Synthesis of C-5 and C-10 Vinyloxybenzene containing substrates for the enzyme Protein Farnesyltransferase

Protein Farnesyltransferase (PFTase) is an enzyme that incorporates farnesyl groups into proteins and peptides that end in a certain amino acid sequence. Previously, non-natural substrates that could have also been transferred by PFTase have undergone bioconjugation reactions via copper catalyzed click chemistry. Because of copper’s cytotoxicity, these substrates are not compatible with in vivo applications. Presented are two bioorthogonal substrates that do not require the use of a copper catalyst and they contain a vinyloxybenzene moeity for a photoreaction on a diaryl tetrazole. Both substrates are predicted to be PFTase substrates that will allow for the eventual incorporation of new properties such as fluorescence on targeted proteins. Because many prenylated proteins are involved in signaling processes, this has generated interest in protein prenyl transferases as possible anticancer targets

“Greening up”: A Multistep Synthetic Transformation

Green Chemistry is an experimental design theory that aims to reduce the use and generation of hazardous substances in order to address problems we face in the world today like water contamination, global warming, ozone depletion, and pollution. When hazardous substances are replaced with less hazardous substances, both risk and cost can be reduced. Teaching the importance and relevance of green chemistry is imperative to the future of chemistry and the environment. Since most useful organic chemical targets require more than one synthetic step, it is important that undergraduate organic chemistry students be exposed to labs that require multiple transformations. This will allow students to understand how reactions work after observing them first-hand. Additionally, since the ‘traditional’ synthesis of most chemical substances utilizes solvents, reagents, and conditions that are harmful and hazardous to the environment, students had to propose their own green alternatives by completing a 3-step synthesis and determining a greener route. The products were purified, characterized and then a metric system was used to compare the greenness of the reactions. A reaction was considered more green if there were relative decreases in the combination of factors that include cost, environmental toxicity, and waste produced. In total, 22 different targets were attempted to be synthesized

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Saturation Transfer Difference NMR Spectroscopy Using Glycopolymers

We report the use of Saturation Transfer Difference (STD) NMR spectroscopy to observe the interaction of various phenylboronic acids (PBAs) with synthetic glycopolymers presenting galactose and glucose. After optimizing experimental parameters to maximize spin diffusion, the binding of boronic acids to the glycopolymers was examined using STD NMR. Efficient amplification factor build-up curves which were used to generate an epitope map for the boronic acid binding to the glycopolymers. STD-NMR was also used to detect the interaction between indole and a galactosylated glycopolymer, providing an indole-based view of this C-H – π interaction.</p