海洋细菌NJ6-3-1次级代谢产物化学成分的分离与鉴定

目的研究海洋细菌NJ6-3-1次级代谢产物,以期得到有活性的先导化合物。方法采用硅胶柱色谱、凝胶柱色谱、HPLC等方法进行分离纯化,通过理化性质和波谱手段分析确定化合物的结构。结果从海洋细菌NJ6-3-1的乙酸乙酯萃取物中分离得到15个化合物,分别为环(色-脯)二肽(cyclo(Trp-Pro),1)、环(甘-脯)二肽(cyclo(Gly-Pro),2)、环(甘-苯丙)二肽(cyclo(Gly-Phe),3)、环(丙-苯丙)二肽(cylo(Ala-Phe),4)、环(酪-苯丙)二肽(cyclo(Tyr-Phe),5)、环(酪-脯)二肽(cy-clo(Tyr-Pro),6)、环(4-羟基-脯氨酸-苯丙氨酸)(cyclo(4-hydroxyl-Pro-Phe),7)、环(4-羟基-脯氨酸-亮氨酸)(cyclo(4-hydroxyl-Pro-Leu),8)、环(酪-亮)二肽(cyclo(Tyr-Leu),9)、环(丙-亮)二肽(cyclo(Ala-Leu),10)、环(甘-亮)二肽(cyclo(Gly-Leu),11)、环(丙-缬)二肽(cyclo(Ala-Val),12)、异光黄素(isolumichrome,13)、胸腺嘧啶(thymine,14)、尿嘧啶(uracil,15)。结论化合物1~15均为首次从海洋细菌NJ6-3-1次级代谢物中分离得到。     

海洋放线菌S1001中抗肿瘤活性成分的研究

一株来源于海泥的放线菌S1001发酵产物具有致细胞坏死活性，本文采用溶剂萃取、硅胶柱层析及制备HPLC等分离手段对该菌株发酵产物的活性部位进行了活性追踪分离，共分离得到8个化合物，通过理化性质及波谱学手段,鉴定其结构分别为4，，5，7-三羟基异黄酮（1）,4-（2，4-二羟基苯酰胺基）苯甲酸（2），环（甘氨酸-丙氨酸）（3），环（甘氨酸-脯氨酸）（4），环（亮氨酸-酪氨酸）（5），环（缬氨酸-亮氨酸）（6），环（缬氨酸-异亮氨酸）（7）,环（苯丙氨酸-甘氨酸）（8）,并用SRB法初步评价了化合物1～8的抗肿瘤活性，结果表明化合物4、5和7在10μmol／L浓度时对K562细胞表现出了一定的抑制活性。     

红榄李内生真菌Aspergillus terreus HT-1二酮哌嗪类次级代谢产物研究

目的 研究红榄李Lumnitzera littorea内生真菌Aspergillus terreus HT-1的次级代谢产物。方法 对从红榄李中分离得到的内生真菌A. terreus HT-1进行大规模发酵,并采用多种色谱技术对其发酵产物进行分离纯化。通过多种波谱方法鉴定单体化合物结构。结果 从A. terreus HT-1发酵产物的乙酸乙酯萃取物中分离得到了15个二酮哌嗪类化合物,分别鉴定为bis(dethio)bis(methylsulfanyl) gliotoxin（1）,环(D-4-羟基-脯氨酸-L-苯丙氨酸)二肽（2）,环(L-4-羟基-脯氨酸-L-苯丙氨酸)二肽（3）,环(L-4-羟基-脯氨酸-L-酪氨酸)二肽（4）,环(L-4-羟基-脯氨酸-L-亮氨酸)二肽（5）,环(L-丙氨酸-L-4-羟基-脯氨酸)二肽（6）,环(D-4-羟基-脯氨酸-D-异亮氨酸)二肽（7）,环(D-脯氨酸-L-酪氨酸)二肽（8）,环(L-亮氨酸-L-脯氨酸)二肽（9）,环(L-脯氨酸-L-苏氨酸)二肽（10）,环(L-脯氨酸-L-丙氨酸)二肽（11）,环(L-脯氨酸-甘氨酸)二肽（12）,环(L-苯丙氨酸-甘氨酸)二肽（13）,环(谷氨酸-L-酪氨酸)二肽（14）,terezine D（15）,并采用MTT法检测全部化合物的神经保护活性。结论 在200 μmol/L浓度下,化合物1和5显示出较好的神经保护活性,使H2O2诱导氧化损伤的神经细胞（HT22）的细胞存活率从44.06%分别提高到69.51%和76.75%。本研究为红榄李及其内生真菌的开发利用研究提供了理论基础。     

海洋源放线菌Streptomyces sp. 223中二酮哌嗪类成分的研究

目的对采集自烟台逛荡河入海口沉积物的1株放线菌Streptomyces sp.223进行次级代谢产物及活性研究。方法采用硅胶柱层析、Sephadex LH-20凝胶层析、薄层层析以及HPLC等方法对放线菌Streptomyces sp.223发酵产物进行分离纯化,通过波谱数据分析及文献比较对化合物进行结构鉴定,并用MTT法初步评价其细胞毒活性。结果从该菌的发酵产物中分离到了7个二酮哌嗪类化合物,分别鉴定为（3S）-（1,4）-二甲基-3-异丙基-（2,5）二酮哌嗪（1）,环-（L-脯-L-苯丙）二肽（2）,环（L-脯-L-酪）二肽（3）,环（L-4-OH-脯-L-亮）二肽（4）,环（L-苯丙-甘）二肽（5）,环（L-4-OH-脯-L-苯丙）二肽（6）和环-（L-脯-L-缬）二肽（7）。结论化合物1作为1种天然产物为首次从海洋微生物中分离得到,且具有显著的细胞毒活性,对Hela细胞的半抑制浓度IC₅₀=18.7μmol·L^-1。     

海洋放线菌Streptomyces sp.（No.30701）次生代谢产物研究

目的 研究一株海洋放线菌Streptomyces sp.（No.30701）的化学成分。方法 采用硅胶开放柱色谱、Sephadex LH-20凝胶柱色谱以及高效液相色谱等分离手段进行化合物的分离、纯化;利用理化性质和波谱学分析对单体化合物进行结构鉴定。结果 从海洋放线菌Streptomyces sp.（No.30701）发酵物中分离得到9个环二肽类化合物,分别鉴定为环(L-脯-L-缬)二肽（1）、环(D-脯-L-缬)二肽（2）、环(L-脯-L-亮)二肽（3）、环(4-羟基-脯-亮)二肽（4）、环(L-脯-L-异亮)二肽（5）、环(L-脯-L-酪)二肽（6）、环(L-亮-L-缬)二肽（7）、环(D-苯丙-甘)二肽（8）、环(L-苯丙-L-缬)二肽（9）。结论 以上化合物均为海洋放线菌常见的次生代谢产物,但化合物2、8含有天然界中不多见的D型氨基酸,并且化合物2是从链霉菌属放线菌中首次分离得到。     

南海珊瑚内生细菌Brevibacterium sp.中的环二肽成分研究II

目的 对南海珊瑚内生细菌Brevibacterium sp.化学成分进行研究。方法 采用硅胶柱色谱,Sephadex LH-20凝胶柱色谱,高效液相柱层析等分离手段对珊瑚内生细菌Brevibacterium sp.发酵液的乙酸乙酯提取物进行分离纯化,采用NMR、质谱(MS)等现代波谱解析手段,并与文献对照,鉴定化合物结构。结果 分离得到12个已知的环二肽类化合物,其结构分别为环(色-苏)二肽(1)、环(4-羟基-脯氨酸-酪)二肽(2)、环(亮-酪)二肽(3)、环(苯丙-丙)二肽(4)、环(异亮-甘)二肽(5)、环(亮-甘)二肽(6)、环(亮-脯)二肽(7)、环(亮-丙)二肽(8)、环(异亮-丙)二肽(9)、环(亮-苏)二肽(10)、环(异亮-缬)二肽(11)、环(异亮-异亮)二肽(12)。结论 所有化合物均首次从Brevibacterium属中分离得到。     

胎盘脂溶性小分子化学成分

目的研究人胎盘的脂溶性小分子化学成分。方法采用硅胶柱色谱、SephadexLH-20凝胶柱色谱等方法进行分离纯化,通过波谱分析和单晶衍射法进行结构鉴定。结果从胎盘中分离鉴定了21个化合物,分别是环（亮-丙氨酸）（1）,环（缬-亮氨酸）（2）,环（脯-亮氨酸）（3）,环（脯-缬氨酸）（4）,环（亮-苯丙氨酸）（5）,咖啡因（6）,尿嘧啶（7）,胸腺嘧啶（8）,2’-甲氧尿苷（9）,2’-脱氧尿苷（10）,胆固醇（11）,16α-羟基孕甾酮（12）,16α-羟基睾酮（13）,雌三醇（14）,20（尺）-羟基黄体酮（15）,烟酰胺（16）,4-（2’-羟基苯基）-丁烯酮（17）,N-棕榈酰鞘氨醇（18）,N-十八烷基鞘氨醇（19）,棕榈酸甘油单酯（20）,甘油硬脂酸酯（21）。结论化合物1—5和17为首次从人体胎盘中分离得到,也是首次在人体中发现。     

放线菌JX-JDN-F1次级代谢产物化学成分的分离与鉴定

目的研究放线菌JX-JDN-F1次级代谢产物,以期得到有抗肿瘤活性的先导化合物。方法采用硅胶柱色谱、Sephadex LH-20凝胶柱色谱、开放ODS柱色谱以及HPLC等方法进行分离纯化,通过理化性质和波谱手段分析确定化合物的结构。结果从放线菌JX-JDN-F1的乙酸乙酯萃取物中分离得到8个化合物,分别鉴定为环(亮-亮)[cyclo(Leu-Leu),1]、环(亮-脯)[cyclo(Pro-Leu),2]、环(酪-脯)[cyclo(Tyr-Gly),3]、环(脯-缬)[cyclo(Pro-Val),4]、环(羟脯-苯丙)[cyclo(4-hydroxyl-Pro-Phe),5]、环(酪-甘)[cyclo(Tyr-Gly),6]、1-氢吡咯-2-羧酸[1H-pyrrole-2-carboxylic acid,7]和N-(4-苯乙基)-乙酰胺[N-(4-phenylethyl)-acetamide,8)。结论化合物1⁸均为首次从游动属放线菌Actinoplanes sp.属中分离得到。     

海洋细菌成团泛菌(Pantoea agglomerans)中环二肽类代谢产物的研究

目的研究海洋细菌成团泛菌(Pantoea agglomerans)发酵液的乙酸乙酯萃取物中的化学成分,以期得到有活性的先导化合物。方法采用硅胶柱色谱、凝胶柱色谱、高效液相色谱等方法进行分离纯化,通过理化性质和波谱数据分析鉴定化合物的结构。结果从海洋细菌Pantoea agglomer-ans的乙酸乙酯萃取物中分离得到10个环二肽类化合物,分别鉴定为环-(苯丙氨酸-脯氨酸)[cy-clo(Phe-Pro),1]、环-(缬氨酸-脯氨酸)[cyclo(Val-Pro),2]、环-(丙氨酸-亮氨酸)[cyclo(Ala-Leu),3]、环-(色氨酸-脯氨酸)[cyclo(Trp-Pro),4]、环-(色氨酸-甘氨酸)[cyclo(Trp-Gly),5]、环(4-羟基-脯氨酸-苯丙氨酸)[cyclo(4-hydroxyl-Pro-Phe),6]、环-(脯氨酸-酪氨酸)[cyclo(Pro-Tyr),7]、环-(亮氨酸-亮氨酸)[cyclo(Leu-Leu),8]、环-(脯氨酸-亮氨酸)[cyclo(Pro-Leu),9]、环-(缬氨酸-异亮氨酸)[cyclo(Val-Ile),10]。结论化合物1~10均为首次从海洋细菌Pantoea agglomerans中分离得到。     

海洋来源放线菌Demequina litorisediminis SCSIO 53428的化学成分研究

目的对南海深海沉积物来源的放线菌Demequina litorisediminis SCSIO 53428的发酵物化学成分进行研究。方法利用各种色谱技术,包括硅胶柱色谱、ODS反相柱色谱、Sephadex LH-20凝胶色谱、高效液相色谱等分离手段对放线菌Demequina litorisediminis发酵物的乙酸乙酯提取物进行分离纯化,通过波谱学数据分析并结合文献比较鉴定了化合物的结构。结果分离得到13个化合物,其结构分别为:环(L-酪-L-脯)二肽(1)、环(L-苯丙-L-脯)二肽(2)、环(L-缬-L-脯)二肽(3)、环(L-亮-L-脯)二肽(4)、环(反式-4-羟基-L-脯-L-亮)二肽(5)、环(甘-L-脯)二肽(6)、环(L-丙-L-脯)二肽(7)、环(缬-酪)二肽(8)、环(异亮-脯)二肽(9)、对羟基苯甲醛(10)、苯甲酸(11)、N-(2-羟基苯基)-乙酰胺(12)、2-乙酰氨基苯甲酸(13)。结论对海洋来源放线菌Demequina litorisediminis SCSIO53428的化学成分做了初步研究,化合物1～13均为首次从该属放线菌中分离得到。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.