the recent studies of chemically modified vancomycin-related glycopeptide antibiotics with emphasis on multivalent effects.

Modification of vancomycin with lipophilic substituents enhances its antibacterial activity against vancomycin-resistant strains. To further improve the activity of the resulting lipoglycopeptides, it is necessary to understand these compounds' molecular modes of action. By developing a photoaffinity probe, we were able to elucidate in this study the binding targets of a novel lipoglycopeptide (Van-M-02) at the cell membrane of Staphylococcus aureus. The probe could be successfully used to identify penicillin-binding protein 2 (PBP2), an indispensable enzyme in bacterial cell-wall synthesis, as a target. LC-MS/MS analysis of affinity-labeled PBP2 enabled us to map the Van-M-02 binding site in the transpeptidase domain. These findings will allow for the rational design of better antibiotics against vancomycin-resistant bacteria.

Total synthesis and structural revision of onchitriol I, a γ-pyrone-containing polypropionate, are described. Comparison of onchitriols with peroniatriols indicated the striking similarities related to both C3-10 and C13-16 segments.

Abstract Green trichotomine derivatives bearing alkyl groups on C1 and C1′ were prepared. In their absorption spectra, the λmax shifted to longer wavelengths as the 1,1′-substituents became bulkier, and the bathochromism indicated twisting of the central C2=C2′ double bond. A 1,1′ -dimethyltrichotomine derivative underwent autooxidation to give orange-red 1,11b-dihydroxylated and 1,11b-seco-dicarbonyl compounds, in which twisting of the central C2=C2′ double bond might be relieved by the decreasing steric interactions between the substituents on C1 and the C3′ carbonyl groups.

This chapter contains sections titled: Introduction Alkylation of Tertiary Carbon Centers Cycloaddition to Alkenes Diels–Alder Reaction Other Types of Cycloaddition Rearrangement Reactions Carbometallation Reactions Addition of a Carbon Nucleophile to a β,β-Disubstituted α,β-Unsaturated Enone Asymmetric and Diastereomeric Addition of a Carbon Nucleophile to Unactivated Alkenes Catalyzed by Palladium C–H Functionalization Reactions Asymmetric Modification of Enantiotopic/Diastereotopic Substituents of Quaternary Carbon Centers Summary

Abstract Review: 38 refs.

Bacteria-infected cells are known to produce higher level of nitric oxide and reactive oxygen species. Although these reactive chemicals can contribute directly to kill pathogens, in this study, we focus on antibacterial autophagy regulation via downstream mediator. Autophagy is a cellular self-catabolic process in which organelles, biomolecules, and invading pathogens are sequestered in autophagosomes that fuse with lysosomes. However. signaling pathways leading to autophagy activation in innate immunity have not been fully clarified. Figure 1 8-Nitro-cGMP modifies proteinous cysteine. Figure 2 S-Guanylation promotes ubiquitination of invading bacteria. After escape of bacteria from endoosome into the cytosol, their surface is modified by 8-nitro-cGMP via protein S-guanylation, which promotes subsequent Lys63-linked polyubiquitination. Ubiquitin ... A downstream mediator of nitric oxide signaling, 8-nitroguanosine 3’,5’-cyclic monophosphate (8-nitro-cGMP), has been recently identified in various mammalian cell lines [1,2]. This nitrated version of cGMP modifies Cys residues of proteins (protein S-guanylation) to modulate their functions. In this study, we found that endogenous 8-nitro-cGMP promotes autophagic exclusion of invading group A Streptococci (GAS) from murine macrophages [3]. Interestingly, cytosolic GAS were partly modified by the S-guanylation at their surface, and the S-guanylation level was significantly higher with the autophagosome-encapsulated GAS than the cytosolic counterpart. This finding suggests a possible role of S-guanylation as a tag to recruit bacteria for autophagic degradation. Further analysis revealed that S-guanylation-positive bacteria were selectively modified by Lys63-linked polyubiquitin chains, which is a known molecular determinant for selective transport to autophagosomes via autophagy receptor binding. In accordance with this finding, downregulation of S-guanylation suppressed GAS ubiquitination and retarded the clearance of intracellular GAS.

ChemInformVolume 45, Issue 25 Natural Products ChemInform Abstract: Enantioselective Total Synthesis of Pinnaic Acid (I) and Halichlorine (II). Shu Xu, Shu Xu Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorDaisuke Unabara, Daisuke Unabara Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorDaisuke Uemura, Daisuke Uemura Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorHirokazu Arimoto, Hirokazu Arimoto Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this author Shu Xu, Shu Xu Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorDaisuke Unabara, Daisuke Unabara Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorDaisuke Uemura, Daisuke Uemura Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorHirokazu Arimoto, Hirokazu Arimoto Grad. Sch. Life Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this author First published: 05 June 2014 https://doi.org/10.1002/chin.201425217Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume45, Issue25June 24, 2014 RelatedInformation

ChemInformVolume 45, Issue 41 Natural Products ChemInform Abstract: Total Synthesis of the Antibiotic Kendomycin: A Macrocyclization Using the Tsuji—Trost Etherification. Tetsuya Sengoku, Tetsuya Sengoku Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorShu Xu, Shu Xu Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorKenji Ogura, Kenji Ogura Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorYoshinori Emori, Yoshinori Emori Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorKenji Kitada, Kenji Kitada Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorDaisuke Uemura, Daisuke Uemura Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorHirokazu Arimoto, Hirokazu Arimoto Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this author Tetsuya Sengoku, Tetsuya Sengoku Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorShu Xu, Shu Xu Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorKenji Ogura, Kenji Ogura Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorYoshinori Emori, Yoshinori Emori Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorKenji Kitada, Kenji Kitada Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorDaisuke Uemura, Daisuke Uemura Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this authorHirokazu Arimoto, Hirokazu Arimoto Grad. Sch. Life Sci., Tohoku Univ., Sendai 980, JapanSearch for more papers by this author First published: 25 September 2014 https://doi.org/10.1002/chin.201441213Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume45, Issue41October 7, 2014 RelatedInformation

Review: about 50 refs.

Abstract Interestingly, the internal olefin (V) can be cleaved and reduced under similar conditions.