[show abstract][hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo.
Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR.
CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain.
We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.
[show abstract][hide abstract] ABSTRACT: The fluorogenic 1,3-Huisgen dipolar cycloaddition reaction was used as part of a novel immobilization strategy of PNA capture probes on a microarray. By using this click chemistry, azidocoumarin-anchored PNA probes were immobilized on phenyl acetylene-modified glass slides with the simultaneous generation of the fluorescent triazolylcoumarin moiety. Since the emitting moieties are generated in the immobilization reaction itself, fluorescent signals can be used to directly monitor the integrity of immobilization in a nondestructive manner. By using this strategy, PNA microarrays were prepared and successfully employed to perform microarray-based diagnosis of selected mutations in the breast cancer susceptibility gene BRCA1.
Biochemical and Biophysical Research Communications 10/2008; 376(4):633-6. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: A methodology for the synthesis of 2- and 4-aminoquinoline derivatives, which takes advantage of selective activation of 2- or 4-substituent of 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1, has been developed. Since a procedure for formation of 3-aminoquinolinones from the 4-quinolinone 1 was described previously, the new methodology comprises a general methodology for the selective syntheses of three isomeric 2-, 3- and 4-aminoquinoline derivatives starting with the common 4-quinolinone 1.
[show abstract][hide abstract] ABSTRACT: Arylsulfamoyl imidazolium triflates, readily prepared from the corresponding chlorides, react with amines under neutral conditions to form arylsulfamides in high yields. This methodology, which contrasts with the slow and inefficient reactions of amines with arylsulfamoyl chlorides, is applied to the synthesis of arylsulfamide 3a, a bioisotere of muraglitazar.
[show abstract][hide abstract] ABSTRACT: The highly functionalized bicyclic lactam 7 was prepared from diolefinic-2-piperidone 18 by the use of ruthenium-catalyzed RCM, and in turn, 18 was derived via a two-carbon addition process from readily accessible 4-olefinic-2-azetidinone 13. Bicyclic lactams 7 and 20 could serve as potentially valuable intermediates for the chiral synthesis of various hydroxylated indolizidine alkaloids as exemplified by the synthesis of (8S,8aS)-perhydro-8-indolizinol 19.
The Journal of Organic Chemistry 04/2003; 68(6):2471-4. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nonracemic 5,6-disubstituted 2-piperidones were prepared from readily accessible 3,4-disubstituted-2-azetidinones having pre-installed substituents by reductive ring opening of 2-azetidinones followed by stereoselective installation of Z-α,β-unsaturated ester and lactam formation. For the synthetic application to the naturally occurring piperidine alkaloids, such as Prosopis and Cassia alkaloids, 5-hydroxy-2-piperidones (+)-13 and (−)-24 were prepared from 2-azetidinones (−)-6b and (+)-18 via two-carbon ring homologation.
[show abstract][hide abstract] ABSTRACT: 2-Azetidinones were smoothly transformed to unsaturated ketones through the ring opening of activated 2-azetidinone by phosphonate stabilized carbanion and subsequent Horner–Wadsworth–Emmons olefination of the resulting β-ketophosphonates with aldehydes. A formal synthesis of l-erythro-sphingosine and d-lyxo-phytosphingosine from readily available 2-azetidinone was established utilizing this methodology.
[show abstract][hide abstract] ABSTRACT: Chiral 5,6-disubstituted-5,6-dihydro-2(1H)-pyridones were prepared efficiently from readily accessible 3,4-disubstituted-2-azetidinones having preadjusted substituents and stereochemistry through the reductive ring opening of 2-azetidinones followed by Z-selective installation of acetate moiety and re-cyclization to 2-pyridones.
Tetrahedron Letters - TETRAHEDRON LETT. 01/2001; 42(20):3483-3486.
[show abstract][hide abstract] ABSTRACT: Eschenmoser sulfur extrusion reaction is failed to produce vinylogous carbamate II from N-(t-Boc)pyrrolidine-2-thion I but, treatment of methyl bromozincacetate with N-(t-Boc)pyrrolidine-2-thion I afforded good yield of vinylogous carbamate II. This thio-Reformatsky reaction appeared to be sensitive to the structure of substrates i.e. ring size or N-protecting groups.
Tetrahedron Letters - TETRAHEDRON LETT. 01/1999; 40(11):2173-2174.
[show abstract][hide abstract] ABSTRACT: Reaction of various thionolactones, prepared from the lactones and Lawesson's reagent, with methyl bromozincacetate afforded the corresponding vinylogous carbonates in good yields under mild conditions.
Tetrahedron Letters - TETRAHEDRON LETT. 01/1999; 40(34):6267-6270.