Controlled Aerobic Oxidative Dimerization of Hydroxystilbenoids by Chromium Catalysis.

Aerobic oxidative dimerization of hydroxystilbenoids is described. A Cr-salen complex catalyzed the dimerization of hydroxystilbenoids in 1,1,1,3,3,3-hexafluoroisopropanol to form compounds comprising a natural product-like scaffold (quadrangularin) or its precursor depending on the aromatic substituents. The addition of a catalytic amount of scandium triflate [Sc(OTf)3] to the reaction system altered the reaction outcome to give a different natural product-like compound, a pallidol-type dimer.

PurA is the main target of aurodox, a type III secretion system inhibitor.

Anti-microbial resistance (AMR) is one of the greatest threats to global health. The continual battle between the emergence of AMR and the development of drugs will be extremely difficult to stop as long as traditional anti-biotic approaches are taken. In order to overcome this impasse, we here focused on the type III secretion system (T3SS), which is highly conserved in many Gram-negative pathogenic bacteria. The T3SS is known to be indispensable in establishing disease processes but not essential for pathogen survival. Therefore, T3SS inhibitors may be innovative anti-infective agents that could dramatically reduce the evolutionary selective pressure on strains resistant to treatment. Based on this concept, we previously identified a polyketide natural product, aurodox (AD), as a specific T3SS inhibitor using our original screening system. However, despite its promise as a unique anti-infective drug of AD, the molecular target of AD has remained unclear. In this paper, using an innovative chemistry and genetic biology-based approach, we show that AD binds to adenylosuccinate synthase (PurA), which suppresses the production of the secreted proteins from T3SS, resulting in the expression of bacterial virulence both in vitro and in vivo experiments. Our findings illuminate the potential of PurA as a target of anti-infective drugs and vaccination and could open a avenue for application of PurA in the regulation of T3SS.

Electrochemical Characterization of a Novel Organoelectrocatalyst, 7-Azabicyclo[2.2.1]heptan-7-ol (ABHOL), and Its Application to Electrochemical Sensors.

Electrochemical enzyme sensors are suitable for simple monitoring methods, for example, as glucose sensors for diabetic patients; however, they have several disadvantages arising from the properties of the enzyme. Therefore, non-enzymatic electrochemical sensors using functional molecules are being developed. In this paper, we report the electrochemical characterization of a new hydroxylamine compound, 7-azabicyclo[2.2.1]heptan-7-ol (ABHOL), and its application to glucose sensing. Although the cyclic voltammogram for the first cycle was unstable, it was reproducible after the second cycle, enabling electrochemical analysis of ethanol and glucose. In the first cycle, ABHOL caused complex reactions, including electrochemical oxidation and comproportionation with the generated oxoammonium ions. The electrochemical probe performance of ABHOL was more efficient than the typical nitroxyl radical compound, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), and had similar efficiency to 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), which is activated by the bicyclic structure. The results demonstrated the advantages of ABHOL, which can be synthesized from inexpensive materials via simple methods.

C-H Alkylation of Cubanes via Catalytic Generation of Cubyl Radicals.

A catalytic method for the C-H alkylation of cubanes is described. Some hydrogen atom transfer catalysts enable the direct abstraction of a hydrogen atom from the C-H bond of cubanes, followed by conjugate addition of the generated cubyl radicals to electron-deficient alkenes. Synthetic applications of the functionalization method developed are also described.

Design, Synthesis, and Biological Evaluation of Water-Soluble Prodrugs of C5-Curcuminoid GO-Y030 Based on Reversible Thia-Michael Reaction.

Although curcumin and its analogs exhibit anticancer activity, they are still not used as anticancer drugs because of their water insolubility and extremely poor bioavailability. This study describes the development of water-soluble prodrugs of GO-Y030, a potent antitumor C5-curcuminoid, in an attempt to enhance its bioavailability. These prodrugs release the parent compound via a retro-thia-Michael reaction. To endow sufficient hydrophilicity onto GO-Y030 via a single thia-Michael reaction of an aqueous entity, we used a modified glycoconjugate with a thiol group. The water-solubilizing motif was installed on GO-Y030 by the thia-Michael reaction of propargyl-polyethylene glycol (PEG)-thiol and subsequent click chemistry (CuAAC) reaction with 1-glycosyl azide. Turbidity measurements revealed a significantly improved water solubility of the prodrugs, demonstrating that disaccharide conjugates were completely dissolved in water at 100 µM. Their cytotoxicity was comparable to that of the parent compound GO-Y030, indicating the gradual in situ release of GO-Y030. The release of GO-Y030 from GO-Y199 via the retro-thia-Michael reaction was demonstrated through a degradation study in water. Our retro-thia-Michael reaction-based prodrug system can be used for targeting cancer cells.

Biological Evaluation of Isosteric Applicability of 1,3-Substituted Cuneanes as m-Substituted Benzenes Enabled by Selective Isomerization of 1,4-Substituted Cubanes.

We herein evaluate a biological applicability of 1,3-substituted cuneanes as an isostere of m-substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3-substituted cuneanes by selective isomerization of 1,4-substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m-substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry.

Ratiometric analysis of reversible thia-Michael reactions using nitrile-tagged molecules by Raman microscopy.

Ratiometric Raman analysis of reversible thia-Michael reactions was achieved using α-cyanoacrylic acid (αCNA) derivatives. Among αCNAs, the smallest derivative, ThioRas (molecular weight: 167 g mol-1), and its glutathione adduct were simultaneously detected in various subcellular locations using Raman microscopy.

Azetidine synthesis by La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines.

Azetidine is a prevalent structural motif found in various biologically active compounds. In this research paper, we report La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines to afford azetidines. This reaction proceeded in high yields even in the presence of acid-sensitive and Lewis basic functional groups.

Determination of antibiotics by amperometry using nortropine N-oxyl, a highly active nitroxyl radical.

Nitroxyl radical compounds oxidize hydroxy groups and some amino groups upon application of an electric potential. The resulting anodic current depends on the concentration of these functional groups in solution. Thus, it is possible to quantify compounds containing these functional groups by electrochemical methods. Cyclic voltammetry has been used to evaluate the catalytic activity of nitroxyl radicals, and the ability of such radicals to sense biological and other compounds. In this study, we evaluated a method for quantifying compounds using constant-potential electrolysis (amperometry) of nitroxyl radicals for application in flow injection analysis and high-performance liquid chromatography as an electrochemical detector. When amperometry was performed using 2,2,6,6-tetramethylpiperidine 1-oxyl, a common nitroxyl radical compound, little change was observed even with 100 mM glucose due to its low reactivity in neutral aqueous solutions. In contrast, 2-azaadamantane N-oxyl and nortropine N-oxyl, which are highly active nitroxyl radicals, showed a concentration-dependent response in neutral aqueous solution. Responses of 33.8 and 125.9 µA, respectively, were observed. By recognition of hydroxy and amino groups, we have succeeded in the electrochemical detection of some drugs by amperometry. Streptomycin, an aminoglycoside antibiotic, was quantifiable in the range of 30-1000 µM.

Mono-Carbonyl Curcumin Analogs for Cancer Therapy.

Curcumin has long been recognized for its anti-inflammatory properties. An antitumor effect has been recently reported in curcumin and clinical trials are being conducted. However, a large amount of required intake to obtain the antitumor effect of curcumin has been regarded as a problem. Therefore, curcumin analogs have been created by many researchers to enhance the effects of curcumin. We have synthesized >50 curcumin analogs and revealed greater growth suppression of various tumor cells with mono-carbonyl analogs than curcumin. Mechanistically, mono-carbonyl analogs inhibited transcriptional activity (e.g., nuclear factor kappa B, signal transducer, and activator of transcription 3) or activated caspase-3. Additionally, mono-carbonyl analogs of curcumin control tumor cell metabolism. Herein, we summarize the current knowledge about mono-carbonyl curcumin analogs and discuss their potential clinical applications.

Asymmetric Total Synthesis of Cytotrienin A: Late-Stage Installation of C11 Side Chain onto the Macrolactam Scaffold.

Cytotrienin A, an ansamycin-class antibiotic, exhibits potent apoptosis-inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late-stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron-Wittig/iterative Suzuki-Miyaura cross-coupling sequence was effective for the concise and selective construction of the (E,E,E)-conjugated triene moiety. The developed route opens new opportunities for the structure-activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies.

Identification of the Optimal Framework for Nitroxyl Radical/Hydroxylamine in Copper-Cocatalyzed Aerobic Alcohol Oxidation.

8-Azabicyclo[3.2.1]octan-8-ol (ABOOL) and 7-azabicyclo[2.2.1]heptan-7-ol (ABHOL) are the main homologues of hydroxylamine 2-azaadamantan-2-ol (AZADOL) and 9-azabicyclo[3.3.1]nonan-9-ol. Both homologues feature a small bicyclic backbone and are known to be stable; however, to date, they have not been used as catalysts for alcohol oxidation. Herein, we report that these hydroxylamines can efficiently catalyze the oxidation of various secondary alcohols to their corresponding ketones using molecular oxygen in ambient air as the terminal oxidant and copper cocatalysts at room temperature. Furthermore, we show that ABOOL and ABHOL can be easily synthesized from commercially available materials.

Sequential click modification of a lithium-ion endohedral fullerene connecting small molecules through a dieneazide linker.

A versatile method for the chemical modification of a lithium-ion endohedral fullerene (Li+@C60) to connect various small molecules is described. The designed dieneazide linker enables the facile connection of Li+@C60 with small molecules bearing a terminal alkyne via Huisgen annulation and a subsequent Diels-Alder reaction. This strategy significantly expands the diversity of small molecules to be attached by Li+@C60.

Electrochemical reactions of highly active nitroxyl radicals with thiol compounds.

Nitroxyl radicals are known to electrochemically oxidize thiols as well as alcohols and amines. In this study, a preliminary investigation of the electrochemical reaction of thiols with 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), 2-azaadamantane N-oxyl (AZADO), and nortropine N-oxyl (NNO), which are highly active due to their bicyclo structures, for use in electrochemical analysis was performed and the results were compared with those for a typical nitroxyl radical compound, 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO). Mercaptopropane sulfonic acid (MPS) was used as a model compound to investigate the electrochemical response in aqueous solution. In addition, electrochemical detection of glutathione, a biological thiol molecule, was performed.

Comprehensive Structural and Electronic Properties of 2-Azaadamantane N-Oxyl Derivatives Correlated with Their Catalytic Ability.

Herein, a comprehensive kinetic study is performed to compare the catalytic efficiency of 2-azaadamantane N-oxyl (AZADO) derivatives with that of 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) used as radical catalysts in the aerobic oxidation of l-menthol. Furthermore, the correlation between the catalytic activity and structural/electronic parameters of AZADOs and TEMPO is elucidated. The reaction rate constants achieved with several AZADO derivatives exhibit moderate relationships with spectroscopic parameters, such as the hyperfine coupling constant of the N atom (AN) and NO stretching vibration frequency (νNO) observed in electron spin resonance and infrared spectra, respectively. The planarity C-(NO)-C angle (φ) at the N atom, determined by density functional theory (DFT) calculations, also strongly correlates with the AN and νNO. Moreover, the bond order of NO, which strongly depends on the structural and electronic properties of NO radicals, correlates with radical activity; thus, the radical activity can be predicted by DFT calculations, thereby accelerating the synthesis of new AZADO derivatives without requiring alcohol oxidation experiments.

Enantiocontrolled Access to an Intermediate for Highly Functionalized Clovane-Type Terpenoids: Formal Synthesis of Rumphellclovane E.

We describe an enantiocontrolled route to a versatile intermediate for the synthesis of highly functionalized clovane-type terpenoids. The synthetic route commenced with (R)-carvone, a commercially available and enantioenriched building block, and an oxygenative strategy was used to concisely access a clovane scaffold. One example of the versatility of the obtained intermediate was the formal synthesis of rumphellclovane E.

Directing carboxylic acid dehydrogenation.

A palladium ligand can activate carbon-hydrogen bonds yet avoid product olefin reactions.

Toward the Creation of Induced Pluripotent Small (iPS) Molecules: Establishment of a Modular Synthetic Strategy for the Heronamide C-type Polyene Macrolactams and Their Conformational and Reactivity Analysis.

A highly modular synthetic strategy for the heronamide C-type polyene macrolactams was established by synthesizing 8-deoxyheronamide C (2). The developed strategy enabled not only the total synthesis of 8-deoxyheronamide C (2) but also the unified synthesis of four heronamide-like molecules named "heronamidoids" (5-8). Conformational and reactivity analysis of the heronamidoids clarified that (1) the C19 stereochemistry mainly affected the conformation of the amide linkage, resulting in the change of alignment of two polyene units and reactivity toward photochemical [6π + 6π] cycloaddition, and (2) the C8,C9-diol moiety is important for the conversion to the heronamide A-type skeleton from the heronamide C skeleton.

Design, Synthesis, and Antifungal Activity of 16,17-Dihydroheronamide C and ent-Heronamide C.

16,17-Dihydroheronamide C (8) and ent-heronamide C (ent-1) were designed as probes for the mode-of-action analysis of heronamide C (1). These molecules were synthesized by utilizing a highly modular strategy developed in the preceding paper. The evaluation of the antifungal activity of these compounds revealed the exceptional importance of the C16-C17 double bond for the antifungal activity of heronamide C and the existence of chiral recognition between heronamide C (1) and cell membrane components.