2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation: Enhanced Potency as P2Y 1 Receptor Antagonists

Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of P2Y1 receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829–842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y1 receptor and by using the radiolabeled antagonist [3H]2-chloro-N6-methyl-(N)-methanocarba-2′-deoxyadenosine 3′,5′-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y1 receptor was an (N)-methanocarba N6-methyl-2-iodo analogue 12, which displayed a Ki value in competition for binding of [3H]5 of 0.79 nM and a KB value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y1 receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(1-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y1 receptors. An enzymatic method of synthesis of the 3′,5′-bisphosphate from the corresponding 3′-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored

Effects of daily quercetin-rich supplementation on cardiometabolic risks in male smokers

Limited information from human studies indicates that dietary quercetin supplementation influences blood lipid profiles, glycemic response, and inflammatory status, collectively termed cardiometabolic risks. We tested the hypothesis that quercetin-rich supplementation, derived from onion peel extract, improves cardiometabolic risk components in healthy male smokers in a randomized, double blinded, placebo-controlled parallel design. Randomly assigned subjects were instructed to take either the placebo (n = 43) or 100 mg quercetin capsules each day (n = 49) for 10 weeks. Anthropometric parameters and blood pressure were measured, and blood lipids, glucose, interleukin-6, and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined at baseline and after 10 weeks of quercetin supplementation. Quercetin-rich supplementation significantly reduced serum concentrations of total cholesterol (P < 0.05) and LDL-cholesterol (P < 0.01), whereas these effects were not shown in the placebo group. Furthermore, significant increases were observed in serum concentrations of HDL-cholesterol both in the placebo (P < 0.005) and quercetin-rich supplementation group (P < 0.001); however, changes in HDL-cholesterol were significantly greater in subjects receiving quercetin-rich supplementation than the placebo. Both systolic (P < 0.05) and diastolic blood pressure (P < 0.01) decreased significantly in the quercetin-rich supplementation group. Glucose concentrations decreased significantly after 10 weeks of quercetin-rich supplementation (P < 0.05). In contrast, no effects of quercetin-rich supplementation were observed for the inflammatory markers-IL-6 and sVCAM-1. Daily quercetin-rich supplementation from onion peel extract improved blood lipid profiles, glucose, and blood pressure, suggesting a beneficial role for quercetin as a preventive measure against cardiovascular risk

Macronutrient Composition and Sodium Intake of Diet Are Associated with Risk of Metabolic Syndrome and Hypertension in Korean Women

<div><p>Hypertension and hypertriglycemia are the most important contributors to metabolic syndrome (MetS) and cardiovascular disease risk in South Koreans with a relatively lean body mass. These major contributors differ from those identified in Western populations. This study aimed to identify the characteristics of the Korean diet associated with increased risk of MetS, whose prevalence has been steadily increasing in South Korea. On the basis of data collected from 5,320 subjects by the 2007–2008 Korean National Health and Nutrition Examination Survey, 3 dietary patterns were identified using factor analysis and their association with the risk of MetS and its components was examined. The balanced Korean diet, a typical Korean diet of rice and kimchi intake supplemented by a variety of foods had a desirable macronutrient composition and was associated with a lower risk of elevated blood pressure (OR=0.61, 95% CI=0.45–0.84) and hypertriglyceridemia (0.69, 0.49–0.88) in men and a lower risk of elevated blood pressure (0.59, 0.41–0.85) and MetS (0.67, 0.47–0.96) in women. The unbalanced Korean diet, characterized by a high intake of carbohydrates and sodium and little variety, was associated with a higher risk of MetS (1.44, 1.03–2.01) and elevated blood pressure (1.41, 1.00–1.98) in women. The semi-western diet, characterized by a relatively high intake of meat, poultry, and alcohol, was associated with a lower risk of low high-density lipoprotein cholesterol (0.70, 0.54–0.89) in women. Thus, macronutrient composition and sodium intake are associated with the risk of MetS and prehypertension in women. Maintaining a desirable macronutrient composition and avoiding excessive consumption of carbohydrates and sodium should be emphasized for prevention of MetS and hypertension in South Korean women. </p> </div

Metabolic syndrome risk and macronutrient composition of balanced Korean diet and unbalanced Korean diet.

<p>A and D: Macronutrient composition by quintiles (Q1: lowest, Q3: middle, Q5: highest; Q3 and Q5 was calculated on the base of Q1); % of energy is the percentage of energy obtained from carbohydrate, protein and fat; A dotted line is recommended intake of carbohydrate for Korean; ‡, p for trend <0.001. B and E: Multivariate OR and 95% CI (bar) of elevated blood pressure; *, Significant odd ratio, ‡, p for trend <0.001; Adjusted for age, smoking, alcohol and physical activity. C and F. Multivariate OR and 95% CI (bar) of hypertriglyceridemia for men and metabolic syndrome for women; *, Significant odd ratio, †, p for trend < 0.05; Adjusted for age, smoking, alcohol and physical activity.</p