Synthesis of A83586C/citropeptin hybrid and synthetic studies toward azinothricin

The Azinothricin family of cyclodepsipeptides are a class of antitumour antibiotics whose antitumour properties are attributed to their ability to selectively repress the expression of genes essential for the progression of the cell cycle from G1 to S phase. They have been shown to inhibit E2F transcription factors, which are critical regulators of mammalian cellular proliferation. This biological observation has made them a potentially important new therapeutic target for the control of proliferative diseases, such as cancer. An asymmetric total synthesis of an A83586C-citropeptin hybrid is presented in this thesis, along with a synthetic route to the azinothricin cyclodepsipeptide. The A83586C- citropeptin hybrid will serve as a useful intracellular probe that will provide valuable insights into the mechanism of the antitumour action of this class, which may contribute to a greater understanding of cancer biology. The cyclodepsipeptide components of these molecules have been assembled via a 2+2+2 -fragment condensation strategy and a HATU-mediated macrolactamisation. In the case of the A83586C-citropeptin hybrid, a chemoselective coupling was performed between the fully elaborated N-hydroxybenzotriazole activated ester and the citropeptin cyclodepsipeptide

Risk of cause-specific mortality according to waist-hip ratio stratified by body mass index, Shanghai, China, Shanghai Men’s Health Study 2002–2006, Shanghai Women’s Health Study 1996–2000.

<p>Hazard ratios for the associations between waist-hip ratio with cardiovascular disease, cancer and other-cause mortality, stratified by baseline body mass index. Point estimates are plotted on the logarithmic scale.</p

Risk of all-cause mortality according to waist-hip ratio stratified by selected factors, Shanghai, China, Shanghai Men’s Health Study 2002–2006, Shanghai Women’s Health Study 1996–2000.

<p>Hazard ratios for the association between all-cause mortality and waist-hip ratio stratified by age, body mass index, physical activity and smoking status. Point estimates are plotted on the logarithmic scale.</p

Baseline Characteristics by Quintiles of Waist-hip Ratio, Shanghai, China, Shanghai Men’s Health Study 2002–2006, Shanghai Women’s Health Study 1996–2000.

<p>IQR = interquartile range.</p><p>Baseline Characteristics by Quintiles of Waist-hip Ratio, Shanghai, China, Shanghai Men’s Health Study 2002–2006, Shanghai Women’s Health Study 1996–2000.</p

Multivariate hazard ratios for all-cause mortality in (a) men and (b) women by waist-hip ratio and body mass index, Shanghai, China, Shanghai Men’s Health Study 2002–2006, Shanghai Women’s Health Study 1996–2000.

<p>X-axes display adiposity measures; Y-axes display hazard ratio risk values for all-cause mortality plotted using the logarithmic scale. Body mass index hazard ratios are adjusted for education, occupation, regular exercise, dietary intake of saturated fats, fruits and vegetables, alcohol consumption, height, menopausal status (women only), and smoking status (men only). Waist-hip ratios are additionally adjusted for body mass index. Sex-specific medians were used as reference points: waist-hip ratio = 0.90 for men and 0.81 for women; body mass index = 23.8 for men, and 23.7 for women.</p

Sensitivity analyses using pooled data for associations between genetically predicted BMI and breast cancer risk in the BCAC.

<p>(A) Adjusted for age, study sites, and the first eight principal components. (b) Adjusted for age, study sites, the first eight principal components, and additional breast cancer risk factors: age at menarche, parity, use of contraceptive, use of hormone replacement therapy, breast feeding, and smoking status. Weighted: the BMI-GS was constructed using the additive model weighted by external beta reported from previous literatures. Unweighted: the BMI-GS was constructed using the additive model without any weight.</p

Associations of the weighted BMI-GSs with BMI and traditional breast cancer risk factors.

<p>Associations of the weighted BMI-GSs with BMI and traditional breast cancer risk factors.</p

Associations between genetically predicted BMI and breast cancer risk.

<p>Associations between genetically predicted BMI and breast cancer risk.</p

Significant associations detected at <i>p</i> < 0.05 between breast cancer risk and BMI-related SNPs.

<p>Significant associations detected at <i>p</i> < 0.05 between breast cancer risk and BMI-related SNPs.</p

Meta-analysis of the association between genetically predicted BMI and breast cancer risk in the BCAC.

<p>The summary OR was calculated by combining individual analysis results from each study in BCAC (<i>p</i> for heterogeneity = 0.06).</p