不饱和双键化合物与药物活性研究进展

化合物分子中的不饱和双键与其药物活性之间有着十分密切的关系。在不同的化合物中不饱和双键起到不同的作用：可作为活性中心,可增强药理活性;但有时也会降低药理活性。本文就化合物分子中的不饱和双键与其抗肿瘤、抗氧化、抗炎以及抗菌滑性之间的构效关系进行综述,对进一步了解不饱和双键化合物与药物活性之间的关系以及更好地寻找新药具有重要意义。     

取代2H-苯并吡喃-3-甲酰苯胺化合物的合成及抗辐射活性评价

目的 发现新结构的活性分子,为抗辐射药物研究提供候选化合物。方法 使用构象固定和官能团转换策略对Ex-RAD进行结构改造,设计并合成取代2H-苯并吡喃-3-甲酰苯胺化合物。通过照射细胞存活模型进行抗辐射活性筛选,并考察活性化合物的细胞毒性。优选活性化合物进行Western印迹实验,考察对照射细胞凋亡相关蛋白表达的影响,并通过照射小鼠模型评价其抗辐射活性。结果 合成目标化合物21个,通过筛选发现8个化合物可以显著提高照射细胞的存活,选择4个化合物进行复筛和细胞毒性评价。优选化合物D19进行Western印迹实验,发现D19可以影响照射AHH-1细胞凋亡相关蛋白的表达。与辐射组相比,D19可以使全身8.6 Gy照射小鼠30 d存活率提高70%。D19对非致死剂量照射小鼠的血液系统具有保护作用。结论 新结构的化合物D19具有明确的抗辐射活性,值得进一步深入研究。     

雌三醇、表-雌三醇的合成和抗放效应

雌三醇[E_3,全名雌甾1,3,5(10)三烯-3,16α,17β-三醇](Ⅰ)是防治急性放射病的有效药物。但市售的E_3常混有一定量的表-E_3[雌甾1,3,5(10)三烯-3,16β,17β-三醇](Ⅱ)这两种E_3的差别仅在于C_(16)羟基立体构型之不同:一个为αOH;另一个为βOH。药物的立体结构不同可能会导致疗效和毒副作用很大不同。为此,我们用不同方法合成了单纯的E_3及表-E_3。比较和研究了OH立体构型与理化性质,雌活力和抗放效果的关系,兹报告结果如下:     

几种雄甾化合物的抗辐射作用

几种雄甾化合物的抗辐射作用史建栋郑思新马成禹除雌甾化合物外，雄甾化合物也可以减轻放疗对造血系统的损伤，促进造血系统及免疫系统的恢复等，因此也可用于急性放射病的防治。本文对８种５α－双氢睾酮Ｂ环衍生物（１～８）进行抗辐射作用的比较，以期寻找新型的抗辐射...     

一些5位取代的4—硝基咪唑化合物对体外培养的乏氧哺乳动物细胞的辐射敏化作用

一系列芳香族和杂环化合物对乏氧细胞的辐射敏化效率主要与它们的电子亲和性有关。体外培养的哺乳动物细胞的敏化作用可用结构-活性关系来分析: -logC=b_0 b_1E_7~ b_2logP式中C为产生一定敏化作用所需要的化合物浓度,E_7~1为该化合物的单电子还原电位,P为该化合物在辛醇和水中的分配系数,b_0、b_1和b_2为常数。研究表明,亲电子项E_7~1是影响受照射的体外培养乏氧中国仑鼠细胞敏化效率的主要因子,而一系列类似敏化剂在含     

雌二醇衍生物分子结构与雌激素受体的亲和力及雌活性构效关系的分析

雌激素和受体的相互作用表现出高度的亲和性特异性,可在离体简单体系中显示出来.为此利用标记雌二醇[~3H]E_2与家兔胞液受体结合的实验模型,研究了雌二醇衍生物对这种结合反应的竞争性抑制作用和对小鼠子宫增重雌活性作用,总结了40多种衍生物的构效关系.     

用FREE WILSON方法分析四氢噻唑类抗辐射药物结构与效果的相互关系

在各种含硫和氮的抗辐射化合物中,四氢噻唑(Ⅰ)是一类具有不同程度抗辐射作用的化合物。不取代的,2-取代的和3-取代的四氢噻唑的效果已在文献中报导了。在2-取代衍生物中观察到的效果比3-取代的衍生物更好。     

16-β-表雌三醇的合成及其抗辐射作用的探讨

本文报道了16-β-表雌三醇的新合成,即以雌酚酮为原料经△~(16)-脱氢雌二醇二乙酸酯、16α,17α—甾体环氧化合物(4),再与氢氧化钾的甲醇溶液反应制得其关键中间体16-羰基雌二醇(7),经 NaBH_4还原即得目的物(2)。表雌三醇对受照射小鼠有一定防护效果。防护作用与照射剂量之间有较密切的关系,在照射剂量较高的条件下其效价高于 E_(30)。本文还对作用机理及构效关系进行了讨论。     

枸杞多糖对受照射大鼠生殖系统的保护作用

枸杞多糖(LBP)含有多种微量元素和氨基酸,具有多种生理活性[1].近几年来,国内外对枸杞多糖做了大量的研究工作,但鲜见于生殖系统抗辐射之报道.本研究目的在于通过观察枸杞多糖对生殖系统辐射损伤雄性大鼠的抗氧化作用及对性激素水平的影响,探讨其对雄性大鼠生殖系统抗辐射保护作用的可能机制.     

对一系列新的硝基芳香族辐射增敏剂及生物还原剂的评价

对六类150种硝基芳香族化合物(即呋喃类、噻吩类、咪唑炎、吡唑类、吡咯类和三唑类)进行了试验,这些化合物的单电子还原电位(E_7~1)差别很大。5-硝基呋喃表现出很强的辐射增敏活性,其C_(1.6)在10～50μmol/L,它还表现出特异性的生物还原细胞毒性,但由于亲电性太强(E_7~1=-250mV),     

回心草单体成分对H2O2诱导心肌细胞损伤的保护作用研究

目的 建立过氧化氢（H202）诱导心肌细胞损伤模型,并在此模型上研究胡椒碱、胡椒酸甲酯、咖啡酸甲酯、尿嘧啶苷对心肌细胞损伤的保护作用。方法 用H202诱导造成原代培养的心肌细胞损伤模型,将单体化合物分为3个剂量组,作用于正常和损伤的心肌细胞,利用全自动生化分析仪对细胞悬液中乳酸脱氢酶（LDH）和肌酸激酶同功酶（CK-MB）含量进行测定。结果 回心草各单体成分对正常心肌细胞无明显影响。胡椒碱和胡椒酸甲酯各剂量组作用的心肌细胞悬液中LDH和CK-MB值与模型组对照有非常显著性差异（P＜0．01）,咖啡酸甲酯对CK-MB有非常显著性差异（P＜0．01）,尿嘧啶苷无显著性差异（P＞0．05）。结论 对H202诱导的心肌细胞损伤,胡椒酸甲酯和胡椒碱具有明显的保护作用,咖啡酸甲酯具有部分保护作用,尿嘧啶苷无保护作用。     

Protection of Tissue-culture Cells against Ionizing Radiation

Summary

The radioprotective activity of a number of biological amines, disulphide compounds and thiols at various concentrations was tested in an in vitro system, based on the cloning technique devised by Puck et al.

It was found that none of the biological amines (histamine, adrenaline, noradrenaline and serotonin) or disulphide compounds (cystamine and cystine) showed a protective activity. A defininitive protection on the other hand was observed with the thiol compounds (cysteamine, cysteine and AET).

The protective activity of the latter compounds depended on the concentration which was used. Concentrations of 2–4 mM gave dose–reduction factors (DRF) between 1 and 2. At higher concentrations (cysteamine 32 mM and cysteine 128 mM) DRF's approaching 4 were obtained. The best protection with AET was observed at a concentration of 128 mM (DRF 2·2). The protection by AET was meliorated if higher serum concentrations in the culture medium were used. The best protection on a mM basis was provided by cysteamine. None of the compounds protected when applied after irradiation.     

高压氧对缺氧缺血性脑损伤新生大鼠脑皮质线粒体生物合成的影响

 目的 观察高压氧对缺氧缺血性脑损伤新生大鼠脑皮质线粒体生物合成的影响及其相关信号通路。方法 新生7日龄Wistar大鼠48只随机分为假手术组(Sham,16只),HIBD模型组(HIBD,16只)和高压氧治疗HIBD组(HBO+HIBD,16只)。结扎左侧颈总动脉后暴露于92% 氮气和8%氧气缺氧环境中2 h 制备HIBD 模型。HIBD +HBO 组在缺氧缺血后给予高压氧干预,每次持续90 min,每日1次,连续7 d。末次高压氧干预后24 h,每组动物随机抽取8只处死,检测脑皮质COXⅣ、PGC-1α、Tfam和NRF1表达。剩余动物饲养至40日龄进行Morris水迷宫检测。结果 HBO+HIBD组与HIBD组比较,逃避潜伏期显著缩短[(21.49 ±3.77)s vs (42.50±6.46)s,P<0.01],穿越平台次数、COXⅣ、PGC-1α、Tfam和NRF1表达均显著升高[分别为(7.41±1.13)次 vs (5.26±0.78)次,(82.15±14.84)kPa vs (62.83±11.02)kPa,(112.19±18.41)kPa vs (67.26±10.40)kPa,(92.15±13.99)kPa vs (76.40±9.32)kPa和(72.29±12.88)kPa vs (49.28±7.14)kPa,P<0.05~0.01]。结论 高压氧可通过上调PGC-1过-NRF1/Tfam通路促进脑皮质线粒体生物合成,从而改善大鼠HIBD后空间学习记忆能力。     

The Intracellular Distribution and Binding of Radiation-protective Mercaptoalkylguanidines

Both the tissue distribution and intracellular distribution of mercaptoethylguanidine hydrobromide (MEG), d-mercaptobutyl-2-guanidine hydrobromide (d-MBG-2), and l-mercaptobutyl-2-guanidine hydrobromide (L-MBG-2) were studied in an attempt to determine how these radiation-protective compounds may function in vivo. The tissue distributions of all three compounds, which differ by as much as 5 : 1 in their protective activity in mice, were similar, both qualitatively and quantitatively. Their intracellular distribution in mouse liver, rat liver, and rat spleen was selective. Furthermore, a relation between protective activity and intracellular distribution was observed. The intracellular-distribution pattern was altered when the compound was given after irradiation. It is inferred that the microsomal fraction may be involved in radiation death.

An investigation of the nature of the binding of each of these compounds to the cellular constituents was made. Dialysis techniques were used in several solvents, including water, denaturants, and oxidizing or reducing agents previously shown to be effective in breaking the disulphide bond. Three general types were found: one relatively loose and similar to enzyme-substrate complexes, a mixed-disulphide binding, and a rather tight binding of unknown nature. A hypothesis is proposed that the protective agent is localized within the cell in such a way that it covers preferentially radiation-sensitive sites, being held for the most part relatively loosely similar to an enzyme-substrate complex, so that it may effectively quench free radicals formed in the medium.     

The Mechanism of Radiation Protection by Histamine and Other Biological Amines

Summary

The radioprotective activity of a number of biological amines, amongst them histamine and epinephrine, has been shown to be related to their pharmacological activity in mice. Pharmacological antagonists were found to counteract the protective activity of these compounds. The protective effect could not be correlated with the effects of the amines on the blood pressure.

By the use of a polarographic technique it could be shown that the protective compounds cause a decrease of the oxygen tension in the spleen, the magnitude and duration of which is correlated to the degree of radioprotection.

Similarly a reduction of the oxygen content of the inspiratory air reduces the oxygen tension in the spleen and affords protection against irradiation.

It is concluded that histamine, epinephrine and a number of other biological amines protect against irradiation by reducing the oxygen tension in the spleen and possibly in other blood forming organs.     

苯丙氨酸二肽类化合物190对小鼠CCl4肝损伤的保护作用

目的观察苯丙氨酸二肽类化合物190对四氯化碳致小鼠急性肝损伤的保护作用。方法将180只小鼠随机分为正常组,CCl4模型对照组,联苯双酯阳性药物组和PDC190低、中、高（25、50、100mg.kg^-1）3个剂量组。应用0.12%CCl4腹腔注射致小鼠急性肝损伤模型,通过测定小鼠血清中谷丙转氨酶、谷草转氨酶活性以及小鼠肝组织中丙二醛含量和超氧化物歧化酶活力,并观察肝脏组织病理学变化,对PDC190的保肝作用进行研究。结果模型组小鼠肝功能明显异常,肝组织变性、坏死严重;PDC190组能明显改善C l4中毒小鼠肝功能,其降酶率以低、中、高剂量分别为22.1%、70.2%、78.5%;肝组织切片镜检证实,苯丙氨酸二肽类化合物190能减轻中毒小鼠肝细胞损伤程度。结论苯丙氨酸二肽类化合物190对急性肝损伤小鼠有较好的保肝作用。     

LRP16基因抗紫外线DNA损伤作用的研究

目的根据基因编码序列推测其氨基酸序列，预测LRP16基因编码蛋白的功能并通过实验加以证实。方法利用GeneBank数据库获取LRP16基因序列，然后推测出该基因编码蛋白质的一级结构，对该序列蛋白结构域的同源性进行搜索；将LRP16基因ORF插入pcDNA3．1，构建LRP16基因的真核表达质粒，采用Superfect稳定转染急性粒细胞白血病细胞系HL-60，筛选稳定表达LRP16基因的细胞；以紫外灯照射筛选后有HL-60稳定过表达的HL-60细胞和对照细胞；采用单细胞凝胶电泳技术检测有LRPl6过表达对HL-60细胞增殖及DNA损伤后修复的影响。结果在LRPl6基因理论蛋白序列的第148至315氨基酸残基之间具有与人类组蛋白H2A1C末端相类似的同源序列hismacro、COG2110和A1PP，同源性高达80％以上。LRP16基因的过表达具有抗紫外线引起HL-60细胞DNA损伤和增强损伤后的修复作用。结论LRP16基因编码蛋白可能具有抗紫外线的DNA损伤作用。     

壬基酚体外类雌激素活性评价及其作用

目的：评价壬基酚(NP)的类雌激素素活性，并对其作用机制进行初步研究。方法：采用了体外MCF—7细胞增殖试验检测了NP的类雌激素活性，并用生长曲线分析、细胞周期分析、他莫昔芬拮抗试验和细胞凋亡检测对其作用机理进行了初步探讨。结果：NP有明显刺激MCF—7细胞增殖的类雌激素活性；细胞周期分析NP组细胞增殖指数均明显高于溶剂对照组；NP刺激MCF—7细胞增殖的类雌激素活性可被他莫昔芬拮抗；NP能明显抑制MCF—7细胞凋亡的发生。结论：NP具有刺激MCF—7细胞增殖的类雌激素活性，其机制可能是与雌激素受体结合后，影响细胞增殖及细胞凋亡过程，从而产生一系列生物效应。     

The synthesis of [36Cl]-, [82Br]- and [123I]-labelled 1-(3'-chloro-(bromo and iodo)-3'-deoxy-beta-D-arabinofuranosyl)uracil

Reaction of the epoxy nucleoside 1-(2',3'-epoxy-beta-D-lyxofuranosyl)uracil (1) with [36Cl]HCl afforded [36Cl]-1-(3'-chloro-3'-deoxy-beta-D-arabinofuranosyl)uracil (2a) with a specific activity of 5.48 MBq mmol-1. A similar reaction of 1 with [82Br]NH4Br yielded [82Br]-1-(3'-bromo-3'-deoxy-beta-D-arabinofuranosyl)uracil (2b) with a specific activity of 29 MBq mmol-1. Alternatively neutron activation of the preformed [81Br]-1-(3'-bromo-3'-deoxy-beta-D-arabinofuranosyl)uracil (2b) gave low yields of the [82Br)-labelled 2b with a specific activity of 8.99 MBq mmol-1. [123I]-1-(3'-Iodo-3'-deoxy-beta-D-arabinofuranosyl)uracil (2c) was similarly prepared with a specific activity of 125 GBq mmol-1 by the reaction of [123I]HI with the epoxide. These compounds were prepared for evaluation as non-invasive tumor imaging radiopharmaceuticals.     

Synthesis of 18F-fluoroalkyl-beta-D-glucosides and their evaluation as tracers for sodium-dependent glucose transporters.

Three omega-(18)F-fluoro-n-alkyl-beta-D-glucosides (alkyl = ethyl (5a)), n-butyl (5b), and n-octyl (5c)) were synthesized and evaluated as potential substrates for the sodium/D-glucose cotransporter SGLT1. METHODS: The ligands were prepared by (18)F-fluoride displacement of the corresponding tetraacetyl-protected tosylate alkylglucoside precursors in CH(3)CN, followed by hydrolysis of the protective acetate esters with NaOMe/MeOH. Transport of the nonradioactive analogs 5a, 5b, and 5c by the human sodium-D-glucose cotransporter hSGLT1 was characterized in vitro in oocytes of Xenopus laevis that expressed hSGLT1. The biodistribution of the tracers was determined in mice and the presence of metabolites in the blood was investigated. Compound 5a was also evaluated in mice pretreated with phlorizin. The intrarenal distribution of 5a in mice kidney was visualized using autoradiography. RESULTS: The radiochemical yield of 5a, 5b, and 5c was in the range of 8%-15% (end of bombardment) with a total synthesis time of 90 min. The in vitro evaluation after expression of the hSGLT1 showed that 2'-fluoroethyl-beta-D-glucoside (5a) was transported with similar Michaelis-Menten K(m) and V(max) (maximum velocity) values as compared with methyl-alpha-D-glucopyranoside (alpha MDG). The more lipophilic compounds 5b and 5c were not transported but inhibited transport of alpha MDG. In vivo tissue distribution in mice revealed that 5a, 5b, and 5c were cleared mainly by the renal pathway and that 5a showed a significantly higher accumulation in the kidneys and a slower renal excretion as compared with 5b and 5c. Compound 5a was retained mainly in the renal outer medulla containing S3 segments of proximal tubules and the accumulation could be blocked by phlorizin pretreatment. Compound 5c passed the blood-brain barrier to some extent. CONCLUSION: The data indicate that 2'-(18)F-fluoroethyl-beta-D-glucoside (5a) is a specific tracer of Na(+)-dependent glucose transport that may be used to visualize this transport activity in the S3 segments of renal proximal tubules.