一株壳聚糖酶产生菌的鉴定和产酶条件优化D张子瑞1,2,孙谧1*,郝建华1,刘均忠1

对一株产壳聚糖酶菌株Y116进行了形态学观察、生理生化特征鉴定和16S rDNA序列同源性分析,初步确定该菌株属于芽孢杆菌属(Bacillus)。采用单因素法和响应面法,对菌株Y116产酶的培养基成分和培养条件进行了优化。首先筛选碳源、氮源、初始pH、金属离子、NaCl浓度、酵母浸粉浓度、接种量、发酵温度和时间8个因素。研究结果显示：当酶活达到最高值时,最终确定各因素的值分别为：乳糖 35 g/L,豆饼粉30 g/L, Mg₂₊ 0.5 g/L,NaCl 5 g/L,初始pH 5.0,接种量5%,培养温度30 ℃和发酵时间96 h。再通过Plackett-Burman(PB)设计对影响壳聚糖酶产量的8个主要因素进行评价,确定了豆饼粉浓度、初始pH和Mg₂₊浓度是影响产酶量的3个主要因素;利用中心组合设计(CCD)及响应面分析,最终得到3个主要因素的最优值：豆饼粉浓度39.44 g/L,pH 5.12,Mg₂₊ 浓度5.12 g/L,酶活力比优化前提高了5倍。     

CCL21对胃癌SGC-7901细胞发生上皮间质转化的影响史冠男1,袁媛2,彭琼1,戴 夫1

目的 探讨趋化因子CCL21能否参与诱导胃癌SGC-7901细胞发生上皮间质转化。方法 取不同浓度的CCL21(0、50、100、150ng/ml)作用胃癌SGC-7901细胞,划痕试验检测细胞侵袭能力。镜下观察细胞形态的变化。Western blot法检测E-cadherin、N-cadherin、Vimentin、MMP-9的蛋白表达。结果 150ng/ml CCL21作用胃癌SGC-7901细胞后,较其它浓度侵袭能力最强,同时使胃癌SGC-7901细胞形态发生变化,细胞逐渐变为长梭状,部分可见伪足生成。E-cadherin蛋白表达下降(p<0.05),N-cadherin、Vimentin、MMP-9蛋白表达升高(p<0.05)。结论 趋化因子CCL21可能参与诱导胃癌SGC-7901细胞发生上皮间质转化,进而促进该肿瘤细胞的侵袭转移。     

积雪草酸C2、C3、C23、C28衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成积雪草酸C2、C3、C23、C28衍生物,并对其体外抗肿瘤活性进行研究。方法以天然产物积雪草酸为先导化合物,对C2、C3、C23位羟基及C28位羧基进行结构改造,并采用SRB法对目标化合物进行初步的体外抗肿瘤活性研究。结果设计并合成了目标化合物,利用MS及1H-NMR确证了结构;体外实验中,积雪草酸衍生物的抗肿瘤活性明显高于积雪草酸,并优于对照药吉非替尼。结论积雪草酸衍生物具有良好的抗肿瘤活性,值得进一步研究。     

微管蛋白抑制剂Combretastatin A-4类似物的研究进展

微管蛋白在细胞生长、维持形态、信号传导及有丝分裂等过程中,均起着重要的作用。微管蛋白抑制剂是近年来热门的抗肿瘤药物。Combretastatin A-4(CA-4)从南非灌木柳树皮Combretum caffrum树干中提取分离得到的二苯乙烯类化合物,是目前已知微管蛋白抑制剂中活性最强的化合物之一,但是也存在着众多缺陷。近年来围绕提高CA-4水溶性、保持顺式构型等衍生物的设计研究成为了热点。本文就CA-4的结构改造及类似物设计的研究进展进行综述。     

高效液相色谱法同时测定普那布林原料药中9种有关物质

摘要：目的 建立普那布林原料药中有关物质的检测方法。方法 采用高效液相色谱法,色谱柱YMC-Pack Pro C18（250×4.6 mm,5 μm）;以乙腈为流动相A,0.1%乙酸水溶液为流动相B;流速为1.0 mL·min-1梯度洗脱;检测波长为254 nm和365 nm;进样量为10 μL;柱温为35 ℃。结果 普那布林峰与各杂质峰均达到有效分离,各杂质浓度和峰面积线性关系良好,平均回收率在98.09%-108.82%。结论 本方法专属性强、灵敏、准确,可用于普那布林原料药有关物质的检测。     

以和微管相互作用的药物治疗癌症

癌细胞通过有丝分裂而无限制地增殖。由微管蛋白所形成的微管在有丝分裂过程中促使姐妹染色单体分离，从而形成两个子细胞并获得质与量都相同的遗传信息在抗癌药中，发现有一类药的作用机制是与微管蛋白相结合从而干扰了染色体的分离，导致癌细胞停滞于有丝分裂的早期或前中期而死亡。这一发现启发了能干扰微管功能的新型药物的研究与开发目前，已有一些与微管蛋白结合机制不同的这类药物，具有明显的抗癌疗效且副作用轻微，尤其是那可丁及其衍生物。后者若与免疫疗法药物伍用则更具有良好的前景。     

微管的生物学特性与药物研究

微管是构成细胞骨架的主要成分 ,由 13条原纤丝纵向排列构成中空的圆柱状结构 ,每条原纤丝是由微管蛋白α和 β形成的异二聚体组装成的多聚体。微管普遍存在于真核细胞中 ,有聚合和解聚的动力学特性 ,在保持细胞的形态、细胞的分裂增殖、细胞器的组成与运输及信号物质的传导等方面发挥重要作用。自 0 37ｎｍ分辨率的微管蛋白异二聚体电子晶核图谱[1] 获得后 ,人们对微管的结构与功能有了更全面和深入的认识。本文综述了近年来微管的生物学特性研究以及以微管蛋白为靶点的药物研究的进展情况。1　微管的结构特点及相关功能微管是通过微管蛋…     

美西律衍生物对α1肾上腺素受体的作用

为寻找新的α₁受体阻断剂,用[³H]-WB4101配体测定法测定了18种美西律衍生物。结果表明,其中6种化合物对大鼠脑皮层α₁受体有不同程度的亲和力。凡具有手性碳结构的化合物亲和力都较高。化合物M-85001的亲和力较妥拉唑林(tolazoline)高一个数量级并能抑制苯肾上腺素引起的大鼠肛尾肌收缩,其pA₂(6.86)与pK_i(6.51)相近。结果提示,美西律衍生物对α₁-受体的亲和力可能与手性碳结构有关,从美西律衍生物中研制新的α₁-受体阻断剂是有前途的。     

甘草次酸C3、C30衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成甘草次酸C3、C30衍生物,并对其体外抗肿瘤活性进行研究。方法以甘草次酸为先导化合物,对其C3位羟基、C30位羧基进行结构修饰,并采用SRB法对目标化合物进行体外抗肿瘤活性研究。结果设计合成了12个新型甘草次酸衍生物,并利用MS、1H-NMR及元素分析确证了结构;体外实验中,目标化合物对MCF-7和A549肿瘤细胞的抑制活性均明显强于甘草次酸,其中化合物GA-I1、GA-I2和GA-II1对MCF-7和A549两种细胞表现出很好的抑制活性,明显高于对照药吉非替尼。结论甘草次酸衍生物具有良好的抗肿瘤活性,值得进一步研究。     

微管蛋白聚合抑制剂秋水仙碱衍生物的研究进展

微管是真核细胞骨架的重要组成部分,它由α和β微管蛋白异二聚体聚合形成,在细胞有丝分裂中具有非常重要的作用。因此,微管成为抗癌药物的重要靶点之一,微管蛋白抑制剂也成为一类有效的抗癌药物。秋水仙碱是典型的微管蛋白聚合抑制剂,但由于不良反应大,限制了其作为抗肿瘤药物在临床的应用。近年来,对秋水仙碱的结构修饰主要集中在C环的10位和B环的7位侧链,包括C环10位的甲氧基被脂肪胺、芳香胺、巯基衍生物取代、B环7位的乙酰氨基被各种酰胺置换,以及在C_(10)位和C_7位同时修饰。本文主要介绍近5年来秋水仙碱结构修饰的研究进展。     

Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure

Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.     

章鱼胺衍生物的合成及抗氧化活性研究

目的以章鱼胺为原料合成其衍生物,考察它们的抗氧化活性。方法利用DPPH法对酪胺、章鱼胺及章鱼胺衍生物的抗氧化活性进行测定。结果与结论既往研究指出,章鱼胺的前体化合物酪胺具有较高的抗氧化活性。本研究结果表明,章鱼胺及其两种衍生物具有高于酪胺的抗氧化活性,值得进一步研究。     

他克林衍生物及其类似物的研究进展

他克林是一个选择性较好但毒副作用明显的乙酷胆碱酯酶抑制剂。为了克服其不足，许多他克林衍生物和类似物都已被合成并进行了药理研究。从他克林的芳环、脂环和侧链氨基等3个方面对他克林衍生物及类似物的合成和药理研究进行综述。     

Anticancer activity and mechanisms of norcantharidin-Nd3II on hepatoma

Norcantharidin (NCTD), a demethylated form of cantharidin, is currently used as an anticancer drug in China, but five newly synthesized derivatives have not been tested for antitumor efficacy. In this study, we investigated the in-vitro and in-vivo activity of five derivatives on Bel-7402, HeLa and PC-3M1E8 cell lines on a sulfarhodamine B assay. All of the derivatives showed significant antiproliferative activity, hence we elected to study further one of them, NCTD-Nd3II, in an in-vivo mouse model, and to examine its effects on cell cycle and protein expression. NCTD-Nd3II inhibited H22 tumors in mice in a dose-dependent manner with low toxicity. Flow cytometry results showed that apoptosis and G2/M cell cycle arrest contributed to the cytotoxic and cytostatic effects of NCTD-Nd3II. Further studies showed that Bax and p21 protein expression was upregulated, whereas cyclin B1, Cdc-2 and Bcl-2 protein expression was downregulated. Our findings show that NCTD-Nd3II might be a promising chemotherapeutic agent for hepatomas.     

新活性红霉素衍生物的研究进展

目的综述新活性红霉素衍生物的研究进展。方法依据国内外近期公开发表的30篇文献,对新活性红霉素衍生物的研究进展进行分类、归纳与总结。结果长期以来,红霉素及其衍生物作为抗菌药物被广泛使用。临床与实验数据显示,该类化合物还具有一些新的生物活性,例如促进消化道运动活性、抗炎与免疫调节活性、拮抗黄体生成素释放激素活性以及抑制磷酸二酯酶-3活性等。在提高红霉素的新活性并降低其抗菌作用的研究中,已设计、合成了多种类型的新结构的红霉素衍生物。结论利用红霉素衍生物的新活性研制、开发新药,已逐步成为红霉素衍生物研究的重要内容,呈现良好的发展势头。     

Synthesis of novel 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/-nonsubstituted benzal)hydrazone derivatives and acetylcholinesterase and butyrylcholinesterase inhibitory activities in vitro

In this study thirteen 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/nonsubstituted benzal)hydrazone V derivatives were synthesized as acetylcholinesterase and butyrylcholinesterase inhibitors. Ten of the synthesized compounds were synthesized for the first time in this study and the rest of them had been synthesized in a previous study. The structures of compounds V were elucidated by IR, 1H-NMR and MASS spectra. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChe) inhibitory activities of V derivatives were measured using Ellman's method. While some of the 6-substituted-3(2H)-pyridazinone-2-propyl-3-(substituted/-nonsubstituted benzal)hydrazone V derivatives exhibited significant AChE inhibitory activity, none of the compoundsshowed BChE inhibitory activity. Theseresults indicate that V derivatives were AChE inhibitors with AChE/ BChE selectivity.     

松属素及其衍生物的合成与抗菌活性

目的 合成松属素及其衍生物,研究其抗菌活性.方法 以2,4,6-三羟基苯乙酮为起始原料,经羟基保护、缩合、环化、脱保护合成目标化合物.用平皿二倍稀释法研究目标化合物的体外抗菌活性.结果共得到18个目标化合物,经1H-NMR、MS确证其结构.初步药理实验结果表明,多数化合物表现出较好的体外抗菌活性.结论松属素及其衍生物有可能成为新型结构的抗菌药物.     

Analytical and biological characterization of quinazoline semicarbazone derivatives

A number of organic compounds obtained by chemical synthesis as model compounds have useful antimicrobial activities. Quinazoline ring is an aromatic benzopyrimidine system; many of its derivatives possess interesting biological activities, such as analgesic, anti-inflammatory, anti-microbial, and anti-tumor. In our study, the biological activity of synthesized quinazoline semicarbazone derivatives were characterized by antimicrobial screening against several gram-positive, gram-negative bacteria, and fungus. The purity of the synthesized compounds was characterized by physicochemical properties, such as solubility, melting point, and thin layer chromatography (TLC). Elemental analysis for carbon, nitrogen, hydrogen, and oxygen was performed according to standard procedures. The presence of functional groups was analyzed using FT-IR spectra. Molecular structural information for the compounds was analyzed by ¹H-NMR spectroscopy. The wavelengths of maximum absorbance for all the synthesized compounds were measured by UV-Visible spectroscopy. Thereby the chemical structures of the synthesized quinazoline derivatives were confirmed. Antimicrobial screening for all the compounds exhibits characteristic microbial inhibition. A detailed study is in progress to modify the synthetic route, structural activity, and toxicological barriers for the enhanced pharmacological efficiency of synthetic antibiotics.     

盐酸异丙肾上腺素及注射液的有关物质研究

目的:对盐酸异丙肾上腺素及注射液中所含的有关物质进行了研究。方法:采用液相色谱法对原料和注射液中的有关物质进行了测定;液质联用法鉴定主要杂质的结构;合成出其中最大的杂质;四谱解析确证其结构;进行了初步的药理、毒理研究。结果:该杂质即主成分与抗氧剂焦亚硫酸钠反应生成的磺酸化物,对麻醉猫的血压无影响,大剂量给药情况下不引起小鼠明显毒性反应。结论:有关物质研究结果为方法的建立和限度的确定提供了依据。     

Synthesis and antinociceptive behaviors of new methyl and hydroxyl derivatives of phencyclidine

Phencyclidine (I) and its derivatives show such pharmacological behaviors as analgesic, anticonsulvant, anti-anxiety and antidepressant, while interacting with central nervous system. In this study, new methyl and hydroxyl derivatives of PCP were synthesized and their antinociceptive behaviors in animals were examined by measuring the number of writhing in a writhing test of visceral pain and the pain scores in Formalin test. Compared to control and PCP groups, findings in experimental groups indicated the new synthesized analogues (compounds II, III and V, 10 mg/kg) of PCP were able to produce more analgesic effects in formalin and writhing tests, especially for compound V. It was concluded that the new synthesized derivatives of PCP could substantially and respectively diminish acute and chronic pains.