三尖杉酯碱衍生物的合成及抗肿瘤活性

目的设计一条适合制备C_3′-N上不同取代的三尖杉酯碱及桥氧三尖杉酯碱的合成路线。方法以光活的中间体I(2′R，3′S)β-苯基缩水甘油酸酯为原料，经过五步反应得到保护侧链酸VI(4′S，5′R)，以2-DPC/DMAP为缩合剂与母核缩合、酸水解，再用不同的酸酐酰化，得到相应的C_3′-N取代的新酯碱。结果合成7个新酯碱化合物，药理筛选结果表明C_3′-N上取代基对抗肿瘤活性有一定影响。结论为进一步结构修饰提供了依据。     

三尖杉酯碱类似物的合成及其抗肿瘤活性

合成了新结构类型的三尖杉酯碱类似物C₁Z,C₂E,C₃E,C₄E,考察了侧链烯酯酸B₁,B₂,B₃,B₄形成时顺、反异构体的比例,发现顺式构型在酸催化下易转化成反式构型。C₁E对肿瘤细胞HL-60有明显的分化诱导作用及对白血病L₁₂₁₀有抑制作用。     

脱氧三尖杉酯碱和高三尖杉酯碱的立体专一性合成

本文报道脱氧三尖杉酯碱(Ⅵa)和高三尖杉酯碱(Ⅵc)的不对称合成。采用(+)R-对甲苯亚磺酰基乙酸叔丁酯(Ⅰ)与相应的三尖杉碱酮酸酯(Ⅱa)、(Ⅱb)进行立体选择性缩合反应,经过若干步骤,合成了具有C₂′R构型的(Ⅵa)和(Ⅵc)。中间产物(Ⅲa),(Ⅲb)或(Ⅲc)以铝汞齐脱硫得(Ⅳa、(Ⅳc)。再以三氟醋酸处理,选择性水解叔丁酯得(Ⅴa)、(Ⅴc)。最后以重氮甲烷甲酯化。再次证实了(+)R-对甲苯亚磺酰基乙酸叔丁酯(Ⅰ)具有较高的立体选择性反应。     

异三尖杉酯碱的合成及其异构体的分离

本文报道对实验动物肿瘤有抑制作用的异三尖杉酯碱的合成。以天然的三尖杉碱为原料,经过三尖杉碱-5-甲基-2-氧己酸酯与α-苄氧溴乙酸酯和活化锌进行Reformatsky反应,产品为苄氧异三尖杉酯碱及其三个立体异构体的混合物(8),收率51%。所含四个异构体的量相近。经旋转薄层层析分离为(8 a)和(8 b)两部分。分别以10%钯炭氢解生成(9 a)和(9 b),氢解产物再分别分离为(9 a₁),(9 a₂)和(9 b₁),(9 b₂)。(9 b₁)的物理常数和各种光谱均与天然异三尖杉酯碱一致。根据核磁共振光谱推测了其它三个立体异构体的绝对构型。     

三尖杉属植物中生物碱的研究——Ⅷ.二种新的抗癌三尖杉酯碱生物碱的结构和半合成

从安徽产三尖杉(Cephalotaxusfortunei Hook f.)弱碱中分到二种新的抗癌生物碱,命名为新三尖杉酯碱(neoharringonine,1)和脱水三尖杉酯碱(anhydroharringtonine,2)。从本种植物中还首次分到二个已知生物碱:脱氧三尖杉酯碱(deoxyharringtonine,3)和异三尖杉酯碱(isoharringtonine,4)。     

几种三尖杉酯碱衍生物的合成

通过三尖杉碱α-酮酸酯与相应的溴代乙酸酯进行Reformatsky反应,合成了在侧链甲酯部分具有不同烷基结构的5个脱氧三尖杉酯碱衍生物。动物试验结果表明甲酯部分的甲基被其它烷基取代导致活性丧失。这又一次说明这类化合物抗癌活性的结构专属性较强。     

HPLC荧光法测定高三尖杉酯碱在大鼠体内的分布

目的 研究高三尖杉酯碱注射液在大鼠体内的组织分布,为该药进行临床研究及合理应用提供依据。方法 生物样品在碱性条件下通过氯仿提取,用Kromasil C₁₈柱(4.6 mm×150 mm,5 μm),乙腈-10 mmol·L^-1 KH₂PO₄缓冲液(含0.2%三乙胺,用H₃PO₄调pH至2.5)(25∶75)为流动相,荧光检测波长为λex 280 nm,λem 320 nm。结果 绝对回收率为91.27%~102.4%,最低检测限为0.5 ng·mL^-1。SD大鼠单次尾静脉注射高三尖杉酯碱注射液0.5,1,2 h后主要效应器官的浓度分布特点是：C_骨髓>C_心,主要消除器官的浓度分布特点是C_肝>C_肺>C_肾。结论 本法准确,灵敏度高,可用于高三尖杉酯碱的体内过程研究。高三尖杉酯碱在骨髓中有较高浓度分布,应引起重视。     

三尖杉酯碱对肿瘤细胞核苷酸代谢的影响

本文用标记核苷参入艾氏腹水癌细胞各成分以研究三尖杉酯碱对有关的核苷酸代谢的影响。结果表明,该药在抑制DNA合成的同时,使³H-胸腺嘧啶核苷参入酸溶部分明显增加,其中以³H-胸苷三磷酸的增加最为显著。³H-胸苷-磷酸、³H-胸苷二磷酸也有明显增加;但各胸腺嘧啶核苷酸占酸溶部分掺入的百分比与对照组相同。说明三尖杉酯碱不抑制胸腺嘧啶核苷的磷酸化,而抑制脱氧核苷三磷酸到DNA的聚合过程。在³H-尿嘧啶核苷和³H-次黄嘌呤参入实验中,三尖杉酯碱对四种³H-核苷三磷酸及RNA的合成无明显影响。综合核苷三磷酸及脱氧核苷三磷酸的测定结果,表明该药似乎对核糖核苷二磷酸的还原无抑制作用。     

高三尖杉酯碱在大鼠及小鼠的代谢

本文报告³H-高三尖杉酯碱在正常大鼠、小鼠和荷瘤小鼠体内的吸收、分布和排泄。给大鼠静注后,t_1/2(α)和(β)分别为2.1和53.7分钟。静注后15分钟,以骨髓、肾和肝的放射性最高。荷瘤小鼠体内的放射性分布情况与正常大鼠的趋势相仿。静注后24小时,自大鼠尿排泄剂量的42.2%,在粪中排出6.3%,其中原形药放射性占剂量的15.9%。静注后48小时,自胆汁排泄剂量的57.7%,其中原形药放射性占剂量的20.2%。该碱经肌注也可被迅速吸收入血。     

三尖杉酯碱和高三尖杉酯碱诱导人早幼粒白血病细胞的程序性死亡

体外实验证明2×1O^-7 mol·L^-1 三尖杉酯碱和 1O^-7 mol·L^-1高三尖杉酯碱与HL-60细胞作用 4 h，可诱导该细胞产生程序性死亡。提取细胞DNA进行琼脂糖凝胶电泳呈现典型的DNA 梯，同时出现细胞核染色体断裂、核固缩及细胞空泡样变等形态变化。并且在一定范围内具有作用时间和浓度依赖性，二者诱导HL-60细胞程序性死亡作用的强弱与其细胞毒作用平行。     

Structure and toxicity of alkaloids and amino acids of Sophora secundiflora.

Seeds from Sophora secundiflora were extracted into three major fractions: lipids, alkaloids, and amino acids. Most of the lipid material was composed of steroid esters. These esters were hydrolyzed, and the fatty acid compositions were determined. The major alkaloid component was cytisine, with N-methylcytisine, anagyrine, and the fatty acid compositions were determined. The major alkaloid component was cytisine, with N-methylcytisine, anagyrine, and termopsine in lower concentration. The major free ninhydrin-positive compound was gamma-glutamyltyrosine. In addition to several common amino acids, pipecolic acid and 4-hydroxypipecolic acid were identified. Both the amino acid fraction and the alkaloid fractions caused minor pharmacological disorder when injected into rats. However, when both fractions were simultaneously administered, they were lethal.     

甲基莲心碱的药理作用

甲基莲心碱是一种双苄基异喹啉类生物碱。该文就甲基莲心碱的扩血管、降压 ,抗心律失常 ,抗血小板聚集 ,抗血栓形成 ,抗氧化 ,抗有机磷农药中毒 ,抗瘢痕形成以及化疗增敏等药理作用作一综述     

酮洛芬丹皮酚酯及其类似物的合成及抗炎活性研究

目的 合成5种酮洛芬酯类化合物,并研究其抗炎活性和胃肠道不良反应。方法 以丹皮酚及结构类似物和酮洛芬为原料,通过碳二亚胺法合成5种化合物;采用二甲苯致小鼠耳廓肿胀模型和角叉菜胶致大鼠足趾肿胀试验对化合物抗炎活性做了初步的药理学筛选;同时考察化合物对胃肠道不良反应的影响。结果 化合物的结构经¹H-NMR及MS得到确证;5个目标化合物均能显著地减轻小鼠的耳肿胀和大鼠的足趾肿胀程度,与其相应的阳性和阴性对照组相比,都具有良好的抗炎效果;同时,5个目标化合物对胃肠损伤面积明显小于阳性组和阴性组,能够明显地减轻胃肠道的不良反应。结论 合成了5种酮洛芬酯类化合物;抗炎活性均明显强于酮洛芬;且对胃肠道的不良反应明显地减轻。     

三尖杉酯碱类的高速液相色谱法分离与测定

本文报道以Lichrosorb SI-60及Nucleosil C-18为固定相,用正相和反相高速液相色谱法分离三尖杉总生物碱、混合酯碱、及半合成三尖杉酯碱差向异构化合物,并用于混合酯碱、半合成三尖杉酯碱差向异构化合物的含量测定,比较了各种参数变化对色谱过程的影响,以拟定的方法对各种酯碱提取物、制剂及半合成产品作了定量分析。本法的灵敏度为1×10^-6g,平均偏差1.9%。     

Quinolizidine alkaloids from plants and their cell suspension cultures

The alkaloid composition of cell suspension cultures and differentiated plants of LUPINUS POLYPHYLLUS was evaluated using quartz capillary gas-liquid chromatography, GLC-MS and FD-MS. Lupanine (97% of total alkaloids), sparteine, 13-angeloyloxylupanine and 13-tigloyloxylupanine were detected in alkaloid extracts of L. POLYPHYLLUS cell suspension cultures. Lupanine, 13-cis and 13-trans-cinnamoyloxylupanine were found in the spent cell culture medium. No significant difference was found in the alkaloid composition of photomixotrophic and heterotrophic cell strains although the alkaloid content was 5 to 10 times higher in photomixotrophic cell strains. In the respective plants we could identify 18 alkaloids which include the following esters of 13-hydroxylupanine: 13-tigloyloxylupanine, 13-angeloyloxylupanine, 13-cis-cinnamoyloxylupanine, 13-trans-cinnamoyloxylupanine, 13-benzoyloxylupanine, 13-(2-methylbutyryl)-oxylupanine; and 13-vanilloyloxylupanine.     

Synthesis and Biological Evaluation of Novel Alkyl-Imidazolyl Carbinols and their Esters: Potent Antimycotics

A novel series of imidazol-5-yl carbinols and their 4-chlorobenzoyl esters has been synthesized by the Grignard reaction and subsequent esterification. These compounds were screened for their antimicrobial activities in an agar diffusion assay. The compounds with C₁₀ to C₁₂-alkyl side chains displayed significant antimycotic activity.     

Fluorinated retinoic acids and their analogues. 1. Synthesis and Biological activity of (4-methoxy-2,3,6-trimethylphenyl)nonatetraenoic acid analogues.

(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo in a chemically induced mouse papilloma test; the toxicities were assessed in an in vivo mouse hypervitaminosis A test. Antipapilloma activity greater than the parent nonfluorinated ester was found for 1c (ethyl 12-fluororetinoate) and 23 and 39 (aromatic 4- and 6-fluororetinoid esters, respectively). A similar increase in antipapilloma activity was observed for 71 and 72, the aromatic 4- and 6-fluororetinoic acids, respectively, relative to 2 and for 73 (aromatic 4-fluororetinoid amide) relative to 4.     

M3/M1-Selective antimuscarinic tropinyl and piperidinyl esters.

The binding affinities of some tropinyl and piperidinyl esters for the submandibulary glands (M3/M1) and heart ventricle (M2) were determined from displacement experiments using 3H-labelled N-methylscopolamine as radioligand. The antimuscarinic activities of these esters were also evaluated on guinea pig bronchi. The esters inhibited the M3-mediated carbachol-induced contraction of the bronchial smooth muscle and a reasonable correlation was obtained between the binding affinities of the esters for the submandibulary glands (pKM3,M1) and their inhibitory activities (pIC50) on guinea pig bronchi. A promising compound, N-methylpiperidinyl cyclohexylphenylpropionate (NCPP) which combined good antimuscarinic activity (pA2=9.34) with a 20-fold selectivity at the M3/M1 receptors, was identified. Quantitative structure-activity relationships (QSAR) showed that the size of the ester was the main structural feature determining both binding affinity for the M3/M1 receptors and inhibitory activity on guinea pig bronchi. Esters with substituted acyl side chains (fewer hyperconjugable H atoms at the alpha-carbon) are generally associated with better activity and affinity.     

Antiplasmodial and antitrypanosomal activity of new esters and ethers of 4-dialkylaminobicyclo[2.2.2]octan-2-ols

Only three drugs are available for the treatment of East African trypanosomiasis. Patients suffer from painful application, severe side effects and increasing resistance against these drugs. Malaria tropica kills more than 2 million people every year mainly due to growing drug resistance. 4-Dialkylaminobicyclo[2.2.2]octan-2-ols and some of their esters have shown activity against both the causative organisms, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Ethers and new esters with markedly higher lipophilicity were prepared in three-step procedures from acyclic synthons. The new compounds were screened for their antiprotozoal activities against T. b. rhodesiense (STIB 900) and P. falciparum K1 (resistant to chloroquine and pyrimethamine), and for their cytotoxicity with l-6 cells by means of in vitro microplate assays. The results were compared to those of the parent compounds indicating that higher lipophilicity increases the antiprotozoal activities. The pivalate 10a showed the highest antitrypanosomal activity. The 4-chlorobenzoate 9b exhibited good antiplasmodial activity and low cytotoxicity. The most active antiplasmodial agent was the benzhydryl ether 13c which was nearly as active as chloroquine against sensitive strains.