The effect of substituted thiophene and benzothiophene derivates on PPARγ expression and glucose metabolism

Eighteen substituted thiophene and benzothiophene derivatives were studied for their effects on peroxisome proliferator-activated receptor γ (PPARγ) in HepG2 cells. Three derivatives (compounds 5, 120.97%; 15, 102.14%; and 17, 113.82%) were found to transactivate PPARγ in vitro. By comparison, the positive control rosiglitazone (Ros) transactivated PPARγ by 311.53%. The three compounds were studied for their effects on glucose metabolism in vivo in KK/Ay diabetic mice. In vivo, the 2-(β-carbonyl/sulfonyl) butyryl-thiophene compounds 5 and 15 significantly decreased blood glucose levels (compounds 5, to?<?15.6?mmol/L; 15, to?<?10?mmol/L), improved glucose tolerance, improved impaired pancreatic islet β-cells, and lowered serum insulin levels.     

Design,synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives

Abstract

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in?vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC₅₀ values in the µM range. In addition, the in?vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.     

Synthesis and interaction of bovine serum albumin with p‐hydroxybenzoic acid derivatives

Three novel p‐hydroxybenzoic acid derivatives (HSOP, HSOX, HSCP) were synthesized from p‐hydroxybenzoic acid and sulfonamides (sulfamonomethoxine sodium, sulfamethoxazole and sulfachloropyridazine sodium) and characterized by elemental analysis, HNMR and MS. Interactions between derivatives and bovine serum albumin (BSA) were studied by fluorescence quenching spectra, UV–vis absorption spectra and time‐resolved fluorescence spectra. Based on fluorescence quenching calculation and Förster's non‐radioactive energy transfer theory, the values of the binding constants, basic thermodynamic parameters and binding distances were obtained. Experimental results indicated that the three derivatives had a strong ability to quench fluorescence from BSA and that the binding reactions of the derivatives with BSA were a static quenching process. Thermodynamic parameters showed that binding reactions were spontaneous and exothermic and hydrogen bond and van der Waals force were predominant intermolecular forces between the derivatives and BSA. Synchronous fluorescence spectra suggested that HSOX and HSCP had little effect on the microenvironment and conformation of BSA in the binding reactions but the microenvironments around tyrosine residues were disturbed and polarity around tyrosine residues increased in the presence of HSOP. Copyright © 2012 John Wiley & Sons, Ltd.     

An Efficient Alternative Route To 3,6-Disubstituted-Furo[2,3-d]Pyrimidin-2-One Analogues

Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrimidin-2-one analogues.     

Toward the Development of Metal‐Free Synthetic Nucleases: Cleavage of a Model Substrates by 1,4‐Diazabicyclo[2.2.2]Octane Derivatives

Artificial ribonucleases of A_nBCL series were synthesized by solid‐phase method. They consist of a hydrophobic alkyl radical A (n = 3–12 carbon atoms), an “RNA‐binding domain” B (bisquaternary salt of 1,4‐diazabicyclo[2.2.2]octane), a “catalytic domain” C (histidine residue) and a “linker” L that joins the domains B and C. The effect of the alkyl radical on the catalytic properties of the chemical catalyst was studied using three activated phosphate ester substrates: p‐nitrophenyl phosphate, bis‐p‐nitrophenyl phosphate, and thymidine‐3′‐p‐nitrophenyl phosphate.     

REACTION Of GLYCOSYL ISOTHIOCYNATES WITH 3-INDOLYLAMINOMETHYL-KETONE HYDROCHLORIDE

ABSTRACT

Reaction of glycosyl isothiocyanate 1a-c with 3-indolylaminomethyl-ketone hydrochloride(2) yielded glycosylthiourea derivatives 3a-c. Cyclodehydration of 3a-c with acetic anhydride afforded 5-(indol-3-yl)-2-[N-per-O-acetyl-D-glycopyranosyl)amino]thiazoles 4a-c. Deacetylation of 4a-c gave 5-(indol-3-yl)-2-[N-(D-glycopyranosyl) amino]thiazoles 5a-c.     

SYNTHESIS AND CHARACTERIZATION OF NUCLEOSIDE DERIVATIVES,N-(BENZOYL)-N-(DEOXYGUANOSIN-8-YL)-4-AMINOBIPHENYL AND N-(2′-DEOXYGUANOSIN-8-YL)-4-AMINOBIPHENYL VIA α-PHENYL-N-(4-BIPHENYL)NITRONE

ABSTRACT

Lead tetraacetate (LTA) oxidation of α-Phenyl-N-(4-biphenyl)nitrone (8) to give a new ultimate carcinogen, N-acetoxy-N-benzoyl-4-aminobiphenyl (9) which was reacted with deoxyguanosine (dG) at pH 6.9 to give nucleoside derivative, N-(benzoyl)-N-(deoxyguanosin-8-yl)-4-aminobiphenyl (10). Following debenzoylation with sodium carbonate-methanol leads to N-(2′-deoxyguanosin-8-yl)-4-aminobiphenyl (11).     

Aryldiazomethane Derivatives as Reagents for Site Specific Labeling of Nucleic Acids at Phosphate

Abstract

An efficient and direct labeling method based on direct alkylation of nucleic acids at phosphates by aryldiazomethane derivatives is described.     

Synthesis,Conformational and Configurational Studies of Some New Acetylated Glycosides of 2-Thio-3-aryl-4(3H)-quinazolinones,Their Thiono and 3,1-Benzothiazin-2,4-dithione

Abstract

A series of some new acetylated S-glycosides of 2-thioxoquinazolin-4-ones, their thiono analogues and 3,1-benzothazin-2,4-dithione derivatives, including a D-glucose and a D-galactose derivatives and a D-xylose, and an L-arabinose derivatives have been synthesized. The conformation and configuration of these carbohydrate derivatives were determined by analysing their ¹H and ¹³C NMR chemical shifts and coupling constants. The biological activity of these compounds has been studied.