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Conformationally locked uridine in the ‘southern’ conformation, which could be an important precursor for corresponding nucleotides, was stereoselectively synthesized. Southern uridine nucleotides are expected to be full agonists for the P2Y6 receptor. Poor diastereoselectivity in the osmium-mediated dihydroxylation on the allyl amine was overcome by introduction of an allyl azide on which osmium medium hydroxylation, and subsequent cyclization yielded 6-oxabicyclo[3.2.0]heptane in a 9:1 ratio. High regio�selectivity between the 2′- and 3′-hydroxyl groups in the intramolecular O-alkylation and construction of uracil moiety from the azido group provided the final target, a southern 2′-benzoylated uridine derivative. [ABSTRACT FROM AUTHOR]

The article discusses the concise synthesis of xanthylentin, a crucial synthetic intermediate of (+)-decursinol, (+)-decursin and their derivatives. It says that the synthetic procedure include blocking of a more reactive carbon (C-8) with a halo group for the regioselective Claisen rearrangement, dehalogenation with Zn/AcOH, and construction of a cyclic ether. It states that the halo group were examined for stability during harsh conditions in Claisen rearrangement.

We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A2B receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2′-amino-4′-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding Ki value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with Ki values in the micromolar range. Since no enhancement of A2B receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched. [Copyright &y& Elsevier]

[Display omitted] A 2B adenosine receptor (A 2B AR) antagonists have therapeutic potential in inflammation-related diseases such as asthma, chronic obstructive pulmonary disease and cancer. However, no drug is currently clinically approved, creating a demand for research on novel antagonists. Over the last decade, the study of target binding kinetics, along with affinity and potency, has been proven valuable in early drug discovery stages, as it is associated with improved in vivo drug efficacy and safety. In this study, we report the synthesis and biological evaluation of a series of xanthine derivatives as A 2B AR antagonists, including an isothiocyanate derivative designed to bind covalently to the receptor. All 28 final compounds were assessed in radioligand binding experiments, to evaluate their affinity and for those qualifying, kinetic binding parameters. Both structure-affinity and structure-kinetic relationships were derived, providing a clear relationship between affinity and dissociation rate constants. Two structurally similar compounds, 17 and 18 , were further evaluated in a label-free assay due to their divergent kinetic profiles. An extended cellular response was associated with long A 2B AR residence times. This link between a ligand's A 2B AR residence time and its functional effect highlights the importance of binding kinetics as a selection parameter in the early stages of drug discovery. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin has been shown to induce apoptosis in many cancer cells. However, the molecular mechanism(s) responsible for curcumin-induced apoptosis is not well understood and most probably involves several pathways. In HL-60 cells, curcumin induced apoptosis and endoplasmic reticulum (ER) stress as evidenced by the survival molecules such as phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2α, glucose-regulated protein-78, and the apoptotic molecules such as caspase-4 and CAAT/enhancer binding protein homologous protein (CHOP). Inhibition of caspase-4 activity by z-LEVD-FMK, blockage of CHOP expression by small interfering RNA, and treatment with salubrinal, an ER inhibitor, significantly reduced curcumin-induced apoptosis. Removing two double bonds in curcumin, which was speculated to form Michael adducts with thiols in secretory proteins, resulted in a loss of the ability of curcumin to induce apoptosis as well as ER stress. Thus, the present study shows that curcumin-induced apoptosis is associated with its ability to cause ER stress. [Copyright &y& Elsevier]

Abstract: We report the first total synthesis of glycyrol. Glycyrol, isolated from Glycyrrhizae Radix, has a unique skeleton of a benzofuran coumarin. The key steps are Smiles rearrangement and selective introduction of prenyl and O-methyl groups. The first application of a novel precursor for Smiles rearrangement, 3-benzyloxy-substituted (diacetoxyiodo)benzene, showed the synthetic possibility for diverse precursors. The introduction of a benzyl protecting group was important because selective deprotection was hard due to the low solubility of intermediates. [Copyright &y& Elsevier]