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  • In summary synthetic routes with moderate to high yields hav

    2019-07-11

    In summary, synthetic routes with moderate to high yields have been developed to produce difluoro-dioxolo-benzoimidazol-benzamides including reference standards and , and -desmethylated precursors and , and carbon-11-labeled difluoro-dioxolo-benzoimidazol-benzamides target tracers [C] and [C]. The radiosynthesis employed [C]CHOTf for -[C]methylation at -desmethylated precursor, followed by product purification and isolation using a semi-preparative RP HPLC combined with SPE. [C] and [C] were obtained in high radiochemical yield, radiochemical purity and chemical purity, with a reasonable short overall synthesis time, and high molar activity. This will facilitate studies to evaluate carbon-11-labeled CK1 inhibitors [C] and [C] as new candidate PET radiotracers for imaging of AD. Acknowledgments This work was partially supported by Indiana University Department of Radiology and Imaging Sciences in the United States. 1H NMR and 13C NMR spectra were recorded at 500 and 125 MHz, respectively, on a Bruker Avance II 500 MHz NMR spectrometer in the Department of Chemistry and Chemical Biology at Indiana University Purdue University Indianapolis (IUPUI), which is supported by the United States National Science Foundation (NSF) Major Research Instrumentation Program (MRI) grant CHE-0619254.
    Introduction Obesity is characterized by an increase in adipose tissue mass and is correlated to the development of obesity-related disorders including hypertension, heart disease, type 2 AZD3264 (T2D), and cancer (Kang, 2013, Kaur, 2014, Sundaram et al, 2013). In obesity, the level of circulating factors including insulin, adipocytokines, cytokines, vascular integrity factors, plasminogen activator inhibitor (PAI), and fatty acids as well as the deposition of lipids in liver and skeletal muscle are altered (Fan et al, 2013, Mlinar, Marc, 2011). For a long time, white adipose tissue was considered as a passive organ storing energy as triglycerides. To date, it is becoming increasingly clear that adipose tissue is a complex endocrine organ (Adamczak, Wiecek, 2013, Al-Suhaimi, Shehzad, 2013, Cao, 2014, Fischer-Posovszky et al, 2007, Leal Vde, Mafra, 2013, Wozniak et al, 2009). In addition to adipocytes, adipose tissue contains preadipocytes, nerve terminals, blood vessels, and macrophages. In particular, adipocytes and immune cells secrete a wide range of hormones and other factors, termed adipocytokines. At present, more than 20 adipocytokines have been identified as critical regulators of energy (lipid and glucose) homeostasis, appetite, insulin sensitivity, inflammation, and vascularization (Al-Suhaimi, Shehzad, 2013, Cao, 2014). Adiponectin, an adipocytokine with anti-inflammatory, anti-diabetic, and anti-atherogenic features, is mainly secreted by adipocytes and its expression level is reduced in obesity (Fiaschi et al, 2014, Lim et al, 2014). Human adiponectin is a 244 amino acid (aa) polypeptide, containing a N-terminal secretory sequence, a collagen-like domain, and a C-terminal globular domain with large sequence and structural similarities to the complement factor C1q (Crouch et al, 1994, McCormack et al, 1997, Wong et al, 2004). Like other proteins of the C1q family adiponectin is able to build characteristic homomeres including low molecular weight (LMW) trimers, middle molecular weight (MMW) hexamers and high molecular weight (HMW) 12–18-mers (Liu, Liu, 2014, Pajvani et al, 2004). Posttranslational modifications, especially the formation of disulfide bridges, hydroxylation, and glycosylation, play an important role in regulating activity and complex formation of adiponectin (Peake et al, 2007, Richards et al, 2006, Wang et al, 2002, Wang et al, 2008). Phosphorylation is considered to be another most common and reversible covalent posttranslational modification that may alter the activity, life span, or cellular localization of proteins. However, the role of site-specific phosphorylation in regulating adiponectin complex formation and activity is still elusive. Since adiponectin contains several potential phosphorylation sites for tyrosine- and serine/threonine-specific kinases, we hypothesize that adiponectin is able to interact with cellular kinases and that its complex formation is modulated by site-specific phosphorylation. Among those potential adiponectin targeting kinases are also members of the serine/threonine-specific CK1 family, which are involved in the regulation of various processes, like immune response, differentiation, cell proliferation, transport processes, chromosome segregation, and lipid metabolism (Brookheart et al, 2014, Knippschild et al, 2014).