本文選題：金屬氧酸鹽 + 致畸敏感期��； 參考：《吉林大學(xué)》2013年碩士論文

【摘要】：雜多化合物，是一類前過渡金屬氧陰離子簇化合物，亦是一類多核配合物。它具有高電荷、高分子量、氧化還原性強(qiáng)以及結(jié)構(gòu)組成具有多樣性等特點(diǎn)。雜多化合物具有廣泛的用途，除了傳統(tǒng)上用于催化、功能材料、相轉(zhuǎn)移等領(lǐng)域，它的用途正逐漸延伸至分析化學(xué)、臨床化學(xué)和藥物化學(xué)等領(lǐng)域。 在藥物化學(xué)研究中，雜多化合物表現(xiàn)出對(duì)多種RNA病毒和部分DNA病毒具有廣譜的抗病毒作用，主要體現(xiàn)在抗HIV、流感病毒和SARS病毒等方面，雜多化合物抗病毒研究正在引起醫(yī)學(xué)界的廣泛關(guān)注。本課題組在前期的研究基礎(chǔ)上，自主設(shè)計(jì)合成了一種新型雜多化合物（代號(hào)：NCW-6），對(duì)其單晶進(jìn)行了解析，明確其結(jié)構(gòu)；同時(shí)研究該化合物對(duì)乙型肝炎病毒的抑制作用和一般毒性試驗(yàn)，結(jié)果表明，NCW-6具有良好的抗乙肝病毒的作用，作用效果優(yōu)于陽性對(duì)照藥物；一般毒性（急性毒性、90d喂養(yǎng)）結(jié)果證實(shí)，該化合物毒性較低。本研究是在前期研究工作的基礎(chǔ)上，選用致畸敏感期試驗(yàn)和胎鼠中腦微團(tuán)試驗(yàn)進(jìn)一步探索NCW-6對(duì)大鼠的生殖毒性的影響，為開發(fā)具有我國自主知識(shí)產(chǎn)權(quán)的新型非核苷類似物藥物奠定基礎(chǔ)。 本課題主要內(nèi)容是通過體內(nèi)生殖發(fā)育毒性試驗(yàn)和體外生殖毒性試驗(yàn)兩個(gè)方面來進(jìn)行評(píng)價(jià)受試藥物NCW-6的生殖發(fā)育毒性。選用具有實(shí)驗(yàn)周期短、費(fèi)用低、重現(xiàn)性好，便于不同實(shí)驗(yàn)室間的比較等特點(diǎn)的生殖發(fā)育毒性體外替代方法即中腦細(xì)胞微團(tuán)試驗(yàn)進(jìn)行體外毒性研究，基于大鼠受孕13d時(shí)處在神經(jīng)分化前期的胚胎中腦細(xì)胞對(duì)化學(xué)毒物的作用非常敏感，細(xì)胞毒物可抑制該時(shí)期細(xì)胞分化增殖，從而使細(xì)胞集落及細(xì)胞數(shù)目減少的原理，探索外源性化學(xué)物質(zhì)的致畸作用，進(jìn)而從體外和體內(nèi)試驗(yàn)綜合研究受試藥物的致畸作用機(jī)制。 1致畸敏感期試驗(yàn) 應(yīng)用體內(nèi)生殖發(fā)育毒性試驗(yàn)中較重要的致畸敏感期試驗(yàn)來的評(píng)價(jià)受試藥物NCW-6對(duì)孕鼠一般情況、胎鼠的生長發(fā)育、胚胎的形成以及對(duì)胎鼠的外觀、內(nèi)臟和骨骼畸形的影響等生殖發(fā)育毒性。動(dòng)物在飼養(yǎng)兩周后，隨機(jī)分為5組，分別設(shè)為陰性對(duì)照組，陽性對(duì)照組，以及NCW－6高、中、低三個(gè)劑量組，劑量分別為1467.5mg/kg、366.8mg/kg、91.7mg/kg陰性對(duì)照組給予5mL/kg蒸餾水；陽性對(duì)照組給予130mg/kg的維甲酸。陰性對(duì)照組和3個(gè)給藥組于各組雌鼠于受孕后第6-15天連續(xù)給藥，每天固定時(shí)間灌胃一次；陽性對(duì)照組于妊娠第10天，一次灌胃給藥。每3天稱量體重，并根據(jù)體重變化隨時(shí)調(diào)整給藥量。給藥期間觀察動(dòng)物的一般狀態(tài)，，記錄體重變化及死亡情況。結(jié)果顯示:受試藥物對(duì)孕鼠的體重和增重對(duì)照組比較差異無顯著性(P0.05)；對(duì)鼠的平均黃體數(shù)、著床數(shù)、活胎數(shù)、死胎數(shù)和吸收胎數(shù)與陰性對(duì)照組比較差異不明顯(P0.05)；各給藥組胎鼠的平均體重、身長、尾長以及平均胎重、窩重與陰性對(duì)照組比較差異無顯著性(P0.05)；各給藥組胎鼠外觀、內(nèi)臟畸形率、骨骼畸形率與陰性對(duì)照組比較差異無顯著性(P0.05)，依據(jù)新藥毒理學(xué)評(píng)價(jià)方法，表明NCW-6對(duì)母體的影響、對(duì)胚胎，對(duì)胎鼠外觀、內(nèi)臟和骨骼畸形均無明顯影響，表明在本實(shí)驗(yàn)條件下，NCW-6對(duì)孕鼠無母體毒性、對(duì)胎鼠無胚胎毒性及致畸作用。 2.中腦微團(tuán)試驗(yàn) 選用實(shí)驗(yàn)周期短、費(fèi)用低、重現(xiàn)性好、便于不同實(shí)驗(yàn)室間的比較等特點(diǎn)的生殖發(fā)育毒性體外替代方法—中腦細(xì)胞微團(tuán)試驗(yàn)進(jìn)行體外生殖毒性研究，本實(shí)驗(yàn)采用13d孕鼠的胚胎中腦細(xì)胞制成密度為5×106個(gè)細(xì)胞/ml的細(xì)胞懸液分別進(jìn)行細(xì)胞增殖試驗(yàn)和細(xì)胞分化實(shí)驗(yàn)，實(shí)驗(yàn)結(jié)果顯示，受試藥物IV50為1074.17μg·mL-1，ID50為394.36μg·mL-1，R值為2.72，表明該化合物生殖毒性較低。 綜上所述，受試藥物在本研究的體外和體內(nèi)生殖發(fā)育毒性試驗(yàn)中均表現(xiàn)出較低生殖發(fā)育毒性，該實(shí)驗(yàn)結(jié)果為NCW-6的進(jìn)一步應(yīng)用研究提供毒理學(xué)依據(jù)。
[Abstract]:Heteropoly compounds, a class of pre transition metal oxygen anion clusters, are also a class of polynuclear complexes. It has the characteristics of high charge, high molecular weight, strong oxidation-reduction and diversity of structure. Heteropoly compounds have a wide range of uses, except in the fields of catalysis, functional materials, phase transfer and so on. Gradually extended to analytical chemistry, clinical chemistry and pharmaceutical chemistry.
In the study of drug chemistry, heteropoly compounds show a broad spectrum of antiviral effects on a variety of RNA viruses and partial DNA viruses, mainly in the anti HIV, influenza virus and SARS virus. The study of the antivirus of heteropoly compounds is arousing widespread concern in the medical field. A new type of heteropoly compound (code name: NCW-6) was used to analyze the single crystal and to clarify its structure, and to study the inhibitory effect of the compound on hepatitis B virus and the general toxicity test. The results showed that NCW-6 had good anti HBV effect, and the effect was better than that of the positive control drug; the general toxicity (acute toxicity, 9) was better than that of the positive control drug. The results of 0d feeding confirmed that the toxicity of the compound was low. On the basis of previous research work, the effect of NCW-6 on the reproductive toxicity of rats was further explored by teratogenic sensitivity test and fetal rat midbrain micro mass test, and the foundation for the development of new non nucleoside analogues with our own intellectual property rights was established.
The main content of this topic is to evaluate the reproductive toxicity of the tested drug NCW-6 through the two aspects of the toxicity test of the body reproductive development and the test of the reproductive toxicity in vitro, and select the substitutes for reproductive development toxicity, which has the characteristics of short experimental period, low cost, good reproducibility and convenient comparison between different laboratories. The cytotoxicity study was conducted in vitro, based on the sensitivity of the embryonic mesencephalic cells in the early stage of the 13D pregnancy to the chemical toxicants. The cell toxicants could inhibit the proliferation of cells in this period, thus the principle of cell colony and cell number reduction to explore the teratogenic effect of exogenous chemicals. In vitro and in vivo experiments were conducted to study the teratogenic mechanism of the tested drugs.
1 teratogenic sensitivity test
An important teratogenic period test was used to evaluate the reproductive development toxicity of the tested drug NCW-6 on the pregnant rats, the growth and development of fetal mice, the formation of embryos, the appearance of fetal mice, the visceral and skeletal malformation of the pregnant mice. After two weeks of feeding, the animals were randomly divided into 5 groups, which were set negative. The control group, the positive control group, and the NCW 6 high, middle and low three dose groups, the dose of 1467.5mg/kg, 366.8mg/kg, 91.7mg/kg negative control group were given 5mL/kg distilled water, the positive control group was given 130mg/kg retinoic acid. The negative control group and the 3 administration group were given the female rats continuously after the pregnancy after the pregnancy. One time, the positive control group was given the medicine at tenth days of pregnancy. The weight was weighed every 3 days, and the dosage was adjusted at any time according to the weight change. The general state of the animals was observed during the period of administration and the body weight change and death were recorded. The results showed that there was no significant difference in the weight and weight gain between the pregnant rats and the control group (P0.05); The average corpus luteum number, the number of implantation, the number of live births, the number of stillbirths, the number of stillbirths, and the number of absorbed tyres were not significantly different from those of the negative control group (P0.05). The average weight, length, tail length and average fetal weight of the pregnant rats were not significant (P0.05); the appearance of the fetal rats, the rate of visceral malformation, the rate of bone malformation and the negative rate (P0.05) The sex control group had no significant difference (P0.05). According to the new drug toxicology evaluation method, it showed that the influence of NCW-6 on the mother body had no obvious influence on the embryo, the fetal mouse appearance, the visceral and bone malformation. It showed that under this experimental condition, NCW-6 had no maternal toxicity to pregnant rats, and had no embryo toxicity and teratogenic effect on fetal mice.
2. mesencephalic micro mass test
The reproductive toxicity of reproductive development toxicity in vitro, which is characterized by short experimental period, low cost, good reproducibility and convenient for comparison between different laboratories, is used to study the reproductive toxicity of the mesencephalic cell micromass test. In this experiment, the cell suspension with a density of 5 x 106 cells from the mesencephalic cells of the embryo of 13D pregnant mice was added to the cell suspension respectively. The experimental results showed that the IV50 was 1074.17 mu g / mL-1, ID50 was 394.36 mu g and mL-1, and the R value was 2.72, indicating that the reproductive toxicity of the compound was low.
In summary, the tested drugs showed low reproductive toxicity in both in vitro and in vivo reproductive toxicity tests in this study. The results provided a toxicological basis for the further application of NCW-6.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R114

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 吳新宇;�？∑�;吳荻;王宏芳;徐坤;孫志偉;李娟;;新型稀土雜多化合物對(duì)乙型肝炎病毒復(fù)制的抑制作用[J];吉林大學(xué)學(xué)報(bào)(醫(yī)學(xué)版);2007年02期

2 原野;李金華;王娟;張士堯;鞠文;齊燕飛;李娟;徐坤;;新型多酸化合物NCW-6的毒理學(xué)安全性評(píng)價(jià)[J];吉林大學(xué)學(xué)報(bào)(醫(yī)學(xué)版);2012年01期

3 劉術(shù)俠,翟宏菊,王恩波,韓正波,劉艷波,曾毅,李澤琳;多金屬氧酸鹽的抗艾滋病毒活性和機(jī)理的探討[J];東北師大學(xué)報(bào)(自然科學(xué)版);2004年01期

4 劉術(shù)俠,李陽先,韓正波,王恩波,曾毅,李澤淋;新型稀土雜多藍(lán)的合成及其抗艾滋病病毒(HIV-1)活性和毒性研究[J];高等學(xué)�；瘜W(xué)學(xué)報(bào);2002年05期

5 劉杰,梅文杰,李安興,譚彩萍,石碩,計(jì)亮年;混合價(jià)態(tài)鎢硼稀土雜多藍(lán)在MDCK細(xì)胞內(nèi)抑制流感病毒的活性[J];高等學(xué)校化學(xué)學(xué)報(bào);2004年01期

6 李娟,李靜,齊燕飛,王宏芳,王恩波,胡長文,許林,吳新宇;12-鎢硼酸5-氟尿嘧啶鹽的合成及抗癌活性研究[J];高等學(xué)�；瘜W(xué)學(xué)報(bào);2004年06期

7 邵琛;王建萍;楊國春;蘇忠民;胡冬華;孫家鍾;;六鉬酸鹽有機(jī)胺雜化衍生物與SARS-CoV 3CL~(pro)相互作用的分子動(dòng)力學(xué)模擬[J];高等學(xué)�；瘜W(xué)學(xué)報(bào);2008年01期

8 劉杰;王恩波;計(jì)亮年;;多金屬氧酸鹽抗病毒藥物研究[J];化學(xué)進(jìn)展;2006年01期

9 李松田;吳春篤;閆永勝;呂曉萌;霍鵬偉;;雜多酸光催化降解有機(jī)污染物[J];化學(xué)進(jìn)展;2008年05期

10 王升富，孫蓮，曾百肇，周性堯;雜多化合物在分析化學(xué)中的應(yīng)用[J];化學(xué)通報(bào);1996年07期

本文編號(hào)：1819875