Coumarins are widely present in a variety of plants and have a variety of pharmacological activities. In this study, we isolated a coumarin compound from Microsorium fortunei (Moore) Ching; the compound was identified as esculetin by hydrogen and carbon spectroscopy. Its anti-hepatitis B virus (HBV) activity was investigated in vitro and in vivo. In the human hepatocellular liver carcinoma 2.2.15 cell line (HepG2.2.15) transfected with HBV, esculetin effecting inhibited the expression of the HBV antigens and HBV DNA in vitro. Esculetin inhibited the expression of Hepatitis B virus X (HBx) protein in a dose-dependent manner. In the ducklings infected with duck hepatitis B virus (DHBV), the levels of DHBV DNA, duck hepatitis B surface antigen (DHBsAg), duck hepatitis B e-antigen (DHBeAg), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) decreased significantly after esculetin treatment. Summing up the above, the results suggest that esculetin efficiently inhibits HBV replication both in vitro and in vivo, which provides an opportunity for further development of esculetin as antiviral drug.

The design and synthesis of a series of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]-pyrrol-5-ones are described. All the synthesized compounds were evaluated for raising leukocyte count activities in normal mice. Four compounds (8a, b, d, h) exhibited raising leukocyte count activities close or higher than positive control recombinant human granulocyte colony stimulating factor (rhG-CSF), and some (8e-g, k, p, r) had a moderate effect. Among them, the most potent compound 8a was evaluated for its antileukopenia activity in cyclophosphamide (CTX) treated mice. Interestingly, 8a exhibited significant antileukopenia activity as compared to rhG-CSF. The results suggest that this kind of compounds might be utilized for the development of new candidate for treatment of leukocytopenia. and from other organisms since that time.2-4) This group of compounds includes thiolutin, aureothricin, isobutyropyrrothin, holomycin, xenorhabdins and thiomarinols A-G 5-9) ( Fig. 1). Dithiolopyrrolones are reported with diverse biological activities including against various Gram-positive and Gram-negative bacteria, yeasts, fungi and amoeboid parasites.10-12) Dithiolopyrrolones have also been reported to have anticancer activity. 13,14)The modifications of the dithiolopyrrolones have been extensively reported in literature. [15][16][17][18][19][20][21] However, all the modifications were intended to improve the antibacterial or anticancer activity. In our previous work, we first observed that ZL-004 (Fig. 2) exhibited antileukopenia activity, 22) which can significantly raise the white blood cells (WBC) count in normal mice and chemotherapy-induced mice. The mechanism of ZL-004 23) is to act on the mouse bone marrow causing proliferation and differentiation, the elevation of WBC is due to an increase in the absolute neutrophil count, which could promote the recovery of hemopoiesis. Also, it can raise WBC count in a dose-dependent manner without significant changes in erythrocyte, platelet counts or hemoglobin concentrations.In order to better understand the structure-activity relationship (SAR) and discover novel antileukopenia agents with higher potency and good safety profiles, we embarked on design and synthesis of analogues of ZL-004. In this study, we reported the practical synthesis, the SAR, the raising leukocyte count activity in normal mice and the antileukopenia activity in CTX-treated mice of the newly synthesized dithiolopyrrolones. 24,25) Results and DiscussionChemistry The synthesis of the target compounds was accomplished by the procedures shown in Chart 1. 1,3-Bis(tert-butylthio)propan-2-one was prepared from 1,3-dichloroacetone in the presence of potassium carbonate in acetone, which was coupled with 2,4-dimethoxyanile in toluene utilizing p-toluenesulfonic acid as catalyst. The reaction mixture was refluxed for 5h, and then the mixture was allowed to cool to −5°C, oxayl chlorite was added to the reaction mixture to generate the compound 3 in 75% yield. Ammonization of 3 by in situ synthesis of amm...

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Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC 50 value of 6.4 µM against LXRα and an IC 50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists.Key words liver X receptor α; liver X receptor β; antagonistic activity Nuclear receptors (NRs) are ligand-activated transcription factors that coordinate gene expression in response to the modulation of metabolism, development, proliferation, and inflammation.1,2) Liver X receptors (LXRs) belonging to the NR superfamily are activated by specific oxidized forms of cholesterol and intermediate products of the cholesterol biosynthetic pathway. 1,3,4) There are two LXR isoforms in mammals, termed LXRα and LXRβ. LXRα is abundantly expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRβ is more ubiquitously expressed, with particularly high levels in the developing brain. [5][6][7][8] Both isoforms share almost 80% homology of their amino acid sequences in their DNA-binding domain and ligand-binding domain. 5,7)The LXR consists of four domains: N-terminal ligandindependent activation function domain (AF-1); DNA-binding domain (DBD); hydrophobic ligand-binding domain (LBD); and C-terminal ligand-dependent transactivation sequence (AF-2).5,9,10) By forming heterodimers with retinoid X receptors (RXRs), LXRs bind to LXR response elements (LXREs) in the promoter or enhancer elements of LXR target genes. The activation of LXR-RXR heterodimers not only induces the expression of a variety of target genes (CYP7A, ABCA1, SREBP-1) that are involved in lipid and glucose metabolism, but also results in the inhibition of genes encoding inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ. 1,[11][12][13][14][15] In the last decade, GlaxoSmithKline and other several pharmaceutical companies have been active in developing synthetic LXR agonists (Fig. 1). T0901317 (1, Tularik) and GW3965 (2, GSK) exhibit nonselectivity for LXRα and LXRβ with high affinity.11,16-18) The first compound to enter the clinic was LXR-623 (3, Wyeth), an LXRα/β partial agonist for the potential treatment of atherosclerosis and dyslipidemia. Unfortunately, the trial was terminated due to adverse central nervous system effects.19-21) LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others 22-28) (Fig. 1).SR-9238 was the first selective synthetic LXR inverse agonist that displays a degree of LXRβ selectivity with an IC 50 value of 214 nM for LXRα and 43 nM for LXRβ, and this compound effectively suppressed hepatic lipogenesis, inflammation, and hepatic lipid...