nists have been characterized largely in terms of their effects on lipids and glucose metabolism, whereas little has been reported about effects on amino acid metabolism. We studied responses to the PPAR␣ agonist WY 14,643 (30 mol⅐ kg Ϫ1 ⅐ day Ϫ1 for 4 wk) in rats fed a saturated fat diet. Plasma and urine were analyzed with proton NMR. Plasma amino acids were measured using HPLC, and hepatic gene expression was assessed with DNA arrays. The high-fat diet elevated plasma levels of insulin and triglycerides (TG), and WY 14,643 treatment ameliorated this insulin resistance and dyslipidemia, lowering plasma insulin and TG levels. In addition, treatment decreased body weight gain, without altering cumulative food intake, and increased liver mass. WY 14,643 increased plasma levels of 12 of 22 amino acids, including glucogenic and some ketogenic amino acids, whereas arginine was significantly decreased. There was no alteration in branched-chain amino acid levels. Compared with the fat-fed control animals, WY 14,643-treated animals had raised plasma urea and ammonia levels as well as raised urine levels of N-methylnicotinamide and dimethylglycine. WY 14,643 induced changes in a number of key genes involved in amino acid metabolism in addition to expected effects on hepatic genes involved in lipid catabolism and ketone body formation. In conclusion, the present results suggest that, in rodents, effects of pharmacological PPAR␣ activation extend beyond control of lipid metabolism to include important effects on whole body amino acid mobilization and hepatic amino acid metabolism.peroxisome proliferator-activated receptor-␣ PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␣ (PPAR␣) agonists are used clinically to treat dyslipidemia and to reduce the risk of cardiovascular complications (7). The beneficial effects of these agents appear to be most significant in patients with insulin resistance and diabetes (32). It is clear that a major and primary action of PPAR␣ activation is the transcriptional regulation of genes involved in lipid metabolism (36). However, the effects of PPAR␣ activation may not be limited to lipid metabolism, given the established interactions between the major substrate classes (19), e.g., the glucose-fatty acid cycle (29) and the glucose-alanine cycle (10). In terms of glucose metabolism, an important physiological role of PPAR␣ is suggested by the hypoglycemia in response to prolonged fasting developed by mice lacking PPAR␣ (17). Furthermore, treatment of fat-fed rats with the selective PPAR␣ agonist WY 14,643 resulted in increases in whole body and skeletal muscle insulin-stimulated glucose utilization, with the enhancement in muscle insulin sensitivity related to the degree of reduction in local lipid accumulation (39). Surprisingly little has been reported concerning effects of PPAR␣ activation on amino acid metabolism, although work based largely on analysis of mRNA in mouse liver (23) suggests an important influence on the handling of this substrate class.The aim of the present study was to provide...

A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC50 of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.

3 (8%). When 2 was obtained as pure nitrilium salt (free from excess Et3OBF4 and volatile impurities) and hydrolyzed, the reaction products were exceptionally dependent on temperature and reaction times. For example, when 2 was hydrolyzed with boiling water for 60 min, boric acid was the only boron-containing product observed. However, when hydrolysis time was reduced to 5 min, a 12% yield of 4 was obtained apart from boric acid formation. At 40-50 °C for 30 min, there was no acid 4 formation but only imine 3 product. A systematic study using different reaction times and temperatures showed that hydrolysis of pure 2 at 60-70 °C for 15 min offers 4 in reasonably good yield (41%).Cold alkaline hydrolysis of 2 gave 5, whose IR and NMR data (Table I) are consistent with the anticipated structure. Characteristic absorptions of boranocarbamoyl at 1593 and 1488 cm"1 (amide I and II bands) were observed.Reaction of 2 with methanol in CH2C12 followed by alkaline treatment gave C5H5N-BH2C(OCH3)=NEt (6). The IR spectrum showed an absorption at 1620 cm"1 for C=N, overlapping with the C=C band at 1625 cm"1. The 'H NMR spectrum was consistent with the structure. For an acyclic imidate, the typical products of hydrolysis at low pH are an ester and amine.9 Acidic hydrolysis of 6 with 0.5 N HC1 did not proceed to the ester even at 50 °C for 6-8 h but formed a stable salt of imino ether. This may be due to greater basicity of the imino ether adjacent to a boron moiety, as was observed for boranocarbamoyl derivatives.10 Under forced reaction conditions (100 °C) boric acid formation resulted. However, hydrolysis of 6 at neutral pH (50 °C, 8 h) gave a 40% yield of the ester C5H5N-BH2COOCH3 7. The IR spectrum exhibited characteristic B-H and C=0 absorptions, and the NMR spectrum was consistent with the structure (Table I).The nB NMR spectrum (Table I) of each compound consisted of a distinct triplet (except 2, which was a very broad triplet, which collapsed to a singlet upon 'H-decoupling. Only salts 2 and 3 showed another boron signal, but this was attributable to BF4".Since other amine-BH2X adducts (X = CN, CONHR, COOR, C02H) including C5H5-BH2C02H possess biological activity,2"4 these compounds are being examined to determine the effect these functional groups have on the biological activity of the molecule.

No abstract

Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.