棉酚及其衍生物的制備及抗血吸蟲(chóng)病活性研究
發(fā)布時(shí)間：2019-05-09 12:26
【摘要】：血吸蟲(chóng)病是威脅人類(lèi)健康的重大疾病之一,唯一有效的治療藥物是吡喹酮,大規(guī)模單一用藥產(chǎn)生的耐藥性血吸蟲(chóng)的出現(xiàn),使開(kāi)發(fā)新型抗血吸蟲(chóng)病藥物的工作顯得非常迫切。老藥新用的策略可以提高抗血吸蟲(chóng)病藥物的研發(fā)速度。文獻(xiàn)報(bào)道,擁有廣泛生物活性的棉酚具有抑制重組日本血吸蟲(chóng)的乳酸脫氫酶的活性,棉酚很有可能像青蒿素一樣,具有抗日本血吸蟲(chóng)的殺蟲(chóng)活性。本文研究的基本思路是,通過(guò)提取棉仁中的棉酚,驗(yàn)證棉酚抗日本血吸蟲(chóng)的殺蟲(chóng)活性;通過(guò)化學(xué)合成獲得多樣性的棉酚衍生物化合物庫(kù),獲得結(jié)構(gòu)新穎、活性?xún)?yōu)越的抗日本血吸蟲(chóng)藥物先導(dǎo)物。具體實(shí)施過(guò)程分以下兩部分:1)以棉仁為原料,分別運(yùn)用丙酮提取-苯胺沉淀法和堿液提取-苯胺沉淀法,通過(guò)評(píng)價(jià)兩種提取方法獲得的棉酚產(chǎn)率以及棉酚的純度數(shù)據(jù),獲得新的棉酚提取工藝,提高棉酚的產(chǎn)量與質(zhì)量;2)圍繞棉酚的結(jié)構(gòu)骨架,基于分子中的醛基,合成一系列棉酚衍生物,將得到的棉酚和棉酚衍生物進(jìn)行體外抗血吸蟲(chóng)活性評(píng)價(jià),獲得構(gòu)效關(guān)系信息,選取具有代表性的棉酚衍生物,進(jìn)一步進(jìn)行體內(nèi)抗血吸蟲(chóng)活性研究,獲得初步的體內(nèi)治療血吸蟲(chóng)的活性數(shù)據(jù)。研究結(jié)果顯示,棉仁(20 g)經(jīng)過(guò)丙酮提取得到棉酚粗提物(1 g,產(chǎn)率5%),獲得的棉酚粗提物(1 g)利用苯胺沉淀法得到精制醋酸棉酚(400 mg,產(chǎn)率40%),純度達(dá)到98%,提取到的棉酚質(zhì)量占了棉仁總質(zhì)量的2.0%,提取效果明顯高于堿液提取-苯胺沉淀法。體外抗血吸蟲(chóng)活性結(jié)果顯示,棉酚的殺蟲(chóng)活性?xún)?yōu)于藥物吡喹酮,對(duì)雌蟲(chóng)的殺蟲(chóng)效果優(yōu)于雄蟲(chóng)。合成的9個(gè)棉酚衍生物對(duì)血吸蟲(chóng)產(chǎn)生了不同程度的殺蟲(chóng)活性,構(gòu)效關(guān)系結(jié)果顯示,當(dāng)R為取代苯環(huán)時(shí),苯環(huán)上的氯原子取代不利于殺蟲(chóng)活性的提高,當(dāng)R為苯環(huán)時(shí),棉酚衍生物26的殺蟲(chóng)活性明顯優(yōu)于棉酚及其它取代苯環(huán)衍生物,當(dāng)R為芐基或者環(huán)己基甲基時(shí),殺蟲(chóng)活性明顯低于苯基衍生物26,當(dāng)苯丙氨酸甲酯與棉酚縮合產(chǎn)生衍生物29時(shí),體外殺蟲(chóng)活性最高,在濃度10?M下,在48小時(shí)后,殺蟲(chóng)率達(dá)到100%,并且化合物29體外殺死雄蟲(chóng)的效果好于雌蟲(chóng)。進(jìn)一步抗血吸蟲(chóng)童蟲(chóng)實(shí)驗(yàn)顯示,棉酚衍生物29在濃度僅為2?M時(shí),24小時(shí)、48小時(shí)及72小時(shí),分別對(duì)童蟲(chóng)就顯示了71.7%、75.0%以及81.7%的殺蟲(chóng)率,殺蟲(chóng)活性遠(yuǎn)遠(yuǎn)高于陽(yáng)性對(duì)照青蒿甲酯和棉酚。最后,小鼠體內(nèi)活性評(píng)價(jià)顯示,通過(guò)腹腔給藥,棉酚衍生物29對(duì)成蟲(chóng)的減蟲(chóng)率達(dá)到72.3%,對(duì)雌蟲(chóng)的減蟲(chóng)率達(dá)到76.8%,對(duì)蟲(chóng)卵的減卵率達(dá)到43.3%,棉酚衍生物29的體內(nèi)殺蟲(chóng)活性和減卵率明顯高于棉酚;通過(guò)灌胃給藥,棉酚衍生物29的減蟲(chóng)率達(dá)到57.4%,減雌率達(dá)到53.5%,減卵率達(dá)到22.2%,體內(nèi)殺蟲(chóng)效果高于棉酚。本研究發(fā)現(xiàn)新型抗日本血吸蟲(chóng)病藥物并做出了全新的嘗試,為發(fā)現(xiàn)新型抗血吸蟲(chóng)病藥物提供新的研究思路。
[Abstract]:Schistosomiasis is one of the major diseases threatening human health. Praziquantel is the only effective therapeutic drug. The emergence of drug-resistant schistosomiasis produced by large-scale single drug makes the development of new anti-schistosomiasis drugs very urgent. The strategy of new use of old drugs can improve the research and development speed of anti-schistosomiasis drugs. It has been reported that gossypol, which has a wide range of biological activities, has the activity of inhibiting lactic dehydrogenase of recombinant Schistosoma japonicum. Gossypol, like artemisinin, has insecticidal activity against Schistosoma japonicum. The basic idea of this study is to verify the insecticidal activity of gossypol against Schistosoma japonicum by extracting gossypol from cotton kernel. A diverse library of gossypol derivatives was obtained by chemical synthesis, and a novel and active precursor of anti-Schistosoma japonicum (Schistosoma japonicum) was obtained. The implementation process is divided into the following two parts: 1) using cotton kernel as raw material, the yield of gossypol and the purity data of gossypol were evaluated by acetone extraction-Aniline precipitation method and Alkali extraction-Aniline precipitation method, respectively. A new extraction process of gossypol was obtained to improve the yield and quality of gossypol. 2) A series of gossypol derivatives were synthesized based on the aldehyde group in the molecule around the structural skeleton of gossypol. The antischistosomiasis activity of gossypol and gossypol derivatives in vitro was evaluated, and the structure-activity relationship information was obtained. Some representative gossypol derivatives were selected to study the anti-Schistosoma activity in vivo, and the preliminary data of anti-Schistosoma activity in vivo were obtained. The results showed that the crude extract of gossypol (1 g, yield 5%) was extracted from cotton kernel (20 g) by acetone, and the crude extract of gossypol (1 g) was obtained by phenylamine precipitation method. The yield of gossypol acetate was 40%, and the yield of gossypol acetate was 40%. The purity of gossypol reached 98%, and the extracted gossypol accounted for 2.0% of the total mass of cotton kernel. The extraction effect was obviously higher than that of alkali extraction-aniline precipitation. The results showed that gossypol had better insecticidal activity than praziquantel in vitro, and the insecticidal effect of gossypol against female was superior to that of male. Nine gossypol derivatives produced insecticidal activity against Schistosoma japonicum in varying degrees. The results of structure-activity relationship showed that the substitution of chlorine atoms on benzene ring was not conducive to the improvement of insecticidal activity when R was substituted for benzene ring, and when R was benzene ring, the structure-activity relationship showed that the substitution of chlorine atom on benzene ring was not conducive to the improvement of insecticidal activity. The insecticidal activity of gossypol derivative 26 is obviously better than that of gossypol and other substituted benzene ring derivatives. when R is benzyl or cyclohexyl methyl, the insecticidal activity of gossypol derivative 26 is significantly lower than that of phenyl derivative 26. when phenylalanine methyl ester is condensed with gossypol to produce derivative 29, The insecticidal activity of compound 29 was the highest in vitro. After 48 hours, the killing rate of compound 29 was 100%, and the killing effect of compound 29 was better than that of female. Further experiments against Schistosoma japonicum showed that gossypol derivative 29 showed 71.7%, 75.0% and 81.7% insecticidal rates against child insects at the concentration of only 2 脳 M for 24 hours, 48 hours and 72 hours, respectively, and the insecticidal rates of gossypol derivative 29 against Schistosoma japonicum were 71.7%, 75.0% and 81.7%, respectively. The insecticidal activity was much higher than that of Artemisia annua methyl ester and gossypol. Finally, the in vivo activity evaluation of mice showed that the worm reduction rate of gossypol derivatives 29 pairs of adults was 72.3%, that of female insects was 76.8%, and that of eggs was 43.3%. The insecticidal activity and egg reduction rate of gossypol derivative 29 were significantly higher than those of gossypol. The worm reduction rate of gossypol derivative 29 was 57.4%, the female reduction rate was 53.5%, and the egg reduction rate was 22.2%. The insecticidal effect of gossypol derivative 29 in vivo was higher than that of gossypol. This study found new anti-schistosomiasis drugs and made a new attempt to provide a new way of thinking for the discovery of new anti-schistosomiasis drugs.
【學(xué)位授予單位】：江南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96
[Abstract]:Schistosomiasis is one of the major diseases threatening human health. Praziquantel is the only effective therapeutic drug. The emergence of drug-resistant schistosomiasis produced by large-scale single drug makes the development of new anti-schistosomiasis drugs very urgent. The strategy of new use of old drugs can improve the research and development speed of anti-schistosomiasis drugs. It has been reported that gossypol, which has a wide range of biological activities, has the activity of inhibiting lactic dehydrogenase of recombinant Schistosoma japonicum. Gossypol, like artemisinin, has insecticidal activity against Schistosoma japonicum. The basic idea of this study is to verify the insecticidal activity of gossypol against Schistosoma japonicum by extracting gossypol from cotton kernel. A diverse library of gossypol derivatives was obtained by chemical synthesis, and a novel and active precursor of anti-Schistosoma japonicum (Schistosoma japonicum) was obtained. The implementation process is divided into the following two parts: 1) using cotton kernel as raw material, the yield of gossypol and the purity data of gossypol were evaluated by acetone extraction-Aniline precipitation method and Alkali extraction-Aniline precipitation method, respectively. A new extraction process of gossypol was obtained to improve the yield and quality of gossypol. 2) A series of gossypol derivatives were synthesized based on the aldehyde group in the molecule around the structural skeleton of gossypol. The antischistosomiasis activity of gossypol and gossypol derivatives in vitro was evaluated, and the structure-activity relationship information was obtained. Some representative gossypol derivatives were selected to study the anti-Schistosoma activity in vivo, and the preliminary data of anti-Schistosoma activity in vivo were obtained. The results showed that the crude extract of gossypol (1 g, yield 5%) was extracted from cotton kernel (20 g) by acetone, and the crude extract of gossypol (1 g) was obtained by phenylamine precipitation method. The yield of gossypol acetate was 40%, and the yield of gossypol acetate was 40%. The purity of gossypol reached 98%, and the extracted gossypol accounted for 2.0% of the total mass of cotton kernel. The extraction effect was obviously higher than that of alkali extraction-aniline precipitation. The results showed that gossypol had better insecticidal activity than praziquantel in vitro, and the insecticidal effect of gossypol against female was superior to that of male. Nine gossypol derivatives produced insecticidal activity against Schistosoma japonicum in varying degrees. The results of structure-activity relationship showed that the substitution of chlorine atoms on benzene ring was not conducive to the improvement of insecticidal activity when R was substituted for benzene ring, and when R was benzene ring, the structure-activity relationship showed that the substitution of chlorine atom on benzene ring was not conducive to the improvement of insecticidal activity. The insecticidal activity of gossypol derivative 26 is obviously better than that of gossypol and other substituted benzene ring derivatives. when R is benzyl or cyclohexyl methyl, the insecticidal activity of gossypol derivative 26 is significantly lower than that of phenyl derivative 26. when phenylalanine methyl ester is condensed with gossypol to produce derivative 29, The insecticidal activity of compound 29 was the highest in vitro. After 48 hours, the killing rate of compound 29 was 100%, and the killing effect of compound 29 was better than that of female. Further experiments against Schistosoma japonicum showed that gossypol derivative 29 showed 71.7%, 75.0% and 81.7% insecticidal rates against child insects at the concentration of only 2 脳 M for 24 hours, 48 hours and 72 hours, respectively, and the insecticidal rates of gossypol derivative 29 against Schistosoma japonicum were 71.7%, 75.0% and 81.7%, respectively. The insecticidal activity was much higher than that of Artemisia annua methyl ester and gossypol. Finally, the in vivo activity evaluation of mice showed that the worm reduction rate of gossypol derivatives 29 pairs of adults was 72.3%, that of female insects was 76.8%, and that of eggs was 43.3%. The insecticidal activity and egg reduction rate of gossypol derivative 29 were significantly higher than those of gossypol. The worm reduction rate of gossypol derivative 29 was 57.4%, the female reduction rate was 53.5%, and the egg reduction rate was 22.2%. The insecticidal effect of gossypol derivative 29 in vivo was higher than that of gossypol. This study found new anti-schistosomiasis drugs and made a new attempt to provide a new way of thinking for the discovery of new anti-schistosomiasis drugs.
【學(xué)位授予單位】：江南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96
【參考文獻(xiàn)】
相關(guān)期刊論文 前10條
1 楊菲菲;湯魯宏;;棉酚全合成及制劑研究進(jìn)展[J];中國(guó)新藥雜志;2016年14期
2 李玲;劉玉秀;汪清民;;棉酚的結(jié)構(gòu)衍生及構(gòu)效關(guān)系研究進(jìn)展[J];中國(guó)科技論文;2015年12期
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