Nickel-catalyzed cross-coupling reactions involving secondary and tertiary alkyl nucleophiles

In the first chapter, introduction of transition metal-catalyzed cross-coupling reactions has been given. These transition metal-catalyzed C-C bond forming reactions have been used extensively in organic synthesis. Among them, C(sp2)-C(sp2) bond forming reactions have been widely studied over decades. More recently, some reports have demonstrated the use of C(sp3) nucleophiles and electrophiles in cross-coupling reactions. However, use of secondary and tertiary alkyl nucleophiles has remained a challenge due to competitive β-hydride elimination and slow transmetallation of bulky secondary and tertiary alkyl organometallic nucleophiles. In the second chapter, the first general nickel-catalyzed Negishi reaction for the cross-coupling of unactivated, acyclic secondary alkylzinc halides and aryl and hetero-aryl iodides has been reported. This process is the first to overcome the β-hydride elimination problem inherent to the use of the analogous palladium-catalyzed processes. This method is very general and tolerates a wide range of functional groups. A detailed study of the effect of salt additives on these reactions has also been presented. In the third chapter, this work has been extended to the use of tertiary alkyl nucleophiles and the first metal-catalyzed Kumada cross-coupling reaction of tertiary alkylmagnesium halides and aryl bromides/triflates has been reported. This reaction has very wide substrate scope, and vinyl bromides and vinyl chlorides can also be employed as electrophiles. Here, the effect of catalyst hydration on the reaction yield and selectivity has been demonstrated. In the fourth chapter, a mild palladium-catalyzed reaction for the monoborylation of primary alkyl halides using bis(pinacolato)diboron as the boron source has been reported. This reaction is very general and can accommodate a wide range of functional groups. To increase the utility of this process, the crude borylation product has been converted into the corresponding boronic acid, trifluoroborate salt and another boronic ester. Aditionally, bis(neopentylglycolato)diboron has also been employed as the boron source

Antidiabetic Properties of Azardiracta indica and Bougainvillea spectabilis: In Vivo Studies in Murine Diabetes Model

Diabetes mellitus is a metabolic syndrome characterized by an increase in the blood glucose level. Treatment of diabetes is complicated due to multifactorial nature of the disease. Azadirachta indica Adr. Juss and Bougainvillea spectabilis are reported to have medicinal values including antidiabetic properties. In the present study using invivo diabetic murine model, A. indica and B. spectabilis chloroform, methanolic and aqueous extracts were investigated for the biochemical parameters important for controlling diabetes. It was found that A. indica chloroform extract and B. spectabilis aqueous, methanolic extracts showed a good oral glucose tolerance and significantly reduced the intestinal glucosidase activity. Interestingly, A. indica chloroform and B. spectabilis aqueous extracts showed significant increase in glucose-6-phosphate dehydrogenase activity and hepatic, skeletal muscle glycogen content after 21 days of treatment. In immunohistochemical analysis, we observed a regeneration of insulin-producing cells and corresponding increase in the plasma insulin and c-peptide levels with the treatment of A. indica chloroform and B. spectabilis aqueous, methanolic extracts. Analyzing the results, it is clear that A. indica chloroform and B. spectabilis aqueous extracts are good candidates for developing new neutraceuticals treatment for diabetes

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

Keyword generation for search engine advertising

Keyword 3 generation for search engine advertising is an important problem for sponsored search or paidplacement advertising. A recent strategy in this area is bidding on nonobvious yet relevant words, which are economically more viable. Targeting many such nonobvious words lowers the advertising cost, while delivering the same click volume as expensive words. Generating the right nonobvious yet relevant keywords is a challenging task. The challenge lies in not only finding relevant words, but also in finding many such words. In this paper, we present TermsNet, a novel approach to this problem. This approach leverages search engines to determine relevance between terms and captures their semantic relationships as a directed graph. By observing the neighbors of a term in such a graph, we generate the common as well as the nonobvious keywords related to a term. 1

A systematic organization of bioinformatics database of radiosensitizers and radioprotectors

Radiosensitizers and radioprotectors are the compounds that modify the radiation therapy treatment. Radiosensitizers make tumor cell more sensitive to radiation therapy which increases the effectiveness of cancer treatment, whereas radioprotectors are the compounds that reduce the damage/spare normal tissue. Several of these compounds have been studied using appropriate biological model system and their efficacy is reported in literature. The main objectives of the bioinformatics database is to bring on single platform for researchers and clinicians. Therefore, we have developed bioinformatics database of radiosensitizers and radioprotectors using information available in PubMed, scientific journals, and other scientific sources. The collected information of these compounds systematically organized on single platform where a user can browse typical information of the compound. The information pertaining to these compounds is mainly on structural features, radiobiological aspects, biological targets, clinical trials, pharmacological aspects, toxicity, etc. Hence, the database would help clinicians, researchers, and scientists for the improvement of radiation therapy treatment