一锅煮合成2′，4＂-O-双（三甲基硅）红霉素A9-O-（1-异丙氧环己基）肟及其副产物

目的 改进克拉霉素合成工艺。方法 分离、鉴定红霉素A肟的醚化、硅烷化的一锅煮副产物。结果 主产物为E-2′，4＂-O-双（三甲基硅）红霉素A9-O-（1-异丙氧基环己基）肟；4个副产物按含量从高到低依次为Z-2′，4＂-O-双（三甲基硅）红霉素A9-O-（1-异丙氧基环己基）肟、E-4＂-O-三甲基硅-红霉素A9-O（1-异丙氧基环己基）肟、Z-4＂-O-三甲基硅-红霉素A9-O-（1-异丙氧基环己基）肟和B-2′-O-三甲基硅-红霉素A9-O-（1-异丙氧基环己基）肟。结论 六甲基二硅氨烷在酸性下生成三甲基硅正离子和NH3，由于3′-叔胺基在酸性下带正电，有排斥作用，硅烷化容易先发生在4＂-OH上，该反应为SN1机制，相应的4＂-OH比2′-OH表现出较高的活性。但由于NH，等碱性物质的干扰，提高了2′-OH的活性，硅烷化的区域选择性不高，却有助于得到2′、4＂-OH的双硅烷化产物。     

Visualizing enveloping layer glycans during zebrafish early embryogenesis

Developmental events can be monitored at the cellular and molecular levels by using noninvasive imaging techniques. Among the biomolecules that might be targeted for imaging analysis, glycans occupy a privileged position by virtue of their primary location on the cell surface. We previously described a chemical method to image glycans during zebrafish larval development; however, we were unable to detect glycans during the first 24 hours of embryogenesis, a very dynamic period in development. Here we report an approach to the imaging of glycans that enables their visualization in the enveloping layer during the early stages of zebrafish embryogenesis. We microinjected embryos with azidosugars at the one-cell stage, allowed the zebrafish to develop, and detected the metabolically labeled glycans with copper-free click chemistry. Mucin-type O-glycans could be imaged as early as 7 hours postfertilization, during the gastrula stage of development. Additionally, we used a nonmetabolic approach to label sialylated glycans with an independent chemistry, enabling the simultaneous imaging of these two distinct classes of glycans. Imaging analysis of glycan trafficking revealed dramatic reorganization of glycans on the second time scale, including rapid migration to the cleavage furrow of mitotic cells. These studies yield insight into the biosynthesis and dynamics of glycans in the enveloping layer during embryogenesis and provide a platform for imaging other biomolecular targets by microinjection of appropriately functionalized biosynthetic precursors.     

米非司酮、炔诺酮、三苯氧胺对人早孕绒毛鞘糖脂的影响

应用Ｌａｄｉｓｃｈ分离及微量分析方法，对服米非司酮、炔诺酮、三苯氧胺及正常妊娠妇女的绒毛神经节苷脂（Ｇｇ）和中性鞘糖脂（Ｎ－ＧＳＬ）进行定量分析。结果证明，正常及各服药组Ｇｇ和Ｎ－ＧＳＬ组成相同；各服药组Ｇｇ总量比正常组明显减少（Ｐ＜０．０１）。各服药组绒毛ＧＭ３、ＧＭＩ与ＧＤ３、炔诺酮及三苯氧胺组ＧＴｌｂｔｂ正常组均减少（ＰＭＯ．０１和Ｐ＜０．０５）。米非司酮及三苯氧胺组的Ｎ—ＧＳＬ总量均比正常组升高，其中米非司出组织毛ＣＤＨ、ＣＴＨ增加（Ｐ＜０．０５）；而炔诺酮组则ＰＧ升高明显（Ｐ＜０．Ｏ１）。     

炔诺酮对入蜕膜雌、孕激素受体的作用

采用Ｄｃｃ法和酶联组化法，检测２７例随机分组的健康早孕妇女服用或未服炔诺酮的蜕膜组织中雌、孕激素受体，并进行定量与定位分析。结果表明：服用炔诺酮每天１５ｍｇ，连续５天，蜕膜组织中的雌激素受体含量降低。提示降调节雌激素受体可能是炔诺酮抗生育的机理之一。     

Synthesis, biological activity, and docking studies of new acetylcholinesterase inhibitors of the bispyridinium type

A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.     

诺美孕酮乙酸酯3—（O—羧甲基）肟的合成及其异构体的分离

诺美孕酮乙酸酯与羧甲氧基胺半盐酸盐在含少量吡啶的甲醇中室温反应,反－诺美孕酮乙酸酯３－（Ｏ－羧甲基）肟的两种立体异构体的混合物。经层析分离以２：１的比例得到两种立体异构体。     

炔诺酮对人早孕蜕膜和绒毛超微结构的影响

用炔诺酮（５ｍｇｑ８ｈ×５天）抗早孕后作人工流产，对蜕膜和绒毛的超微结构进行观察。结果显示绝大部分蜕膜和绒毛滋养细胞均发生不同程度的退变和坏死。蜕膜组织中大蜕膜细胞和绒毛合体滋养细胞变性坏死较重，而蜕膜颗粒细胞和细胞滋养细胞仅轻度变性。细胞退变的超微结构特征皆以线粒体肿胀和粗面内质网扩张为先导，继之，线粒体固缩伴高电子密度颗粒沉积，内质网不规则扩张，直至细胞全面崩解。本文就炔诺酮通过引起子宫局部缺血而导致蜕膜和绒毛滋养层细胞变性坏死的可能性进行了讨论。     

醋炔诺酮丙酰肟对鼠的抗生育作用研究

醋炔诺酮丙酰肟在大鼠和小鼠妊娠1～5天口服的抗着床ED_(50)分别为0.068±0.02和0.31±0.1mg/kg,大鼠妊娠第2天单次肌注或口服的抗着床ED_(50)分别为0.53±0.1和3.5±0.7mg/kg。大鼠妊娠7～8天肌注5～10mg/kg醋炔诺酮丙酰肟有明显的终止早孕作用。醋炔诺酮丙酰肟在终止早孕剂量时,明显抑制假孕大鼠的蜕膜反应且使早孕大鼠的血清孕酮浓度明显下降。提示:醋炔诺酮丙酰肟的终止早孕作用可能与其抑制孕激素活性有关。     

Comparison of a triphasic oestradiol/norethisterone acetate preparation with and without an oestriol component in the treatment of climacteric complaints

This study was undertaken to evaluate the effects of oestriol in combination with oestradiol in the treatment of women with climacteric complaints. Forty-three post-menopausal women were randomly allocated to two groups on a double-blind basis. Over a 28-day cycle 23 of the women were treated sequentially for 12 days with 1 tablet containing 17β-oestradiol 2 mg plus oestriol 1 mg, then for 10 days with 1 tablet containing the same oestrogens plus norethisterone acetate 1 mg, thereafter for 6 days with 1 tablet containing 17β-oestradiol 1 mg plus oestriol 0.5 mg. The other 20 women received the same treatment but without the oestriol. No clinical, laboratory or histological differences were seen between the two groups. Both treatments were found to be equally effective in alleviating climacteric symptoms, with few side effects. It may be stated in conclusion that, on the basis of routine clinical and laboratory parameters no differences were found between the two preparations.     

Influence of intravenously administered lidocaine on cerebral blood flow in a baboon model standardized under controlled general anaesthesia using single-photon emission tomography and technetium-99m hexamethylpropylene amine oxime

The baboon under general anaesthesia as a model to assess drug-induced cerebral blood flow changes ( CBF) using single-photon emission tomography (SPET) offers great in vivo possibilities but has to comply with demands on control of anaesthesia-related influencing factors, such as P _aCO₂ changes. The model sought in this study and described here allows control of P _aCO₂, in the baboon under thiopentone anaesthesia by ventilation, and was evaluated for the functional dependence of CBF vs P _aCO₂, using SPET technetium-99m hexamethylpropylene amine oxime (HMPAO) and the split-dose method together with controlled ventilation. During the experiment the model was validated for normal reactivity to P _aCO₂ changes, and subsequently applied to investigate the mechanisms (still uncertain) of CBF increase known to follow administration of the local anaesthetic lidocaine. Six baboons received 6 mg/kg lidocaine intravenously. CBF was measured between two consecutive SPET acquisitions (split-dose method) respectively relating to HM-PAO distributions in the brain before and after the injection of lidocaine. Meanwhile the animals were maintained at constant respiratory rate and volume. The results indicate that the correlation between CBF and the ensuing fall in P_aCO₂ deviated from the baseline pattern from the model and confirmed a cerebrovascular contribution to the lidocaine-induced CBF increase. This agreed well with mean and systolic blood pressure changes and heart rate. Correspondence to: I.C. Dormehl