岩白菜素:一种通用易得的生物活性修饰前体（英文）

岩白菜素是中药岩白菜的主要生物活性成分和许多植物家族的重要成分或次级代谢产物,岩白菜素及其衍生物因其独特的生物活性和药理性质引起了人们的极大兴趣。在过去的几十年中,大量岩白菜素衍生物合成出来并考察其生物活性,取得了许多积极的结果。这些研究有助于从岩白菜素衍生物中发现和鉴定新的候选药物治疗剂,了解它们的分子靶点和药理作用机制。本工作总结了岩白菜素半合成衍生物的零散信息及在生物活性修饰方面的最新进展。     

岩白菜素的研究进展

目的综述了近年来对岩白菜素的研究进展。方法采用文献查阅,对相关文献进行归纳总结。结果对岩白菜素的研究主要集中于植物来源、提取分离、分析方法、结构改性、生物活性及其药代动力学等方面。结论岩白菜素具有显著的镇咳、镇痛、抗炎、增强免疫、保护肾脏、抗糖尿病、抗HIV、抗凝血等活性,仍具有较为广泛的研究开发空间。     

岩白菜素β-环糊精包合物的制备

目的 采用正交实验法研究岩白菜素β-环糊精包合物制备的最佳工艺. 方法运用饱和水溶液法制备岩白菜素β-环糊精包合物,并采用紫外分光光度法测定岩白菜素包合率,紫外光谱、红外光谱验证包合物. 结果 通过正交实验得到最佳制备工艺：岩白菜素与β-环糊精投料比为 1：1,包合时间为1 h,包合温度为80 ℃,包合率可达92.19%. 结论 饱和水溶液法制备岩白菜素β-环糊精包合物工艺简单可行,适用于岩白菜素口服制剂的改进.     

大鼠血浆中岩白菜素含量分析方法的建立及其体内药动学

目的建立血浆中岩白菜素的HPLC的测定方法,研究岩白菜素及岩白菜素磷脂复合物在大鼠体内的药动学行为。方法采用Odyssil C18色谱柱(250 mm×4.6 mm,5μm),流动相为甲醇-乙腈-质量分数为0.2%的磷酸水溶液(体积比为4∶16∶80),流速为0.8 m L·min-1,检测波长为220 nm。应用液-液萃取法处理血浆,测定两只大鼠分别口服岩白菜及其磷脂复合物后不同时刻血浆中岩白菜素的质量浓度。结果岩白菜素质量浓度在0.01~5 mg·L-1内线性关系良好,定量下限为0.01 mg·L-1;提取回收率均在78.6%~90%之间;日内、日间精密度均小于13.7%。结论该方法准确度高、灵敏度强、专属性好,可作为测定大鼠血浆岩白菜素质量浓度的方法,为探讨岩白菜素的药动学行为提供方法依据。     

HPLC法测定七叶鬼灯檠不同部位岩白菜素的含量

目的分析七叶鬼灯檠不同部位岩白菜素的含量,为充分利用其药用资源提供资料。方法以岩白菜素为测定指标,HPLC测定不同部位七叶鬼灯檠中岩白菜素含量的色谱条件：色谱柱为Kromasil C18（250 mm×4.6 mm,5μm）,流动相为甲醇-水（25∶75）,流速为1 ml.min^-1。结果根状茎、茎枝和叶片中岩白菜素的含量分别是3.929%、0.154%、0.252%。岩白菜素对照品线性范围在0.0848-2.12μg,样品平均回收率为97.86%,RSD为1.91%。结论定量方法简便、准确、重复性好;根状茎、地上部分茎枝、叶均含岩白菜素,其中根状茎含量最高。     

茵柏益肝汤不同配伍对岩白菜素煎出率的影响

目的 建立测定茵柏益肝汤中有效成分岩白菜素的HPLC,考察药材不同配伍对岩白菜素煎出率的影响。方法 采用RP-HPLC测定茵柏益肝汤不同配伍水煎液浸膏粉中岩白菜素的含量,Agilent Zorbax Extend-C₁₈柱(4.6 mm×250 mm,5 μm);流动相为甲醇-水(20∶80,用磷酸调节pH至2.50);流速为1.0 mL·min^-1;检测波长为275 nm;柱温为30 ℃。结果 茵陈可降低茵柏益肝汤中岩白菜素的煎出率;金钱草、凤尾草+岩柏草+六月雪可提高茵柏益肝汤中岩白菜素煎出率,且二者具有协同作用。结论 建立的茵柏益肝汤中岩白菜素测定方法快速、准确、重现性好;不同配伍对茵柏益肝汤中岩白菜素含量影响显著。     

复方岩白菜素片中两种主要成分的含量测定

目的：用高效液相色谱法测定复方岩白菜素片含量。方法：以甲醇-水（30：70）为流动相，在264nm波长处检测。结果：复方岩白菜素片中马来酸氯苯那敏的平均回收率为98.50%，RSD=0.66%；岩白菜素的平均回收率为99.70%，RSD=1.02%。结论：高效液相色谱法简便快速，适用于复方岩白菜素片的含量测定。     

超声提取鬼灯檠中岩白菜素的最佳工艺研究

目的 建立超声波提取鬼灯檠中岩白菜素的最佳工艺。方法 以岩白菜素提取量为指标,在单因素实验的基础上,采用正交实验对岩白菜素的超声提取工艺进行优选。考察提取温度、料液比、提取功率、提取时间及提取次数对岩白菜素提取量的影响。结果 提取次数、提取时间和料液比对岩白菜素提取率的影响起主要作用,超声提取的最佳工艺为：料液比1∶14,超声波功率为60 W,提取温度为70 ℃,超声波提取时间60 min,提取4次。结论 通过验证实验, 表明所选的工艺条件可行,在该工艺条件下岩白菜素的提取率为12.588 5 mg·g^-1。     

岩白菜素片处方、工艺筛选及其含量测定方法研究

目的 :筛选岩白菜素片最佳处方组成及制备工艺 ,并建立其含量测定方法。方法 :以辅料中低取代羟丙基纤维素 (Ls -HPC)、吐温 -80和淀粉为3因素 ,每因素取3水平 ,选用L9(34)正交表 ,以岩白菜素片的体外溶出参数(Td)为指标进行正交实验 ,筛选最佳处方组成和制备工艺 ;用双波长紫外分光光度法测定片剂中岩白菜素的含量。结果 :辅料中影响片剂溶出度的因素是Ls -HPC和吐温 -80(P<0 01)。最佳处方组成为每片含岩白菜素0 125g、Ls-HPC0 0186g、吐温 -800 0248g、淀粉0 1354g、硬脂酸镁0 0032g。双波长紫外分光光度法测定片剂中岩白菜素的含量 ,平均回收率为 (100 92±0 87) %(n=8)。结论 :本处方具有辅料价廉易得 ,有效成分溶出快 ,制备工艺简单 ,质量稳定及测定方法简便、准确等特点     

HPLC法测定愈伤灵胶囊中岩白菜素的含量

目的建立愈伤灵胶囊中岩白菜素的含量测定方法。方法以岩白菜素为测定指标,HPLC测定愈伤灵胶囊中岩白菜素含量的色谱条件：色谱柱为Kromasil C18（250mm×4．6mm,5μm）,流动相为甲醇-水（25：75）,流速为1ml·min^-1。结果岩白菜素对照品线性范围在0．0848～2．12μg,样品平均回收率为97．10％,RSD为2．20％。结论定量方法简便、准确、重复性好,可作为控制愈伤灵胶囊质量的标准的方法使用。     

A cannabinoid derived prototypical analgesic

The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.     

Biological activity of N-terminal fragments of calcitonin gene-related peptide

The i.v. injection of human alpha-calcitonin gene-related peptide (CGRP) in urethane-anesthetized rats produced hypotension and tachycardia. The N-terminal fragments, CGRP-(1-12), CGRP-(1-15) and CGRP-(1-22) displayed biological activity, although with less potency than the natural peptide. These findings provide the first evidence for biological agonist activity of N-terminal CGRP fragments.     

alpha-Melanotropin: the minimal active sequence in the frog skin bioassay

The minimal sequence required for biological activity of alpha-MSH (alpha-melanotropin, alpha-melanocyte stimulating hormone) was determined in the frog (Rana pipiens) skin bioassay. The sequence required to elicit measurable biological activity was the central tetrapeptide sequence, Ac-His-Phe-Arg-Trp-NH2 (Ac-alpha-MSH6-9-NH2), which was about 6 orders of magnitude less potent than the native tridecapeptide. Smaller fragments of this sequence (Ac-His-Phe-NH2, Ac-Phe-Arg-NH2, Ac-His-Phe-Arg-NH2) were devoid of melanotropic activity at concentrations as high as 10(-4) M. We were unable to demonstrate biological activity for the tetrapeptide, Ac-Phe-Arg-Trp-Gly-NH2 (Ac-alpha-MSH7-10-NH2), and for several carboxy terminal analogues including Ac-Lys-Pro-Val-NH2 (Ac-alpha-MSH11-13-NH2). We prepared a series of fragment analogues of alpha-MSH in an attempt to determine the contribution of each individual amino acid to the biological activity of the native hormone. The minimal potency of Ac-alpha-MSH6-9-NH2 could be enhanced about a factor of 16 by the addition of glycine to the C-terminus, yielding Ac-alpha-MSH6-10-NH2 (Ac-His-Phe-Arg-Trp-Gly-NH2). Addition of glutamic acid to the N-terminus provided the peptide, Ac-alpha-MSH5-10-NH2, which was only slightly more potent than Ac-alpha-MSH6-10-NH2, indicating that position 5 contributes little to the biological potency of alpha-MSH in this assay. Addition of methionine to the N-terminus of Ac-alpha-MSH5-10-NH2 resulted in the heptapeptide, Ac-alpha-MSH4-10-NH2, which was only about 4-fold more potent than Ac-alpha-MSH5-10-NH2. Addition of lysine and proline to the C-terminal of the Ac-alpha-MSH4-10-NH2 sequence yielded the peptide, Ac-alpha-MSH4-12-NH2 with a 360-fold increase in potency relative to Ac-alpha-MSH4-10-NH2. This peptide was only about 6-fold less potent than alpha-MSH. A series of Nle-4-substituted analogues also were prepared. Ac-[Nle4]-alpha-MSH4-10-NH2 was about 4 times more potent than Ac-alpha-MSH4-10-NH2. Ac-[Nle4]-alpha-MSH4-11-NH2 also was about 4 times more potent than Ac-alpha-MSH4-10-NH2, demonstrating that lysine-11 contributes somewhat to the biological activity of alpha-MSH on the frog skin melanocyte receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and some pharmacological properties of [4-threonine,7-sarcosine]oxytocin, a peptide with high oxytocic potency, and of [4-threonine,7-N-methylalanine]oxytocin

Two analogues of oxytocin, [Thr4,Sar7]- and [Thr4,MeAla7]oxytocin, were synthesized and their pharmacological properties investigated. [Thr4,Sar7]oxytocin was found to exhibit high biological activity (uterotonic activity of 1174 +/- 104 and milk ejection activity of 731 +/- 57 units/mg) and high selectivity for oxytocin-like relative to vasopressin-like activities (antidiuretic activity of 0.037 +/- 0.012 unit/mg, undetectable pressor activity). [Thr4,MeAla7]oxytocin was characterized by markedly lower biological activities. In both analogues, the additivity of the effects of the residues in positions 4 and 7 of oxytocin on the biological activity of the analogues was ascertained.     

Effect of structural modifications in the C7-C11 region of the retinoid skeleton on biological activity in a series of aromatic retinoids

A series of conformationally restricted analogues of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propenyl ] benzoic acid--(E)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2 - propenyl]benzoic acid, (E)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-bu ten- 2-yl]benzoic acid, trans-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) cyclopropyl]benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid, 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2- naphthalenecarboxylic acid, 6-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2- naphthalenecarboxylic acid and 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-5-methyl-2- naphthalenecarboxylic acid--were synthesized and screened for retinoid biological activity. Comparison of the conformers of these analogues generated by molecular mechanics calculations with the biological activity profiles of these compounds indicates that geometric constraints required for high biological activity are imposed on the bridge joining the two aromatic ring systems by the retinoid receptor.     

The role of hepatic stimulator substance (HSS) on liver regeneration arrest induced by cadmium

BACKGROUND: The mechanism of cadmium-induced liver regeneration arrest in relation to hepatic stimulator substance (HSS) biological activity was investigated. MATERIALS AND METHODS: In Wistar rats subjected to 65 - 70% partial hepatectomy, saline, cadmium, cadmium and HSS were administered. The rats were also subjected to 30 - 34% partial hepatectomy. Mitotic index, immunochemistry for PCNA, 3[H]-thymidine incorporation into DNA and thymidine kinase activity were used as indices of liver regeneration. HSS biological activity was evaluated in all groups of rats using a bioassay. Results: Liver regeneration and HSS activity were arrested by cadmium during the first 24 h after partial hepatectomy. Both in normal and in cadmium-treated rats, the HSS activity was increased and liver regeneration coincided. HSS activity was stable in 30 - 34% hepatectomized rats. HSS administration was able to restore liver regeneration arrest induced by cadmium. Conclusion: The biological activity of HSS increased at the time of G1/S transition of hepatocytes in the cell cycle and no increase was observed with asynchronous G1/S transition (30 - 34% partial hepatectomy). The suppression of HSS biological activity by cadmium seems to represent an important factor for liver regeneration arrest induced by the metal and HSS administration is able to restore liver regeneration.     

Synthesis and antifungal activity of naturally occurring O- and C-prenylated flavanones

Flavonoids is one of the most important groups of naturally occurring O-heterocycles possessing a wide range of biological activity. O- and C-prenylated flavanones as members of flavonoids also show remarkable biological activity such as antibacterial, antiviral, anti-tumor, antifungal, anti-HIV and enzyme inhibition activity. O- and C-prenylated flavanones possessing remarkable biological activity are representatives of this family of natural products. In this paper efficient synthetic methods have been reported for the preparation of O-(2, 3) and C-(4, 5) prenylated flavanones isolated from Monotes engleri and their analogues (26-30; 38-43) starting from commercially available starting materials. In vitro pharmacological examinations of our compounds were performed on different Candida species (Candida albicans, Candida inconspicua, Candida dubliniensis, Candida krusei) by agardiffusion method. Our structure-activity relationship study clearly showed that any modification of the structure of selinone (2) and monotesone-A (3) led to the total loss the fungistatic activity.     

注射用重组人干扰素α-1b溶解后活性稳定性及雾化粒径研究

目的探讨注射用重组人干扰素α-1b(rhIFNα-1b)溶解后的活性稳定性,并考察不同雾化器雾化对微粒粒径的影响。方法rhIFNα-1b分别以氯化钠注射液和灭菌注射用水为溶剂,考察4℃和25℃温度条件下的生物活性变化;用Winner311XP激光粒度仪检测药液用不同雾化器雾化后微粒的粒径分布。结果rhIFNα-1b以灭菌注射用水为溶剂,4℃存放1,6,12,24 h后的生物学活性相当于0 h活性的96.76%~100.46%,在25℃存放1,6,12,24 h后的生物学活性相当于0 h活性的91.24%~103.69%。rhIFNα-1b以氯化钠注射液为溶剂,4℃存放1,6,12,24 h后的生物学活性相当于0 h活性的96.73%~103.74%,在25℃存放1,6,12,24 h后的生物学活性相当于0 h活性的95.35%~105.58%。雾化rhIFNα-1b后,药液微粒可到达肺泡组织。结论rhIFNα-1b溶解后,在4℃及25℃温度条件下24 h内稳定,雾化后的粒径范围符合要求。     

Synthesis of a 11-deoxyprostanoid in the area of preclavulones: (+-)-8,12-trans-(5Z-14Z)-9-oxo-prosta-5,14-dienoic acid from 2-allyl-2-cyclopenten-1-one.

Following our research on the arachidonic acid metabolites and their derivatives with potential biological activity, we describe the synthesis of the (+-)-8,12-trans-(5Z, 14Z)-9-oxo-prosta-5,14-dienoic acid, a 11-deoxyprostanoid correlated to the class of Preclavulones, one of the unusual families of marine eicosanoids from the coral Clavularia Viridis with considerable biological interest.