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A series of novel bis(trifluoroethyl)phosphonomethyl ether derivatives of acyclovir was synthesized and their in vitro anti-HBV activity was evaluated in HepG2 2.2.15 cells. In contrast to acyclovir, most of the described phosphonates emerged as potent inhibitors of HBV replication. Especially, the most active compound 11 with IC 50 value of 2.92 μmol/L was 33 times more potent than acyclovir with IC 50 value of 100 μmol/L.

To examine the insulin sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative YY20 in insulin-sensitive cell lines. The peroxisome proliferator-activated receptor γ (PPARγ) agonist bioactivities of YY20 were detected by a preadipocyte differentiation assay. RT-PCR and Western blotting analysis were used to detect the expression of the target gene or protein. The effects of YY20 on insulin-mediated glucose consumption were determined in the HepG2 human hepatocellular carcinoma line. YY20 could enhance the differentiation of preadipocytes to adipocytes and upregulate the gene expression of PPARγ2, as well as the protein expression of insulin receptor sub-strate-1 (IRS-1), glucose transporter-4 (GLUT4), and adiponectin (ACRP30). The effects on GLUT4 and ACRP30 could be reversed by the PPARγ inhibitor SR-202. Furthermore, YY20 efficiently reduced glucose consumptions in HepG2 cells after 24 h culture, and the effects were related to insulin and YY20 concentrations. YY20, a potential insulin-sensitizing agent like rosiglitazone, could enhance glucose consumption in HepG2 cells in a concentration- and insulin-dependent manner. It may improve the insulin resistance associated with type 2 diabetes.

The epoxidation of three stereolabeled methyl-substituted chiral allylic alcohols with (1,2)A and/or (1,3)A allylic strain, namely 3-methylbut-3-en-2-ol (1a), pent-3-en-2-ol (1b), and 3-methylpent-3-en-2-ol (1c), have been studied by the density-functional theory method, B3LYP/6-31+G(d,p). For each substrate we calculated the two prereaction complexes with Ti(OH)(4)/MeOOH (the oxidant model for Ti(O-i-Pr)(4)/t-BuOOH), their threo and erythro transition states for oxygen transfer, and the corresponding product complexes. For substrate 1a, the erythro transition state is 0.91 kcal/mol of lower energy than the threo one; for substrates 1b and 1c, the threo compared to the erythro transition states are by 1.05 and 0.21 kcal/mol more favorable, respectively. The threo/erythro product ratios have been estimated from the computed free energies for the competing threo and erythro transition states 3a-c in CH(2)Cl(2) solution to be 12:88 (1a), 92:8 (1b), and 77:23 (1c), which are in good accordance with the experimental values 22:78 (1a), 91:9 (1b), and 83:17 (1c). The diastereoselectivity of this diastereoselective oxyfunctionalization is rationalized in terms of the competition between (1,3)A and (1,2)A strain and the electronic advantage for the spiro transition state. In addition, solvent effects are also play a role for the diastereoselectivity at the same time.

Based on our previous result of the three-dimensional model of the μ-opioid receptor, binding conformations of 13 fentanyl analogs and three-dimensional structures for the complexs of these analogs with μ-opioid receptor were constructed employing the molecular modeling method and our binding conformation search program for ligands (BCSPL). Energetic calculation and quantitative structure–activity relationship (QSAR) analysis indicated a good correlation between the calculated binding energies of fentanyl analogs and their binding affinities, pKi's and pK's, and analgesic activities, − log ED50's. Based on the three-dimensional models, the possible interaction mechanism of fentanyl analogs with μ-opioid receptor can be illustrated and the available structure–activity relationship of these analgesic agents can be explained reasonably. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 78: 285–293, 2000

Tetraethylammonium (TEA) and other quaternary ammonium (QA) ions are potent blockers of potassium channels. In order to shed light on the blockade mechanism of QA ions, we have carried out a series of computations on the phenol–ammonium model with density functional theory (DFT) and Moller–Plesset second order perturbation (MP2) methods at levels of 6-31G* and 6-31G** basis sets. NH–aromatic π interaction and NH–OH hydrogen bond interaction, which are important in biological systems, are responsible for the binding of NH4+ to phenol. From analysis of structures, energies, charge populations and transition state features, both the cation–π interaction and hydrogen bond or electrostatic interaction between QAs and the key amino acid residues at the entryways of K+ channels are seen to be significant in the blockade mechanism of QA ions.

A series of novel l -amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.

Combinatorial chemistry is a type of synthetic strategy which systematically connects a set of “building blocks” of varying structures to yield a large array of diverse molecular entities. Since the molecular diversity of combinatorial library used for the two stages of drug discovery process which are exploring lead compounds and performing structural modification on lead compounds is different, choosing appropriate fragments as the building blocks becomes a critical step for combinatorial chemistry. The number of available chemical fragments is often so great that it is impossible to use all of the fragments in one synthetic experiment. An effective method is much needed to select building blocks from the enormous chemical fragments to synthesize a combinatorial library with desired molecular diversity. In this article, we proposed a novel idea to define molecular diversity based on three-dimensional (3D) grid force field properties including electric potential and steric potential parameters and demons...

The powerful anti-malarial drug, Qinghaosu (Artemisinin), has been studied using ab initio methods. The DFT B3LYP method with the 6-31G ∗ basis set gives an excellent geometry compared to experiments, especially for the OO bond length and the 1,2,4-Trioxane ring subsystem. The R (OO) bond length predicted at this level is 1.460 A, only 0.018 A shorter than the experimental measurement. The vibrational analysis shows that the OO stretching mode is combined with the OC vibration mode, having the character of an OOC entity. The OO vibrational band at 722 cm −1 suggested in the experimental studies has been assigned as 1,2,4-trioxane ring breathing.

Ten novel compounds were designed and synthesized on the basis of compound 1, their insulin-sensitizing activities were evaluated in 3T3-L1 cells. Results showed that compound 10 exhibited strong differentiation-stimulating activity on 3T3-L1 cells model, which indicated that compound 10 may possess well insulin-sensitizing activity.

To design and synthesis a series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates with more potent anti-HBV activity, adefovir dipivoxil was used as lead compound, according to the results of enhanced oral bioavailability and antiviral activities of nucleoside L-amino acid ester prodrugs. Eleven novel L-amino acid ester prodrugs of acyclic nucleoside phosphonates were designed and synthesized, their anti-HBV activities were evaluated in HepG2 2.2.15 cells. Eight compounds exhibited antiviral activity, and compound 11 showed the most potent anti-HBV activity and highest selective index in vitro (EC50 0.0952 micromol x L(-1), SI 69523). Moreover, by analyzing the primary structure and activity relationship of these compounds, it could be suggested that L-amino acid ester strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.

Thirteen benzopyran derivatives were synthesized and their activity stimulating the differentiation of preadipocytes into adipocytes were evaluated with 3T3-L1 cells. Compound 8 was also tested for its hypoglycemic activity on db diabetes mice model. Results indicated that compounds 3, 8 and 11 exhibited strong differentiation-stimulating activity on 3T3-L1 cells model, and compound 8 can reduce the blood-sugar level of db diabetes mice dramatically.

To examine the insulin sensitizing effects of a novel alpha-methyl-alpha- phenoxylpropionate derivative YY20 in insulin-sensitive cell lines.The peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist bioactivities of YY20 were detected by a preadipocyte differentiation assay. RT-PCR and Western blotting analysis were used to detect the expression of the target gene or protein. The effects of YY20 on insulin-mediated glucose consumption were determined in the HepG2 human hepatocellular carcinoma line.YY20 could enhance the differentiation of preadipocytes to adipocytes and upregulate the gene expression of PPAR gamma 2, as well as the protein expression of insulin receptor substrate- 1 (IRS-1), glucose transporter-4 (GLUT4), and adiponectin (ACRP30). The effects on GLUT4 and ACRP30 could be reversed by the PPAR gamma inhibitor SR-202. Furthermore, YY20 efficiently reduced glucose consumptions in HepG2 cells after 24 h culture, and the effects were related to insulin and YY20 concentrations.YY20, a potential insulin-sensitizing agent like rosiglitazone, could enhance glucose consumption in HepG2 cells in a concentration- and insulindependent manner. It may improve the insulin resistance associated with type 2 diabetes.

To design and synthesize compounds with insulin-sensitizing activity.Using association principle of drug design, ten title compounds were designed and synthesized on the basis of known compounds with insulin-sensitizing activity, and their insulin-sensitizing activity were evaluated on 3T3-L1 pre-adipocyte cells.One of the synthesized compounds showed strong insulin-sensitizing activity in vitro.This compound may possess good sugar-lowering activity, and will be chosen for further hypoglycemic evaluation in vivo.

We have constructed a structural motif for the pore of voltage-gated K(+) channel by computer modeling. The model developed here predicts that the narrowest part of the pore is formed by the four carbonyl oxygens of Gly444 or Gly446, and that the ion selectivity is achieved through "oxygen cage" mechanism. Residues 447, 448 and 449 make the external entrance to the narrowest part of the pore. Of these residues, 449 and 447 are believed to interact directly with TEA. This model agrees well with many available experimental data.

Lycobetaine prepared from lycorine is a new anticancer agent. The experimental and quantum pharmacological studies revealed that lycobetaine can interact with DNA by intercalation, preferentially into GO base pairs. In order to provide detailed interaction model of lycobetaine-DNA, a self-complementary octanucleotide d(CCGTACGG) was designed and synthesized by using new HELP (high efficiency Liquid phase) According to its nature, the sample was prepared to the desired final concentration by adding salt and buffer solutions. Two-dimensional (1)H-(1)H COSY and NOESY spectra in 99.8% D(2)O and 95% H(2)O were recorded for the duplex, and the NMR techniques of presaturation and WATERGATE were applied to water suppression. Protons of every spin system were identified by their scalar couplings, then through their special couplings all protons in the molecule were assigned except the poorly resolved H5' and H5' ' resonances. The chemical shifts of exchangeable protons and NOE intensities of nonexchangeable protons indicate qualitatively that the d(CCGTACGG) helix is right-handed B-DNA in aqueous solution.