Conjugates of Gd(III) Complexes to Di- and Tri-hydroxy Substituted Cholanoic Acids: Regioselective Oxidation with Hydroxysteroid Dehydrogenases

The preparative-scale oxidation of Gd(III) complexes of ligands containing 7,12-dihydroxy and 12-hydroxy substituted cholanoic moieties to the corresponding 12-oxo derivatives was accomplished by means of 12 &#102 -hydroxysteroid dehydrogenase. The enzymatic transformation appeared preferable to the chemical one because it was highly regioselective and environmentally benign. Other dehydrogenases, namely 3 &#102 - and 7 &#102 -hydroxysteroid dehydrogenases, also proved to be capable of catalysing the regioselective oxidation of the hydroxy groups of a Gd(III) complex containing a subunit of 3,7,12-trihydroxycholanoic acid. The above complexes are of interest as contrast agents for in vivo magnetic resonance imaging.     

Inhibition of plant and microbial ureases by phosphoroamides

Enzyme kinetic studies of inhibition of plant (jackbean) and microbial (Bacillus pasteurii) ureases by eight phosphoroamides [phenylphosphorodiamidate, 4-chlorophenylphosphorodiamidate, phosphoric triamide, N-(diaminophosphinyl)benzamide, N-(diaminophosphinyl)benzeneacetamide, 4-chloro-N-(diaminophosphinyl)benzamide, N-(4-nitrophenyl)phosphoric triamide, N-(diaminophosphinyl)-3-pyridinecarboxamide] demonstrated that these compounds are slow, tight-binding inhibitors of urease enzymes. Measurement of the dissociation constants (Ki^*) of the enzyme-inhibitor complexes (E · I^*) formed by interaction of the ureases and phosphoroamide inhibitors studied showed that these inhibitors had a much higher affinity (i.e., a lower Ki^*) for plant urease than for microbial urease. Measurement of rate constants for formation (k_on) and decay (k_off) of E · I^* showed that, whereas k_on varied greatly with the different inhibitors and ureases, k_off was constant for the phosphoroamides tested and had a characteristic value for each urease. The half-life of E · I^* (30°C; pH 7 THAM buffer) for the plant urease was much longer than that for the microbial urease, and this difference largely accounted for the much higher values of Ki^* (k_off/k_on) observed with microbial urease.     

Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells

1. Download : Download high-res image (156KB)
2. Download : Download full-size image

Highlights

• •Proteomes and phosphoproteomes of radiosensitive and radioresistant PDAC cell lines.
• •Common activation of DDR is proven by ATM activity on known and novel substrates.
• •Resistant cells bear raised NQO1 expression, actin dynamics including FAK activity.
• •Inhibitors of CHEK Rabusertib and FAK Defactinib radiosensitize PDAC cells.

     

基于作用机制的氨基恶唑啉呫吨类BACE1抑制剂的分子设计

天冬氨酰蛋白酶(β-site amyloid precursor protein cleaving enzyme 1, BACE1)作为治疗阿尔兹海默症的潜在靶点,其抑制剂的开发已成为医学领域的重要研究方向。本文以59个氨基恶唑啉呫吨类BACE1抑制剂为研究对象,运用比较分子相似性指数(comparative molecular similarity index, CoMSIA)和分子对接方法,深入挖掘影响抑制剂活性的特征结构,以及抑制剂与BACE1间的结合模式和作用力类型,并以此为基础设计新型抑制剂并预测其活性。CoMSIA模拟结果表明,由立体场、静电场、疏水场和氢键供体场4个场组合建立的构效关系模型具有较强的预测能力,交叉验证相关系数Q2=0.48, 非交叉验证相关系数Rncv2=0.94, 外部预测相关系数Rpre2=0.85;通过分子对接,发现抑制剂占据了靶标的S3、S1和S2'位点,与BACE1之间的结合主要是通过氢键作用力和π-π堆积作用实现的;占据S2'位点的R取代基是立体场、静电场和疏水场影响的敏感区域,氨基恶唑啉核心官能团是氢键供体场的敏感区域。基于以上分析获得的抑制剂特征结构信息及其与蛋白质受体的作用机制,成功设计出了新的分子并预测了抑制活性。实验所得模型和信息,为后续新型BACE1抑制剂的结构优化和改造提供了重要理论依据