1，5-二芳基戊烷类化合物生物活性与结构关系的研究进展

本文对目前已经发现的天然1,5-二芳基戊烷类化合物在植物中的分布、结构特征、生物合成及其改构化合物的结构和生物活性作一简要综述.     

环氧化酶-2与肺损伤

肺损伤是指各种致病因素(物理、化学和生物性因素)作用于肺脏组织而引起的肺组织细胞的变性、坏死及肺功能的改变,多种炎性介质及细胞因子参与了肺损伤的过程.环氧化酶-2(COx-2)为一种诱导酶,当细胞受到炎症等刺激时可高表达,是炎症介导的细胞毒性重要的决定因素之一.在各种原因所导致的肺损伤中,COX-2表达增多的现象提示COX-2在肺损伤发生发展中具有重要作用,COX-2作为肺损伤的治疗靶点将成为今后研究的热点.     

环氧化酶-2与肺损伤

肺损伤是指各种致病因素（物理、化学和生物性因素）作用于肺脏组织而引起的肺组织细胞的变性、坏死及肺功能的改变,多种炎性介质及细胞因子参与了肺损伤的过程。环氧化酶-2（COX-2）为一种诱导酶,当细胞受到炎症等刺激时可高表达,是炎症介导的细胞毒性重要的决定因素之一。在各种原因所导致的肺损伤中,COX-2表达增多的现象提示COX-2在肺损伤发生发展中具有重要作用,COX-2作为肺损伤的治疗靶点将成为今后研究的热点。     

降解1,3-二甲基-2-咪唑烷酮细菌的分离及功能评价

[背景] 1,3-二甲基-2-咪唑烷酮（1,3-Dimethyl-2-Imidazolidinone,DMI）作为一种强极性非质子溶剂,在生产和应用过程的环境中有稳定残留问题,存在安全隐患。[目的] 分离筛选具有降解DMI能力的微生物菌株,为清除环境中残留的DMI提供优良的微生物菌种资源。[方法] 从DMI生产区域土壤采集样品分离DMI抗性微生物,采用形态学及分子生物学鉴定确定其分类地位,并对DMI降解能力进行测定。[结果] 分离到最高能够耐受5%（体积分数） DMI的微生物菌株,形态学及分子生物学鉴定初步表明获得的菌株DT-1和DT-2为贝莱斯芽孢杆菌（Bacillus velezensis）;全细胞及细胞提取液均具有降解DMI的能力;其中菌株DT-1及其细胞提取液对1%（体积分数） DMI的降解率分别达到48%和68%。[结论] 从DMI生产区域土壤中分离到具有DMI降解能力的芽孢杆菌,不但可为DMI污染的微生物治理提供优良微生物资源,而且扩展了人们对芽孢杆菌生物学功能的认识。     

环氧合酶-2在卵巢癌中的表达及其临床意义

目的：探讨COX-2的表达与卵巢癌生物学关系。方法：采用免疫组化SP法,分别测定12例正常卵巢组织、16例良性卵巢肿瘤、70例卵巢癌组织中COX-2的表达。结果：70例卵巢癌组织中COX-2阳性表达62例,明显高于正常卵巢组织,COX-2与临床分期、及淋巴结转移均有一定关系,与病理类型无关。结论：COX-2与卵巢癌的发生、发展及转移有关,可作为观察卵巢癌进展的重要指标。     

聚乙二醇丙烯酸酯的合成与表征

以聚乙二醇-400（PEG400）与丙烯酸直接缩合反应,在不加有毒带水剂的条件下合成了丙烯酸聚乙二醇酯（PEGA）。通过正交实验确定酯化反应的最佳条件：丙烯酸／PEG400的摩尔比为2．0：1．0,反应温度是110℃,阻聚剂对苯二酚为0．4％（以醇酸总质量计）,反应时间为6小时,催化剂对甲苯磺酸为0．8％（以醇酸总质量计）,产率为76．7％。产品结构经IR和1HNMR表征,证明是所需的产物。     

选择性环氧化酶-2抑制剂对乳腺癌细胞的化疗增敏作用

目的:观察选择性环氧化酶-2(COX-2)的抑制剂塞来昔布对表柔比星抗乳腺癌MCF-7细胞增殖和诱导凋亡作用以及探讨其机制.方法:应用四甲基偶氮唑蓝(MTT)比色法分析塞来昔布联用表柔比星对MCF-7细胞的生长抑制作用,流式细胞术检测细胞的凋亡,western blotting检测凋亡相关蛋白Bcl-2、Bax、caspase-3的表达.结果:10μmol/l的cxlecoxib和10μg/l表柔比星联用细胞抑制率和早期凋亡率均显著增高,并引起caspase-3上调及裂解激活,bcl-2下调,bax则变化不大.结论:塞来昔布对表柔比星抗乳腺癌MCF-7细胞有协同作用,其诱导凋亡与caspase-3激活和Bcl-2表达下调有关.     

环氧合酶-2在胃癌中的研究进展

我国胃癌发病人数居全球首位,其发生机制及安全有效的治疗是研究重点。大量研究结果表明,环氧化酶-2(Cyclooxygenase-2,COX-2)过度表达促进肿瘤细胞增殖和抑制细胞凋亡,并与胃癌的发生发展、淋巴转移、分化程度、病理分期及预后密切相关。随着COX-2与胃癌关系的研究的深入,COX-2已逐渐成为胃癌治疗的新的靶点。近年来,针对细胞受体、信号传导、细胞周期和血管生成等靶点的抗肿瘤治疗已成为肿瘤治疗研究的新方向。因此,以COX-2为特异靶点的治疗策略有望为胃癌治疗提供新的思路。     

甘蔗β-1,3-葡聚糖酶基因的电子克隆与分析

以高粱β-1,3-葡聚糖酶基因(β-1,3-glucanase gene)cDNA序列为探针,搜索甘蔗EST数据库,而后通过电子克隆技术,拼接获得甘蔗β-1,3-葡聚糖酶基因ScBG。采用生物信息学方法,对该基因编码蛋白从氨基酸组成、理化性质、跨膜结构域、卷曲螺旋、亚细胞定位、信号肽、功能域及高级结构等方面进行了预测和分析。结果表明:ScBG基因全长1270bp,包含一个长达1011bp的完整开放读码框(open reading frame,ORF),编码336个氨基酸,分子量为34.8KD,理论等电点为4.98。该蛋白质很可能是胞外定位的诱导物释放型酸性葡聚糖酶,是一种稳定的分泌蛋白,且可信度达最高等级1。该蛋白属于糖苷水解酶第17家族,含有N端信号肽,在第7～29位氨基酸处含有跨膜信号区,在第31～321位氨基酸处含有糖苷水解酶17家族结构域,含2个主要的功能结构域。10个物种ScBG蛋白氨基酸序列的同源性分析表明,甘蔗ScBG基因编码蛋白与高粱β-1,3-葡聚糖酶基因的编码蛋白的同源性最高,达79.82%。以上研究结果为ScBG基因下一步的分子克隆、功能鉴定和应用提供基础。     

1-苯基-2-硫脲对斑马鱼胚胎发育与黑色素生成的影响

目的1-苯基-2-硫脲（PTU）可抑制斑马鱼胚胎黑色素的产生,保持斑马鱼透明,便于形态观察和信号检测。本文研究了PTU对斑马鱼胚胎发育的影响和抑制斑马鱼胚胎黑色素生成,保持斑马鱼透明性的最佳浓度。方法用不同浓度PTU处理23hpf（受精后,hourspostfertilization,hpf）斑马鱼胚胎,作用57h后观察80hpf斑马鱼的形态学、生理学改变,计算死亡率和孵化率,测量心率和静脉窦-动脉球之间的距离。结果浓度为0．197mmo]／L、0．296mmol／LPTU可以有效抑制黑色素生成,保持斑马鱼整体透明,对斑马鱼心血管系统结构和生理功能无影响,且不影响斑马鱼正常孵化过程。随着PTU浓度的增加,斑马鱼死亡率增加,孵化率下降,出现心包水肿,心脏畸形等改变,心率下降,静脉窦-动脉球之间的距离增大。结论浓度不高于0．296mmol／L的PTU溶液能有效抑制斑马鱼黑色素生成,对斑马鱼心血管毒性研究无影响。     

Synthesis and antiviral activities of N-9-oxypurine 1,3-dioxolane and 1,3-oxathiolane nucleosides

Two series of 1,3-dioxolanes and 1,3-oxathiolane nucleosides containing N-9-oxypurine were synthesized as potential antiviral agents. These compounds were prepared by reacting the sugar moieties with iodo- or bromotrimethylsilane, followed by treatment with a mixture of sodium hydride and the desired N-hydroxy purine base. The preparation of these N-hydroxybases was also described. No significant antiviral activity was observed against HIV, HBV, HSV-1, HSV-2, or HCMV.     

Synthesis and biological evaluation of L- and D-configuration 1,3-dioxolane 5-azacytosine and 6-azathymine nucleosides

Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.     

2-Aryl-1,3-thiazolidines as masked sulfhydryl agents for inhibition of melanogenesis

As a part of an ongoing project aimed at developing new skin depigmenting agents, the ability of variously substituted 2-aryl-1,3-thiazolidines to inhibit melanogenesis in vitro was investigated. At 0.2 mM concentration 2-(2'-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (Th2), as well as the descarboxy analog (Th1) and, to a lower extent, the 4'-hydroxy isomer (Th3) all proved capable of preventing the tyrosinase catalyzed conversion of 0.2 mM L-tyrosine to melanin. Spectrophotometric monitoring of the reaction course in the presence of Th2 showed the initial formation of a yellow chromophore (lambda max 400 nm) which slowly decayed, being eventually replaced by a new absorption maximum centered at 305 nm. HPLC analysis of the final incubation mixture revealed the presence of a major product (lambda max 306 nm), ninhydrin and ferric chloride positive, which was isolated by gel filtration on Sephadex G-10 and was identified as beta-[7-(3-carboxy-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazinyl)]al anine (DBA) by 1H-NMR spectroscopy. Attempts to isolate the intermediate with lambda max 400 nm were hampered by its marked instability under the usual chromatographic conditions. However, the nature of the chromophore, coupled with mechanistic considerations, suggested for the compound the Schiff base-containing structure 3,4-dihydroxy-5-S-(N-salicylidenecysteinyl)phenylalanine (salcysdopa). This was substantiated by: (i) the formation of a zinc complex (lambda max 349 nm) analogous to that observed with the model Schiff base N-salicylidene leucine; and (ii) detection by 1H-NMR of a Schiff base resonance at delta 8.1 during the yellow chromophoric phase of the reaction. It was concluded that 1,3-thiazolidines inhibit melanin formation by a mechanism that involves the trapping of enzymically generated dopaquinone by the -SH containing Schiff base arising by cleavage of the thiazolidine ring. The salcysdopa adduct thus formed undergoes hydrolysis and subsequent ring closure to give eventually the colorless DBA.     

New 1,3-dioxolane and 1,3-dioxane derivatives as effective modulators to overcome multidrug resistance

Multidrug resistance (MDR) to antitumor agents represents a major obstacle to a successful chemotherapy of cancer. Overexpression of P-glycoprotein (p-gp) seems to be the major factor responsible for MDR. A large number of chemically unrelated compounds are known to interact with p-gp resulting in a decreasing resistance. In our efforts related to structure-activity studies of new potential MDR reversal agents we synthesized a series of compounds that differ in the aromatic core structure, the linker, and the basic moiety. For our search of new aromatic core structures we synthesized novel 2,2-diphenyl-1,3-dioxolane, 2,2- diphenyl-1,3-dioxane, and 4,5-diphenyl-1,3-dioxolane derivatives. A range of lipophilic linker structures and protonable basic moieties were synthesized and investigated to optimize the structure of the potential MDR-modulators. The compounds were tested in vitro using human Caco-2 cells. Both the cytotoxicity of the synthons and their ability to resensitize the cells were determined with a MTT assay. The results show that at low concentration various substances reverse tumor cell MDR. Some of the new structures show better effects than established modulators like trifluoperazine.     

Synthesis and biological evaluation of 5R- and 5S-methyl substituted D- and L-configuration 1,3-dioxolane nucleoside analogs

1,3-Dioxolane and 1,3-oxathiolane nucleoside analogs play an important role in anti-viral and anti-neoplastic chemotherapy. We report here the synthesis of 2-hydroxymethyl-5-methyl-1,3-dioxolanylpurine nucleosides from 4-acetoxy-2-(benzyloxymethyl)-5-methyldioxolane. Dioxolanes of alpha-D-, beta-D-, alpha-L-, and beta-L-configuration were prepared, that included 5-methyl derivatives of both 5R and 5S configuration. Molecular mechanics calculations indicate that the 5S and 5R diastereoisomeric 1,3-dioxolanes possess distinct conformational bias, suggesting that methyl substitution may alter the conformational preference of 1,3-dioxolanes. The ability of the 1,3-dioxolanes to inhibit HCV RNA replication was evaluated in a cell-based, subgenomic replicon assay. In addition, activity against vaccinia and HIV was evaluated in cell-based assays. The 2-hydroxymethyl-5-methyl-1,3-dioxolanes were found to be inactive.     

The role of lone pair and dipolar interactions in the non-planarity of 1,3-dioxolane and 1,3-dioxole

1,3-Dioxole has been shown to be non-planar by infrared and Raman spectroscopy. An MM3 study of this molecule enabled the investigators to suggest that this non-planarity was due to the anomeric effect. Subsequently, an ab initio theoretical study of this molecule was performed, which also concluded that the non-planarity of 1,3-dioxole was due to the anomeric effect and not to dipole-dipole interactions. Neither study used rigorous methods for assessing the role of dipolar interactions in the geometry of 1,3-dioxole. A new study of 1,3-dioxole, 1,3-dioxolane, tetrahydrofuran, cyclopentane, and some related molecules using the new QVBMM (molecular mechanics) force field shows conclusively that the non-planarity of 1,3-dioxole and 1,3-dioxolane is due primarily to torsional and dipolar effects, and not secondary molecular orbital overlap interactions.     

Anti-HIV-1 activities of 1,3-dioxolane guanine and 2,6-diaminopurine dioxolane.

DXG and its prodrug DAPD have been demonstrated to be effective inhibitors of HIV-1 in various cells. The EC50s for DXG were 0.032 microM in CBMCs and 0.05 microM in MT-4 cells, which were generally equipotent as 3TC. 3TC-resistant, but not AZT-resistant, HIV-1 had minimum diminished sensitivity to the compounds. Both DXG and DAPD were non-toxic to cells up to 500 microM.     

Synthesis of 1,3-Dithiane-2-thiones

A number of new 1, 3-dithiane-2-thione derivatives were synthesized from bismesylates of substituted 1, 3-dihydroxypropanes by the reaction with sodium trithiocarbonate provided from Na₂S and CS₂. The cyclic structures were elucidated on the basis of the IR, UV, NMR, and mass spectra, together with elemental analyses and chemical reactions.     

Synthesis and antimalarial activity of some new 1,2-dioxolane derivatives

The synthesis of 1,2-dioxolane derivatives in two different acetophenone series, as simplified models of natural coumarins is described. 2-Acetyl-3-acetoxy-4-(3-hydroperoxy-3-methylbut-1-enyl)phenyl acetate and 2-acetyl-5-acetoxy4-(3-hydroperoxy-3-methylbut-1-enyl) phenyl acetate synthons are used as precursors to these structures. In vitro antimalarial activity of the 1,2-dioxolane derivatives has been investigated.