Rare-Earth-Metal Complexes Supported by New Chiral Tetra-Azane Chelating Ligands: Synthesis, Characterization, and Catalytic Properties for Intramolecular Asymmetric Hydroamination

A number of new chiral tetra-azane proligands (1<i>R</i>,2<i>R</i>)-<i>N</i>,<i>N</i>′-bis­(<i>o</i>-arylamino-benzylidene)-1,2-diaminocyclohexane ((1<i>R</i>,2<i>R</i>)-[(ArHN)­C₆H₄CHN]₂C₆H₁₀, Ar = 2,6-Me₂C₆H₃ (<b>L</b>^<b>1</b>H₂), 2,6-Et₂C₆H₃ (<b>L</b>^<b>2</b>H₂), 2,6-^<i>i</i>Pr₂C₆H₃ (<b>L</b>^<b>3</b>H₂)) have been synthesized via a nucleophilic displacement of the two fluorine atoms in (<i>o</i>-C₆H₄FCHN)₂C₆H₁₀ with the lithium salt of the corresponding aniline derivative. Their rare-earth-metal complexes <b>L</b>^<b>1</b>ScCl₂Li­(THF)₃ (<b>1</b>), <b>L</b>^<b>1</b>YCl₂Li­(THF)₃ (<b>2</b>), <b>L</b>^<b>2</b>YCl₂Li­(THF)₃ (<b>3</b>), and <b>L</b>^<b>3</b>YCl₂Li­(THF)₂ (<b>4</b>) were synthesized in good yields via the salt metathesis of MCl₃ (M = Sc, Y) with the dilithium salts of the ligands <b>L</b>^<b>1</b>Li₂(THF)₄, <b>L</b>^<b>2</b>Li₂(THF),₄, and <b>L</b>^<b>3</b>Li₂(THF)₄, respectively. Further more, the two diethylamido complexes <b>L</b>^<b>1</b>Y­(NEt₂)­ClLi­(THF)₃ (<b>5</b>) and <b>L</b>^<b>3</b>Y­(NEt₂)­ClLi­(THF)₂ (<b>6</b>) were also synthesized from reactions of the corresponding chloride complexes <b>2</b> and <b>4</b> with diethylamidolithium. The new proligands <b>L</b>^<b>1</b>H₂–<b>L</b>^<b>3</b>H₂ and their rare-earth-metal complexes <b>1</b>–<b>6</b> have been characterized by elemental analyses and ¹H and ¹³C NMR spectroscopy. The structures of complexes <b>1</b>, <b>2</b>, and <b>4</b> have been further confirmed by single-crystal X-ray diffraction analysis. The molecular structural analysis reveals that the metal centers in complexes <b>1</b>, <b>2</b>, and <b>4</b> acquire a distorted-octahedral coordination environment in their solid-state structures by sharing the chloride with a LiCl­(THF)_<i>n</i> moiety. After in situ treatment with ^<i>n</i>BuLi or Me₃SiCH₂Li, complexes <b>1</b>–<b>4</b> show reasonable catalytic activity and good enantioselectivity (up to 90%) for intramolecular asymmetric hydroamination reactions of terminal aminoalkenes. The amido complexes <b>5</b> and <b>6</b> can catalyze the intramolecular hydroamination reaction directly and show catalytic activities and enantioselectivities similar to those of the in situ formed alkyl complexes

Additional file 1 of Healthy lifestyles, systemic inflammation and breast cancer risk: a mediation analysis

Supplementary Material 1: Supplementary Table 1. The construction of HLI Supplementary Table 2. The levels of inflammation markers and the risk of breast cancer among women from the UK Biobank Supplementary Table 3. The levels of inflammation markers and the risk of breast cancer by menopausal status Supplementary Table 4. The levels of inflammation markers and the risk of breast cancer grouped by 2 years entering the cohort Supplementary Table 5. The associations between HLI and inflammation markers Supplementary Table 6. The associations between individual components of HLI and inflammation markers Supplementary Table 7. Independent and joint effects of HLI and inflammation markers on breast cancer risk Supplementary Table 8. The association between HLI and the risk of breast cancer by menopausal status Supplementary Table 9. The associations between individual components of HLI and breast cancer risk among overall, premenopausal, and postmenopausal women in UK Biobank Supplementary Table 10. The mediation analysis of the inflammation markers in the association between HLI and breast cancer risk Supplementary Table 11. Mediating effects of inflammation markers on the association between diet score and breast cancer risk Supplementary Table 12. Mediating effects of inflammation markers on the association between physical activity and breast cancer risk Supplementary Table 13. Mediating effects of inflammation markers on the association between BMI and breast cancer risk Supplementary Table 14. Mediating effects of inflammation markers on the association between WC and breast cancer risk Supplementary Table 15. Mediating effects of inflammation markers on the association between smoking and breast cancer risk Supplementary Figure 1. The associations between levels of CRP, LMR, SII, CAR, CLR, MHR and NHR and breast cancer were evaluated on a continuous scale with restricted cubic spline curves based on cox regression with four knots. Solid lines are multivariable adjusted odds ratios, with dashed lines showing 95% confidence intervals. Blue curves show the fraction of breast cancer with different levels of inflammation marker

Table1_The association between plasma chemokines and breast cancer risk and prognosis: A mendelian randomization study.XLSX

Background: Despite the potential role of several chemokines in the migration of cytotoxic immune cells to prohibit breast cancer cell proliferation, a comprehensive view of chemokines and the risk and prognosis of breast cancer is scarce, and little is known about their causal associations.Methods: With a two-sample Mendelian randomization (MR) approach, genetic instruments associated with 30 plasma chemokines were created. Their genetic associations with breast cancer and its survival by molecular subtypes were extracted from the recent genome-wide association study of 133,384 breast cancer cases and 113,789 controls, with available survival information for 96,661 patients. We further tested the associations between the polygenic risk score (PRS) for chemokines and breast cancer in the UK Biobank cohort using logistic regression models, while the association with breast cancer survival was tested using Cox regression models. In addition, the association between chemokine expression in tumors and breast cancer survival was also analyzed in the TCGA cohort using Cox regression models.Results: Plasma CCL5 was causally associated with breast cancer in the MR analysis, which was significant in the luminal and HER-2 enriched subtypes and further confirmed using PRS analysis (OR = 0.94, 95% CI = 0.89–1.00). A potential causal association with breast cancer survival was only found for plasma CCL19, especially for ER-positive patients. Although not replicated in the UK Biobank, we still found an inverse association between CCL19 expression in tumors and breast cancer overall and relapse-free survival in the TCGA cohort (HR = 0.58, 95% CI = 0.35–0.95).Conclusion: We observed an inverse association between genetic predisposition to CCL5 and breast cancer, while CCL19 was associated with breast cancer survival. These associations suggested the potential of these chemokines as tools for breast cancer prevention and treatment.</p

Table2_The association between plasma chemokines and breast cancer risk and prognosis: A mendelian randomization study.DOCX

Background: Despite the potential role of several chemokines in the migration of cytotoxic immune cells to prohibit breast cancer cell proliferation, a comprehensive view of chemokines and the risk and prognosis of breast cancer is scarce, and little is known about their causal associations.Methods: With a two-sample Mendelian randomization (MR) approach, genetic instruments associated with 30 plasma chemokines were created. Their genetic associations with breast cancer and its survival by molecular subtypes were extracted from the recent genome-wide association study of 133,384 breast cancer cases and 113,789 controls, with available survival information for 96,661 patients. We further tested the associations between the polygenic risk score (PRS) for chemokines and breast cancer in the UK Biobank cohort using logistic regression models, while the association with breast cancer survival was tested using Cox regression models. In addition, the association between chemokine expression in tumors and breast cancer survival was also analyzed in the TCGA cohort using Cox regression models.Results: Plasma CCL5 was causally associated with breast cancer in the MR analysis, which was significant in the luminal and HER-2 enriched subtypes and further confirmed using PRS analysis (OR = 0.94, 95% CI = 0.89–1.00). A potential causal association with breast cancer survival was only found for plasma CCL19, especially for ER-positive patients. Although not replicated in the UK Biobank, we still found an inverse association between CCL19 expression in tumors and breast cancer overall and relapse-free survival in the TCGA cohort (HR = 0.58, 95% CI = 0.35–0.95).Conclusion: We observed an inverse association between genetic predisposition to CCL5 and breast cancer, while CCL19 was associated with breast cancer survival. These associations suggested the potential of these chemokines as tools for breast cancer prevention and treatment.</p

Selection pressure.

<p>Selection pressures on the whole sequence (ω) are calculated for the entire coding regions of the NS1, NS2, PA, NP, PB1, PB2, NA, HA, M1, and M2 genes of the novel swine-origin influenza virus A (H1N1) from April 2009 to May 2010. The number of gene sequences used in this study is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056201#pone.0056201.s002" target="_blank">Table S1</a>. The ratio ω = <i>dN/dS</i> has become a standard measure of selective pressure; ω≈1 signifies neutral evolution, ω<1 indicates negative selection, ω>1 indicates positive selection, and ω≤0.1 indicates extreme purifying selection. These results indicate that the NS2 gene was under positive selection in April and August 2009 but was under negative selection from May to July 2009 and from September 2009 to May 2010. The remaining eight genes were under negative selection from April 2009 to May 2010.</p

Worldwide distribution of G1 (A) and G2 (B) type H1N1 viruses.

<p>The G1 genotype was found in early April 2009 throughout North America, Israel, and Portugal. Patients infected in late April and May 2009 with the Mexico type were observed in other countries (e.g., Norway, Thailand, Denmark, the Dominican Republic, Spain, Taiwan, the Netherlands, the United Kingdom, Japan, China, and France). The G2 genotype was also found in the USA, Canada, and Israel, as well as in Taiwan, Malaysia, Singapore, Chile, Russia, Finland, China, Italy, France, and Sweden).</p

Profiling of bleed 4 and 6 rabbit IgGs from each group with the consensus clade B 15-mer peptides.

<p>Profiles of bleed 4 and 6 rabbit IgGs from group 1 (A), 3 (B), 4 (C), 5 (D) and 6 (E) with the consensus clade B 15-mer peptides are shown. Locations of CD4bs peptides, b12 epitope (b12e) and VRC01 epitope (VRC01e), as well as Env variable loops and HR regions (HR1 and HR2) are indicated according to “Neutralizing Antibody Resources” (<a href="http://www.hiv.lanl.gov/content/immunology/neutralizing_ab_resources.html" target="_blank">http://www.hiv.lanl.gov/content/immunology/neutralizing_ab_resources.html</a>). Two serum samples from a same group were profiled separately, but the addition results of the two samples from the same group are shown. X axis: position of the peptides. Y axis: OD450nm.</p

Mutation network for the NS gene of the H1N1 influenza viruses.

<p>A mutation network for Eurasian-“avian-like” swine (Red), classic swine (Orange), human influenza (Blue), triple reassortant swine (Violet), and 2009 H1N1 (Brown). The area of each node is in proportion to the number of sequences the node represents. The ancestral node representing the original sequence type (MV1) is indicated by a black arrow.</p

Protocol for rabbit immunization.

<p>Notes:</p><p>* Equal amounts of (poly)peptides and recombinant Env (gp140_SF162 trimer or RSC3) were mixed.</p><p>P1-4: Equal amounts of synthesized P1-, P2-, P3- and P4-KLH conjugates were mixed.</p><p>Protocol for rabbit immunization.</p

Characterization of bleed 6 sera and IgGs for binding and neutralization activities.

<p>A-B: Titration of bleed 6 sera for gp140_SF162 trimer (A) and RSC3 (B). C-D: Competition of rabbit IgGs with mature human IgG1 b12 for binding to gp140_SF162 (C) and RSC3 (D). Mature IgG1 b12 was included as control. For “blank”, no IgG was added. E: Neutralization breadth. Percent isolates neutralized by rabbit IgGs from each group (IC₅₀ below 150 μg/mL) is shown. IgG1 b12 was tested at a maximum concentration of 20 μg/ml in the TZM-bl assay. IC₅₀ > 20 μg/mL was defined as non-neutralizing. One-way ANOVA was used for statistical analyses using SPSS. Pre-immunization rabbit IgGs from each rabbit were also tested and all IC_50s were > 150 μg/mL (not shown).</p