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We report herein the first total synthesis of saptomycin H (

We report the enantioselective total syntheses of preussomerins EG

In connection with our synthetic study toward the dimeric pyranonaphthoquinone antibiotics, actinorhodin (1) and β-naphthocyclinone (3), we describe herein the synthesis of a monomer, hemi-actinorh...

Substrate scope of the thiolate-mediated reductive cyclization of keto-enones was studied, revealing the applicability and novel mechanistic insights.

Photoirraditation of substituted 1,2-naphthoquinones gives the corresponding oxacycle via intramolecular redox reaction, which enabled net CH functionalization of the proximal position to the excited carbonyl group of the quinones. The substrate scope and mechanistic insights are described.

In our synthetic study on pluramycin-class antibiotics, an unexpected issue arose, i.e., unfavorable regioselectivity of 5-exo rather than 6-endo cyclization to form the pyranone ring. The issue was solved by an addition–elimination process of a phenol–ynone substrate. AZADOL was specifically effective, enabling the first synthesis of saptomycinone H.

A model study for the enantioselective total synthesis of γ-rubromycin has revealed a promising approach for constructing the chiral, nonracemic bicyclic spiroacetal via the stereospecific photoredox reaction of 1,2-naphthoquinone ether.

We report herein the asymmetric total synthesis of (+)-engelharquinone and its epoxide by exploiting two key reactions; (1) Rhodium catalyzed asymmetric 1,4-addition and (2) thiolate-mediated reduc...

Intramolecular photoredox reactions of naphthoquinone derivatives were found to proceed in a stereospecific manner. This method was used as a basis for the enantioselective total synthesis of (-)-spiroxin C.

The pluramycins constitute a group of antibiotics sharing C-glycosylated anthrapyranone skeleton. Their significant bioactivities and intriguing chemical structures attracted synthetic chemists, and many challenges have been performed toward the total synthesis. This chapter focuses on the synthetic approaches on the pluramycins. The Introduction describes the historical background, structural features, and synthetic problems. In the second section, the synthetic approaches to the aglycons are summarized. The methods for the preparation of the rare deoxyamino sugars are overviewed in the third section. Finally, the synthetic studies toward the C-glycosyl tetracyclic skeletons and the completed total syntheses are described.

The aryl C-glycoside structure is, among the plenty of biologically active natural products, one of the distinct motifs embedded. Because of the potential bioactivity as well as the synthetic challenges, these structures have attracted considerable interest, and extensive research toward the total synthesis has been performed. This Review focuses on the synthetic strategies and tactics employed in the total synthesis of this class of natural products. The Introduction describes the historical background, structural features, and synthetic problems associated with aryl C-glycoside natural products. Next the Review summarizes the methods for constructing the aryl C-glycoside bonds. Completed total syntheses—and, in some cases, selected examples of incomplete syntheses—of natural aryl C-glycosides are also summarized. Finally described are the strategies for constructing polycyclic structures, which were utilized in the total syntheses.

Photoinduced intramolecular redox reaction of naphthoquinone derivatives is described, enabling C–H bond oxygenation at the α-position of the quinone nucleus and the quinone reduction under photoirradiation. The substrate scope and mechanistic insight are reported.

The first enantioselective total syntheses of engelharquinone (2) and its epoxide 3 have been achieved. The key steps include (1) catalytic asymmetric 1,4-addition of a naphthylboronic acid derivative to a masked naphthoquinone derivative by using a chiral Rh-complex and (2) thiolate-promoted stereospecific construction of the bicyclo[3.2.1]octadienone scaffold.

Two effective tricyclic platforms are reported for the installation of the two constituent sugars, L-vancosamine and D-angolosamine, in a regio- and stereoselective manner for the synthesis of the pluramycin class of bis-C-glycoside antitumor antibiotics. Two complementary protocols are now available that differ in the order in which the two sugar moieties are installed. Sc(OTf)3 was effective as the Lewis acid.

Objective The purpose of this study was to examine the 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) findings of central nervous system (CNS) germinoma and the diagnostic utility of these findings. Methods We retrospectively evaluated the cases of 10 patients who were diagnosed with CNS germinoma according to their histopathological or clinical findings. All the patients underwent pretreatment MET and/or FDG-PET scans, and the resultant images were assessed qualitatively and quantitatively. In the qualitative assessments, we used 3- and 5-grade visual scoring systems for the MET- and FDG-PET images, respectively. In the quantitative assessments, the maximal standardized uptake value (SUVmax) and the ratio of the SUVmax of the tumor (T) divided by the mean SUV for the normal white or gray matter [T/N (WM), T/N (GM)], was calculated. Results The mean and SD values of SUVmax, T/N (WM), and T/N (GM) were 1.9 ± 1.4, 2.5 ± 1.3, and 1.7 ± 0.9 on MET-PET and 5.8 ± 2.2, 1.6 ± 0.5, and 0.8 ± 0.2 on FDG-PET, respectively. On MET-PET, only one lesion was not detected. On the other hand, on FDG-PET all of the lesions exhibited uptake values that were intermediate between those of the normal white matter and gray matter. Conclusion In terms of its tumor-contouring ability, MET is a good tracer for diagnosing CNS germinomas; therefore, MET-PET is considered to be useful for planning biopsies or surgery. Although FDG-PET is capable of detecting CNS germinomas, it produced insufficient image contrast in the present study. Further studies are needed before FDG-PET can be used in clinical examinations of CNS germinoma.

A novel and efficient synthesis of xanthones is described. 2-(Trimethylsilyl)phenyl 2-fluorobenzoate derivatives undergo Fries-type rearrangement and intramolecular SNAr reaction in a one-pot sequential manner under fluoride ion-promoted mild conditions. The method provides efficient access to xanthones that have significant steric congestion around the C9 carbonyl, which are not readily available by conventional methods.

The purpose of the study was to compare observer performance in the detection of cerebral infarction on a brain CT using medical-grade liquid crystal display (LCD) monitors calibrated with the gray-scale standard display function and with γ 2.2 and using an iPad with a simulated screen setting.We amassed 97 sample sets, from 47 patients with proven cerebral infarction and 50 healthy control subjects. Nine radiologists independently assessed brain CT on a gray-scale standard display function LCD, a γ 2.2 LCD, and an iPad in random order over 4-week intervals. Receiver operating characteristic (ROC) analysis was performed by using the continuous scale, and the area under the ROC curve (A(z)) was calculated for each monitor.The A(z) values for gray-scale standard display function LCD, γ 2.2 LCD, and iPad were 0.875, 0.884, and 0.839, respectively. The difference among the three monitors was very small. There was no significant difference between gray-scale standard display function LCD and γ 2.2 LCD. However, the A(z) value was statistically significantly smaller for the iPad than the γ 2.2 LCD (p0.05).Observer performance for detecting cerebral infarction on the LCD with γ 2.2 calibration was found to be similar to the LCD with gray-scale standard display function calibration. Although observer performance using the iPad was poorer than that using the other LCDs, the difference was small. Therefore, the iPad could not substitute for other LCD monitors. However, owing to the promising potential advantages of tablet PCs, such as portability, further examination is needed into the clinical use of tablet PCs.

An improved practical synthesis of L-vancosamine-related glycosyl donors is described. The key steps include (1) stereoselective addition of methylcerium reagent to oximino ether and (2) stereoselective hydrogenation of exocyclic unsaturated glycoside in the presence of Wilkinson catalyst with C(5) inversion to give L-vancosamine derivatives. Three glycosyl donors were prepared, and their reactivities in the aryl C-glycoside formation were compared. Conversion of primary amine and azide to the corresponding N,N-dimethyl derivative is also described.

Background: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias. Objective: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias. Methods: We searched PubMed (January 2000– March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis. Results: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For differentiating between DLB and Alzheimer’s disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa = 0.85; 95% confidence interval [95% CI], 0.74–0.96) and good (summary kappa = 0.71; 95% CI, 0.43–0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose– positron emission tomography (summary kappa = 0.53; 95% CI, 0.36–0.69) and cerebral blood flow SPECT (summary kappa = 0.40; 95% CI, 0.33–0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa = 0.68; 95% CI, 0.55–0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons. Conclusion: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real-world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers.

Reaction of bisenone (I) under conditions A) produces the desired skeleton (III) via the active intermediate (II).

In connection with the total synthesis of naphthospironone A, a model study has revealed a promising approach to construct a benzobicyclo[3.2.1]octene skeleton possessing an oxaspirocycle by employing an intramolecular aldol cyclization.

A viable method is reported for the synthesis of the bicyclo[3.2.1]octadienone scaffold in naturally occurring octaketide dimers. The procedure employs a reductive cyclization reaction mediated by an unusual ethanedithiol monosodium salt.

Amyotrophic lateral sclerosis is characterized by selective motor neuron degeneration. An apoptotic pathway is thought to be involved. It is difficult, however, to analyze the molecular pathogenic mechanism in single motor neurons because of complexity in the neural tissue, which consists of multiple lineages of cells neighboring motor neurons. We quantified the caspase-1 and -3 mRNA in single motor neurons and neighboring glial cells isolated from the spinal ventral horn of mutant SOD1 transgenic (Tg) mice and littermates. Motor neurons and neighboring glial cells were isolated from spinal sections by laser microdissection, and the mRNAs were quantified by RT-PCR. In the Tg mice, caspase-1 mRNA was first upregulated in motor neurons and second in glial cells. The caspase-3 mRNA was increased in motor neurons following the caspase-1 mRNA. These results indicated that caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells of the Tg mice, and that mRNAs in isolated cells can be accurately assessed using our procedures.

To analyze the genes related to the pathophysiology of sporadic amyotrophic lateral sclerosis (SALS) we performed gene profiling of SALS spinal cords using molecular indexing combined with cDNA microarray. Eighty-four fragments were cloned in the first screening procedure with molecular indexing. Subsequent quantitative microarray screening revealed 11 genes which were differentially expressed in SALS. Real-time RT-PCR verified that the expression level of the following six genes was altered in SALS: dorfin, metallothionein-3, 30 kDa TATA-binding protein-associated factor, neugrin, ubiquitin-like protein 5 and macrophage-inhibiting factor-related protein-8. These results indicated that genes associated with the ubiquitin–proteasome system, oxidative toxicity, transcription, neuronal differentiation and inflammation might be involved in the pathogenesis of SALS.

Mutations in the superoxide dismutase 1 (SOD1) gene cause the degeneration of motor neurons in familial amyotrophic lateral sclerosis (FALS). An apoptotic process including caspase-1 and -3 has been shown to participate in the pathogenesis of FALS transgenic (Tg) mouse model. Here we report that IAP proteins, potent inhibitors of apoptosis, are involved in the FALS Tg mouse pathologic process. The levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA and protein were significantly decreased in the spinal cord of symptomatic G93A-SOD1 Tg mice compared with littermates. In contrast, the levels of cIAP-1 mRNA and protein were increased in symptomatic G93A-SOD1 Tg mice, whereas the levels of cIAP-2 mRNA and protein were unchanged. In situ hybridization showed that the expression of XIAP was remarkably reduced in the motor neurons of Tg mice, and the expression of cIAP-1 was strongly increased in the reactive astrocytes of Tg mice. Overexpression of XIAP markedly inhibited the cell death and caspase-3 activity in the neuro2a cells expressing mutant SOD1. Deletional mutant analysis revealed that the N-terminal domain of XIAP, the BIR1-2 domains, was essential for this inhibitory activity. These results suggest that XIAP plays a role in the apoptotic mechanism in the progression of disease in mutant SOD1 Tg mice and holds therapeutic possibilities for FALS.

A concise, highly convergent total synthesis of saptomycin B, a member of the pluramycin class of antitumor antibiotics, is reported. The target compound was assembled from four building blocks (a tricyclic platform, two sugars, and an alkynal) in 15% yield through 10 synthetic operations. The key steps included the regioselective installation of two amino sugars (L-vancosamine and D-angolosamine) on the tricycle and the efficient construction of the tetracyclic skeleton by an aldol reaction followed by formation of the pyranone. The unknown configuration at C14 was assigned as R.

The title method allows the efficient conversion of 2-fluorobenzoate derivatives into xanthones that have significant steric congestion around the C9 carbonyl and which are not readily available by conventional methods.

A new method, ‘biased impedance analysis (BIA)’, was proposed for in situ measurements of a.c. impedance of polyaniline (PAn) film during and after deposition on an interdigitated array (IDA) electrode under d.c. bias (polarization) potential. With this BIA we designed two types of experiments: one was BIA under cyclic voltammetric (CV) sweep in 1 M HCl on PAn films polymerized via a constant current (40 μA cm −2 ) mode in properly buffered media at different pH (below 1.7) but with the same chloride ion concentration ([Cl − ] = 1 M); the other was BIA on PAn films during and after constant potential (+ 0.75 V) mode polymerization in 1 M HCl or 1 M HClO 4 both at pH = 0.2. As to the effect of pH of the polymerization media, the PAn film obtained at high pH had narrow conductive potential range during CV scans between −0.1 and 1.0 V as compared with that obtained at low pH. The PAn film obtained in HClO 4 exhibited faster and larger impedance increase (than that polymerized in HCl), leading to a poorer performance upon potential scanning especially from the conductive-oxidation state at high potential to the insulating-reduction state at low potential.

A concise, highly convergent total synthesis of saptomycin B, a member of the pluramycin class of antitumor antibiotics, is reported. The target compound was assembled from four building blocks (a tricyclic platform, two sugars, and an alkynal) in 15% yield through 10 synthetic operations. The key steps included the regioselective installation of two amino sugars (L-vancosamine and D-angolosamine) on the tricycle and the efficient construction of the tetracyclic skeleton by an aldol reaction followed by formation of the pyranone. The unknown configuration at C14 was assigned as R.

Purpose The aim of our study was to examine the usefulness of PET with C-methionine (MET) and F-fluorodeoxyglucose (FDG) in the differentiation of glioblastoma multiforme (GBM) and intracranial diffuse large B-cell lymphoma (DLBCL). Materials and methods We evaluated 22 patients retrospectively with an enhancing brain tumor on MRI, including 15 GBM and 7 DLBCL, which was confirmed by histopathology. Dynamic PET scans with MET and FDG were performed for preoperative differential diagnosis. We assessed the images qualitatively and quantitatively. In quantitative assessment, the SUVmax was used on FDG PET and both late and early phases on MET PET. In addition, the ratio of SUVmax in the late and early phases on MET-PET was evaluated (ΔSUVmax). Results SUVmax on FDG PET of DLBCL was significantly higher than that of GBM. Setting an SUVmax of 12.0 as the cutoff for differentiating DLBCL from GBM, 1 GBM and 1 DLBCL were found to be false-positive and false-negative, respectively.SUVmax in the late and early phases of MET-PET was not significantly different between DLBCL and GBM; however, we also found significant differences in ΔSUVmax on MET-PET. Using ΔSUVmax 1.17 as the cutoff, we could differentiate DLBCL from GBM completely. In the present study, ΔSUVmax on MET-PET was slightly superior to SUVmax on FDG PET. Conclusions Both SUVmax on FDG PET and ΔSUVmax on MET-PET were considered to be good diagnostic tests when encountering difficulties in this differential diagnosis.

The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10,245 β-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring β-turn. Unique to the design and because of the C(2) symmetry of the template, a typical 20 × 20 × 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 × 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid-liquid or liquid-solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (100-fold) and affinities (as low as K(i) = 80 nM for KOR). A key insight to emerge from the studies is that the phenol of Tyr in endogenous ligands bearing the H-Tyr-Pro-Trp/Phe-Phe-NH(2) β-turn is important for MOR binding but may not be important for KOR (accommodated, but not preferred) and that the resulting selectivity for KOR observed with its removal can be increased by replacing the phenol OH with a chlorine substituent, further enhancing KOR affinity.

An application of the finite element method to the rapidly propagating crack problem in two-dimensional domain is presented on the basis of the energy balance concept and the consistent mass formulation. The creation of the new crack surface is simulated by splitting the nodal points along the crack line successively. By introducing the Lagrange multiplier approach into the conventional finite element method of crack propagation analysis, the inconsistency in the method is avoided in that the crack grows by one element length at a time. Several numerical examples are given for rectangular plates made of polymethylmethacrylate (PMMA) with and without initial crack to show the applicability of the proposed method.

Crack analysis is performed for plates characterized by the power hardening material law. A new superposition method of the analytical and the finite element models is proposed with the use of the penalty function, which is frequently adopted to solve the optimization problems. The characteristic distributions of the stress and strain around the crack tip are calculated and compared with the analytical results. Numerical discussion is also made regarding the effects of the crack length to plate width ratio and the power exponent in the hardening law on the nondimensional values of the J-integral, the crack opening displacement, and the residual load point displacement.

An effective hydrophilic scaffold composed of D-trihydroxyllysine-based oligopeptides and its application in the synthesis of the various (111)In-DTPA conjugates with mono- to penta-bisphosphonate units for use as bone tracers are described. The D-trihydroxyllysine derivative with three orthogonal protecting groups was conjugated with functional devices at the gamma position and allowed oligomerization based on peptide chemistry. The radiopharmaceutical complexes of (111)In(III) with selected chelators, 4 and 8, were suitable for bone imaging. These results show that D-trihydroxyllysine 2 was an effective building block for the synthesis of multivalent ligands applicable to medical use.

Results are presented from an investigation of crack arrest toughness K a , on ASTM A533B Class 1 and A508 Class 3 steels using ASTM-proposed specimens and ESSO specimens. The results show that the values of K a , measured in accordance with the ASTM test method, increased with an increase in test temperature, and that the size requirements in the method were appropriate to obtain valid values of plane-strain crack arrest toughness K I a . It was also found that the ASTM and ESSO tests lead to about the same crack arrest toughness values when applied to large specimens of the same size. The lower bound of K I a data was significantly under that of K I c data on the test materials, though both bounds were well over the American Society of Mechanical Engineers (ASME) K I R curve.