Palladium-Catalyzed Arylation of Cyanamides

The cross-coupling of alkyl cyanamides with a number of aryl, heteroaryl, and vinyl halide and pseudohalide coupling partners has been developed via a modification of Pd-catalyzed amidation methods. The reactions proceed selectively under mild conditions with reasonable reaction times in moderate to excellent yields

Structure-Based Optimization of Small-Molecule Inhibitors for the β‑Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction

Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of β-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4′-fluoro-<i>N</i>-phenyl-[1,1′-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic α-helical hot spots at positions <i>i</i>, <i>i</i> + 3, and <i>i</i> + 7. Compound <b>29</b> was found to disrupt the β-catenin/BCL9 protein–protein interaction (PPI) with a <i>K</i>_i of 0.47 μM and >1900-fold selectivity for β-catenin/BCL9 over β-catenin/E-cadherin PPIs. The proposed binding mode of new inhibitors was consistent with the results of site-directed mutagenesis and structure–activity relationship studies. Cell-based studies indicated that <b>29</b> disrupted the β-catenin/BCL9 interaction without affecting the β-catenin/E-cadherin interaction, selectively suppressed transactivation of Wnt/β-catenin signaling, downregulated expression of Wnt target genes, and inhibited viability of Wnt/β-catenin-dependent cancer cells in dose-dependent manners. A comparison of the biochemical and cell-based assay results offered the directions for future inhibitor optimization

Structure-Based Optimization of Small-Molecule Inhibitors for the β‑Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction

Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of β-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4′-fluoro-<i>N</i>-phenyl-[1,1′-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic α-helical hot spots at positions <i>i</i>, <i>i</i> + 3, and <i>i</i> + 7. Compound <b>29</b> was found to disrupt the β-catenin/BCL9 protein–protein interaction (PPI) with a <i>K</i>_i of 0.47 μM and >1900-fold selectivity for β-catenin/BCL9 over β-catenin/E-cadherin PPIs. The proposed binding mode of new inhibitors was consistent with the results of site-directed mutagenesis and structure–activity relationship studies. Cell-based studies indicated that <b>29</b> disrupted the β-catenin/BCL9 interaction without affecting the β-catenin/E-cadherin interaction, selectively suppressed transactivation of Wnt/β-catenin signaling, downregulated expression of Wnt target genes, and inhibited viability of Wnt/β-catenin-dependent cancer cells in dose-dependent manners. A comparison of the biochemical and cell-based assay results offered the directions for future inhibitor optimization

Table_1_The association between thyroid-stimulating hormone and thyroid nodules, goiter and thyroid antibody positivity.docx

BackgroundThe relationship between normal thyroid-stimulating hormone (TSH) levels and thyroid disease in adults remains controversial. This study aimed to investigate the correlation between serum TSH levels, particularly those falling within the normal range, and thyroid diseases in Chinese adults, including thyroid nodules (TN), goiter (GR), and thyroid antibody positivity.Materials and methodsThis research was a cross-sectional study conducted in an adult population in Tianjin, China. Thyroid volume (Tvol) and TN were assessed using thyroid ultrasonography. Fasting venous blood and spot urine samples were collected to evaluate thyroid function and iodine status.ResultsA total of 2460 subjects participated in the survey. The prevalence of thyroid dysfunction was 9.76%, and abnormal TSH levels were found to potentially increase the risk of GR and thyroid antibody positivity in adults. A total of 2220 subjects with TSH within the normal reference range were included in the further study. In these patients, Tvol decreased as TSH levels increased, in both men and women (P ConclusionIn adults with normal TSH levels, low TSH levels were associated with an increased risk of TN and GR, whereas high TSH levels were associated with thyroid antibody positivity. The research also suggests that adults whose TSH levels at upper or lower limits of the normal range should be reviewed regularly.</p

Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol

The “butterfly-shaped” bicyclic pyrrolidinol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a­(5H)-yl)-methanol (1) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a­(5H)-yl)-methanol (1) that is amenable for scale-up has been developed. The newly optimized process utilizes readily available N-Boc-trans-4-hydroxy-l-proline methyl ester (8) to establish the challenging stereogenic center bearing the fluoride. Subsequent diastereoselective α-alkylation was achieved by leveraging Seebach’s self-regeneration of stereochemistry (SRS) methodology, which has been exploited for the synthesis of proline derivatives. Finally, intramolecular cyclization/deprotection cascade and carbonyl reduction afford the bicyclic pyrrolidinol 1 in nine linear steps from compound 8. This process significantly reduces the overall production sequence and allows the preparation of product 1 on a multikilo scale with a 40% overall yield and perfect control of chirality (>99% ee and de)

Table_1_Characteristics and predictors of breast milk iodine in exclusively breastfed infants: Results from a repeated-measures study of iodine metabolism.DOCX

BackgroundThe iodine supply of exclusively breastfed infants entirely depends upon breast milk. Changes in breast milk iodine affect infants’ iodine nutritional status. This study aimed to comprehensively assess the characteristics and predictors of breast milk iodine concentration (BMIC).Materials and methodsThis 7-day iodine metabolism experiment was conducted in 25 exclusively breastfed mother-infant pairs. The duplicate portion method was used to measure the mother’s daily iodine intake from foods and water, and maternal 24-h urine excretion was assessed. We recorded the number of breastfeeds per mother per day and collected breast milk samples before and after each feeding.ResultsThe median [quartile (Q)1–Q3 range] of BMIC was 115 (86.7, 172) μg/L. The BMIC before breastfeeding was generally higher than that after breastfeeding. Time-sequential analysis found that morning BMIC was most highly correlated with the prior day’s iodine intake. Breast milk samples taken in the afternoon or after midnight are closer to the median level of BMIC throughout the day. The number of breast milk samples needed to estimate the iodine level with 95% CI within precision ranges of ± 20% was 83 for a population, 9 for an individual, and 2 for an individual’s single day. Maternal total iodine intake (TII) and urine iodine were significantly associated with BMIC. 24-h urinary iodine excretion (24-h UIE) was found to be the best predictive indicator for the BMIC (β = 0.71, 95% CI: 0.64, 0.79).ConclusionBMIC is a constantly changing indicator and trended downward during each breastfeeding. Breast milk samples taken in the afternoon or after midnight are most representative. BMIC was significantly associated with recent iodine intake. Maternal 24-h UIE was the best predictor of BMIC.</p