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

HRs (95%CIs) of reproductive years with total and cause-specific mortality, Shanghai Women's Health Study.

<p>Abbreviation: HR: hazard ratio; CIs: confidence intervals.</p><p>^<i>a</i>Reference category.</p><p>^<i>b</i>Adjusted for age at study enrollment, BMI, WHR, education, occupation, income, regular exercise (met/hour/year), current smoking (yes/no), current alcohol consumption (yes/no), marital status, age at menarche, and number of live births.</p><p>^<i>c</i><i>P_trend</i> for number of reproductive years (categorical).</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

HRs (95%CIs) of age at menopause (years) with total and cause-specific mortality, Shanghai Women's Health Study.

<p>Abbreviation: HR: hazard ratio; CIs: confidence intervals.</p><p>^<i>a</i>Reference category.</p><p>^<i>b</i>Adjusted for age at study enrollment, BMI, WHR, education, occupation, income, regular exercise (met/hour/year), current smoking (yes/no), current alcohol consumption (yes/no), marital status, age at menarche, and number of live births.</p><p>^<i>c</i><i>P_trend</i> for age at menopause (categorical).</p

HRs (95%CIs) of age at menarche (years) with total and cause-specific mortality, Shanghai Women's Health Study.

<p>Abbreviation: HR: hazard ratio; CIs: confidence intervals.</p><p>^<i>a</i>Reference category.</p><p>^<i>b</i>Adjusted for age at study enrollment, BMI, WHR, education, occupation, income, regular exercise (met/hour/year), current smoking (yes/no), current alcohol consumption (yes/no), marital status, age at menopause, and number of live births.</p><p>^<i>c</i><i>P_trend</i> for age at menarche (categorical).</p

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

Association of GWAS-Identified T2D-Related SNPs with T2D Risk.

<p>T2D increasing risk allele identified in prior GWAS study.</p>††<p>ORs and 95% confidence intervals for association with T2D, adjusted for age, sex and BMI.</p>*<p>SNP is used in the calculation of the GRS2 genetic risk score (see Methods).</p

Association between the genetic risk scores and T2D^*.

*<p>Adjusted for age, sex and BMI.</p