Synthesis of tritium and carbon‐14 labelled NNC 61‐4655: a potent dual‐acting PPARα and PPARγ agonist

The synthesis of the potent dual‐acting PPARα and PPARγ agonist NNC 61‐4655 labelled with tritium and carbon‐14 is reported. Tritium labelled NNC 61‐4655 was obtained in three steps with introduction of tritium through catalytic tritium‐halogen exchange of an aryl bromide precursor. This provided [³H]NNC 61‐4655 in 39% overall radiochemical yield with a specific activity of 49 Ci/mmol. Carbon‐14 labelled NNC 61‐4655 was obtained in five steps starting from bromo[1‐¹⁴C]acetic acid. The synthetic sequence, which included a Horner–Wadsworth–Emmons olefination and a Mitsunobu alkylation, provided [¹⁴C]NNC 61‐4655 in 33% overall radiochemical yield with a specific activity of 57.4 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Engineering analysis of diamond-like carbon coated polymeric materials for biomedical applications

Diamond-like carbon (DLC) films have received much attention recently owing to their properties, which are similar to diamond: hardness, thermal conductivity, corrosion resistance against chemicals, abrasion resistance, good biocompatibility, and uniform flat surface. Furthermore, DLC films can be deposited easily on many substrates for wide area coat at room temperature. DLC films were developed for applications as biomedical materials in blood contacting-devices (e.g., rotary blood pump) and showed good biocompatibility for these applications. In this study, we investigated the surface roughness by Atomic Force Microscopy (AFM) and Hi-vision camera, SEM for surface imaging. The DLC films were produced by radio frequency glow discharge plasma decomposed of hydrocarbon gas at room temperature and low pressure (53 Pa) on several kinds of polycarbonate substrates. For the evaluation of the relation between deposition rate and platelet adhesion that we investigated in a previous study, DLC films were deposited at the same methane pressure for several deposition times, and film thickness was investigated. In addition, the deposition rate of DLC films on polymeric substrates is similar to the deposition rate of those deposited on Si substrates. There were no significant differences in substrates' surface roughness that were coated by DLC films in different deposition rates (16-40 nm). The surface energy and the contact angle of the DLC films were investigated. The chemical bond of DLC films also was evaluated. The evaluation of surface properties by many methods and measurements and the relationship between the platelet adhesion and film thickness is discussed. Finally, the presented DLC films appear to be promising candidates for biomedical applications and merit investigation.     

BF3 etherate catalysed formation of [11C]methyl esters: a novel radiolabelling technique

A novel way of preparing ¹¹C labelled methyl esters using [¹¹C]methanol and either BF₃ etherate or trimethylsilyl chloride as catalyst was investigated. Radiochemical yields with BF₃ etherate were between 30 and 33% for [¹¹C]methyl benzoate and less than 1% for [¹¹C]methyl thio salicylate. No [¹¹C]methyl ester formation could be observed with trimethylsilyl chloride for all compounds investigated. This method is an alternative to using [¹¹C]methyl iodide in the presence of a base. It is particularly suited for carboxylic acids bearing functional groups which would compete for [¹¹C]methyl iodide, thus eliminating the need to introduce protecting groups. However, o‐anisic acid formed [¹¹C]methyl salicylate in 33–30% decay corrected radiochemical yield due to hydrolytic cleavage of the methyl ether, and none of the desired [¹¹C]methyl 2‐methoxy benzoate could be obtained. When salicylic acid was used as starting material, [¹¹C]methyl salicylate could only be obtained in 5–8% decay corrected radiochemical yield. Copyright © 2004 John Wiley & Sons, Ltd.     

A rapid one‐step radiosynthesis of the β‐amyloid imaging radiotracer N‐methyl‐[11C]2‐(4′‐methylaminophenyl)‐6‐hydroxybenzothiazole ([11C]‐6‐OH‐BTA‐1)

The promising β‐amyloid PET imaging agent, [¹¹C]‐6‐OH‐BTA‐1, has been radiolabelled in one step using [¹¹C]‐methyl triflate. No protection of the 6‐hydroxy group is required, greatly simplifying the synthetic method. The reaction may be carried out in solution or by the captive solvent ‘loop’ method. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of deuterium,tritium, and carbon‐14 labeled BIRB 796, a p38 MAP kinase inhibitor

1‐(5‐tert‐Butyl‐2‐p‐tolyl‐2H‐pyrazol‐3‐yl)‐3‐[4‐(2‐morpholin‐4‐yl‐ethoxy)naphthalen‐1‐yl]urea (BIRB 796), currently in clinical trials for the treatment of inflammatory diseases, is a potent inhibitor of p38 MAP kinase. Labeled BIRB 796 with stable and radioactive isotopes was required for metabolism, distribution, and absorption studies. We first report the synthesis of carbon‐14 labeled BIRB 796 with a specific activity of 2 GBq/mmol (54.2 mCi/mmol), using [¹⁴C]‐phosgene under modified Schotten–Baumann conditions; second the preparation of tritium‐labeled BIRB 796 with a specific activity of 659 GBq/mmol (17.81 Ci/mmol) by reductive dehalogenation of iodo‐BIRB 796 with tritium gas; and finally, the synthesis of ²H₈‐BIRB 796 using morpholine‐2,2,3,3,5,5,6,6‐²H₈ with isotopic enrichment of 98.9 at% ²H. Copyright © 2004 John Wiley & Sons, Ltd.     

多途径丝裂原激活的蛋白激酶介导一氧化氮引起的肝癌细胞凋亡

目的研究非离子型的diazeniumdiolate类一氧化氮供体引起肝癌细胞凋亡的分子机制.方法利用免疫印迹、免疫沉淀、凝胶阻滞实验研究一氧化氮供体处理Hep3B肝癌细胞后,丝裂原激活的蛋白激酶、AP-1的激活以及和Hep3B肝癌细胞凋亡的关系.结果一氧化氮可引起细胞外信号调节蛋白激酶、c-jun N末端激酶和p38激酶的激活,特别是细胞外信号调节的蛋白激酶的持续激活,其中细胞外信号调节的蛋白激酶和c-jun N末端激酶的特异的阻断剂U0126和JNK抑制剂Ⅱ可阻断AP-1的激活和Hep3B细胞的凋亡,而p38激酶的阻断剂SB203580不能阻断AP-1的激活和Hep3B肝癌细胞的凋亡.结论一氧化氮通过激活细胞外信号调节蛋白激酶、c-jun N末端激酶,进而激活AP-1而引起Hep3B肝癌细胞的凋亡.     

活性碳纤维对NO2气体动态吸附研究

为探讨粘胶基活性碳纤维（ＡＣＦ）对ＮＯ２气体的动态吸附，考察了ＮＯ２浓度、流速、湿度、温度及ＡＣＦ再生次数对吸附效率的影响。结果表明：ＮＯ２在低浓度下，ＡＣＦ能长时间高效工作；流速增加，穿透时间缩短，但穿透吸附量变化不明显；湿度增加，穿透时间缩短，穿透吸附量降低；温度升高、ＡＣＦ再生次数增加，穿透时间缩短，穿透吸附量及饱和吸附量均降低。证明ＡＣＦ对ＮＯ２的吸附以物理吸附为主，但存在一定程度的化学吸     

不同碳源对掌叶大黄毛状根生物量和蒽醌产量的影响

目的研究不同碳源对掌叶大黄毛状根生物量和蒽醌产量的影响。方法选取3个克隆的掌叶大黄毛状根和非转化根,采用统计分析方法,对7种糖作为培养基碳源时对大黄根生物量的积累和5种蒽醌类化合物的产量的影响进行了研究。结果不同糖作为碳源对大黄根生物量积累和蒽醌产量有极显著影响。大黄根类型与糖种类互作分析显示,DH 7a与麦芽糖对于蒽醌产量来说是优势组合,而DH 5a和DH 5c在蔗糖和果糖差异不显著,非转化根在蔗糖作碳源的培养基中蒽醌产量极显著地高于其他6种糖。结论果糖作为碳源最利于大黄根培养的生物量的积累,蔗糖作为碳源时大黄根蒽醌产量最高。     

Precision-cut liver slices as a new model to study toxicity-induced hepatic stellate cell activation in a physiologic milieu.

Hepatic stellate cell (HSC) activation is a key event in the natural process of wound healing as well as in fibrosis development in liver. Current in vitro models for HSC activation contribute significantly to the understanding of HSC biology and fibrogenesis but still fall far short of recapitulating in vivo intercellular functional and anatomic relationships. In addition, when cultured on uncoated plastic, HSC spontaneously activate, which makes HSC activation difficult to regulate or analyze. We have examined whether the use of precision-cut liver slices might overcome these limitations. Liver slices (8 mm diameter, 250 microm thickness) were generated from normal rat liver and incubated for 3 or 16 h with increasing doses of carbon tetrachloride (CCl4). Rat liver slices remained viable during incubation, as shown by minimal enzyme leakage. Expression of markers for HSC activation and the onset of fibrogenesis in the liver slices was studied using real-time PCR and Western blotting. In unstimulated liver slices, mRNA and protein levels of desmin, heat shock protein 47, and alpha B-crystallin remained constant, indicating quiescence of HSC, whereas Krüppel-like factor 6 expression was increased. In contrast, incubation with CCl4 led to a time- and dose-dependent increase in mRNA expression of all markers and an increased alpha B-crystallin protein expression. In conclusion, we have developed a technique to induce activation of quiescent HSC in rat liver slices. This model permits the study of toxicity-induced HSC activation within a physiological milieu, not only in animal but ultimately also in human tissue, and could contribute to the reduction of animal experiments.     

聚苯乙炔/碳纳米管复合材料的制备及导电性

以无水A lC l3为催化剂合成了聚苯乙炔(PPA)、用浓H2SO4进行磺化改性,并通过共混制得了PPA/碳纳米管(CNT)及磺化PPA/CNT复合材料;研究了复合材料的导电性及电导率与CNT含量的关系。结果表明:磺化PPA/CNT导电阈值比PPA/CNT的降低了1%,前者达到极限电导率所需CNT的量是后者的10%;X-射线衍射(XRD)测试表明,在CNT界面上的磺化PPA有新的晶型产生。