Correction to “Development of a Concise Synthesis of (+)-Ingenol”

Correction to “Development of a Concise Synthesis of (+)-Ingenol

Development of a Concise Synthesis of (+)-Ingenol

The complex diterpenoid (+)-ingenol possesses a uniquely challenging scaffold and constitutes the core of a recently approved anti-cancer drug. This full account details the development of a short synthesis of <b>1</b> that takes place in two separate phases (cyclase and oxidase) as loosely modeled after terpene biosynthesis. Initial model studies establishing the viability of a Pauson–Khand approach to building up the carbon framework are recounted. Extensive studies that led to the development of a 7-step cyclase phase to transform (+)-3-carene into a suitable tigliane-type core are also presented. A variety of competitive pinacol rearrangements and cyclization reactions were overcome to develop a 7-step oxidase phase producing (+)-ingenol. The pivotal pinacol rearrangement is further examined through DFT calculations, and implications for the biosynthesis of (+)-ingenol are discussed

Marker levels in non-small cell lung cancer (NSCLC) tumors (T), normal LNs (nN), patient LNs (ptN), normal blood (nB) and patient blood (ptB).

<p>Median values are indicated by short horizontal lines, whereas samples with levels below the limit of detection (LOD) are indicated below the dashed horizontal line. The levels of the different markers are relative to a calibrator sample and are not directly comparable.</p

Biplot showing principal component analysis of <i>CK19</i>, <i>CEACAM5</i>, <i>DSG3</i>, <i>SFTPA</i> and <i>SFTPC</i> mRNA level in the 55 primary tumor biopsies.

<p>Black numbers indicate histology type (1 = adenocarcinoma, 2 = adenosquamous carcinoma, 3 = bronchioloalveolar carcinoma, 4 = carcinoid, 5 = large cell carcinoma, 6 = small cell carcinoma, 7 = squamous cell carcinoma).</p

Biplot showing the results from principal component analysis of the 16 tumor samples.

<p>The black circles show the sample data projected onto the first and second principal components. The red arrows shows the old variable axes projected unto the principal components.</p

Relative marker levels in non-small cell lung cancer (NSCLC) tumors (T), normal LNs (nN) and peripheral blood samples (nB).

<p>Median values are indicated by short horizontal lines, whereas samples with levels below the limit of detection (LOD) are indicated below the dashed horizontal line. The levels of the different markers are relative to a calibrator sample and not directly comparable.</p

Clinicopathological parameters according to molecular examination of regional LNs and peripheral blood samples.

*<p>Mann-Whitney test.</p

Number of patients with LNs and PB sampes positive for our 5 marker panel.

<p>Number of patients with LNs and PB sampes positive for our 5 marker panel.</p

Additional file 1: Table S1. of The MYCN-HMGA2-CDKN2A pathway in non-small cell lung carcinoma—differences in histological subtypes

Characteristics of the microRNA sample set. Table S2: Characteristics of the adenocarcinoma validation sample set. Table S3: Characteristics of the squamous cell carcinoma (TCGA) validation sample set. Table S4: Independent samples t-test. Mean let-7 microRNA expression in tumour and normal tissue samples. Table S5: Independent samples t-test. Mean let-7 microRNA expression and association with MYCN mRNA expression in tumour samples. Table S6: Independent samples t-test. Mean let-7 microRNA expression and association with HMGA2 mRNA expression in tumour samples. Table S7: Independent samples t-test. Mean let-7 microRNA expression and association with CDKN2A mRNA expression in tumour samples. Table S8: Independent samples t-test. Mean let-7 microRNA expression and association with DICER1 mRNA expression in tumour samples and additional figures (Figure S1: REMARK diagram detailing sample availability and use of different analytical techniques in the present study. Figure S2: Boxplots illustrating the distribution of gene expression (fold change) from the RT-qPCR . Figure S3: Scatterplots illustrating significant correlations. Figure S4: Associations between HMGA2 protein expression and patient outcome). Figure S1. REMARK diagram detailing sample availability and use of different analytical techniques in the present study. Figure S2. Boxplots illustrating the distribution of gene expression from the RT-qPCR. Figure S3. Scatterplots illustrating significant correlations. Figure S4. Associations between NSCLC stage, HMGA2 protein expression and patient outcome. HMGA2 protein expression values dichotomized to low expression (blue) and overexpression (green) based on immunohistochemistry. Low expression of HMGA2 protein had a significantly better prognosis compared to overexpression in stage I non-small cell lung cancer tumour samples (A, p = 0.034). No significant association in stage II (B, p = 0.492) or stage III (C, p = 0.862) patients was seen. (DOCX 401 kb

Selective mGAT2 (BGT-1) GABA Uptake Inhibitors: Design, Synthesis, and Pharmacological Characterization

β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1–4. The parent amino acids were also characterized. Compounds <b>13a</b>, <b>13b</b>, and <b>17b</b> displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound <b>17b</b> displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors