基于串聯(lián)反應(yīng)構(gòu)建優(yōu)勢骨架和抗腫瘤藥物發(fā)現(xiàn)
發(fā)布時間：2018-07-13 12:48
【摘要】：基于優(yōu)勢骨架的多樣性導(dǎo)向合成(privileged-substructure-based diversity oriented synthesis,p DOS)是構(gòu)建高質(zhì)量類藥性小分子化合物庫的有效策略,發(fā)現(xiàn)和構(gòu)建具有反應(yīng)活性的優(yōu)勢骨架是該策略的關(guān)鍵。本論文基于多種串聯(lián)反應(yīng)構(gòu)建了優(yōu)勢骨架并通過表型篩選發(fā)現(xiàn)了藥物先導(dǎo)物,內(nèi)容主要包括:(1)通過基于有機小分子催化的不對稱串聯(lián)反應(yīng)構(gòu)建了新型螺環(huán)吡唑酮抗腫瘤骨架并進行了抗腫瘤活性研究;(2)通過有機小分子催化的異羅丹寧與α,β-不飽和醛不對稱Michael加成反應(yīng),發(fā)展了高效構(gòu)建手性優(yōu)勢骨架4,5-二取代異羅丹寧的方法;(3)通過氧化還原-氨基化-芳構(gòu)化-Friedel-Crafts�；�(lián)反應(yīng)快速構(gòu)建了吡咯[1,2-b]異喹啉-10(5H)-酮優(yōu)勢骨架并發(fā)現(xiàn)了新型拓?fù)洚悩?gòu)酶抑制劑。一、基于有機小分子催化的不對稱串聯(lián)反應(yīng)構(gòu)建新型螺環(huán)吡唑酮抗腫瘤骨架及其抗腫瘤活性研究(一)有機小分子催化的不對稱串聯(lián)反應(yīng)構(gòu)建新型螺環(huán)吡唑酮及其抗腫瘤構(gòu)效關(guān)系研究表型篩選在藥物發(fā)現(xiàn)中日益受到重視。相比于基于靶點的藥物篩選,表型篩選可以直接評估化合物在細(xì)胞整體水平的活性。高質(zhì)量的類藥性小分子化合物庫是表型篩選的物質(zhì)基礎(chǔ),將高質(zhì)量類藥性小分子庫與表型篩選相結(jié)合,以發(fā)現(xiàn)新的藥物先導(dǎo)物,進而闡明其作用機制,有著有廣闊的發(fā)展前景。為了構(gòu)建高質(zhì)量的小分子化合物庫,本課題組前期將藥物分子中普遍存在的優(yōu)勢骨架與發(fā)散性有機催化的串聯(lián)反應(yīng)整合,發(fā)展了發(fā)散性有機催化的不對稱串聯(lián)反應(yīng)策略(DOCA)。通過簡單易得的手性吡唑四氫吡喃半縮醛高效的合成了立體結(jié)構(gòu)多樣性的骨架,并成功發(fā)現(xiàn)了新型螺環(huán)吡唑酮抗腫瘤骨架。在此基礎(chǔ)上,本課題通過設(shè)計合成了不同取代基、不同立體構(gòu)型的新型螺環(huán)吡唑酮對其進行了初步構(gòu)效關(guān)系研究,發(fā)現(xiàn)了一個高活性抗腫瘤化合物。(二)有機小分子催化的串聯(lián)反應(yīng)構(gòu)建新型吡唑酮螺環(huán)己二烯酮骨架及其抗腫瘤活性研究通過簡單易得的手性吡唑四氫吡喃半縮醛高效合成了新型吡唑酮螺環(huán)己二烯酮抗腫瘤骨架。通過對底物適用范圍的探討,確定了該底物的適用范圍。選取部分目標(biāo)產(chǎn)物進行了初步的體外抗腫瘤活性測試,其中化合物5s表現(xiàn)出最好的體外抗腫瘤活性,可用于發(fā)展新型抗腫瘤藥物,具有深入研究的價值。二、有機小分子催化異羅丹寧與α,β-不飽和醛的不對稱Michael加成反應(yīng)構(gòu)建藥物分子中的手性模塊有機小分子催化的不對稱反應(yīng)在有機合成中應(yīng)用廣泛,它可以環(huán)境友好地快速高效合成生物活性分子和天然產(chǎn)物,特別是不對稱的Michael加成可以有效的構(gòu)建具有立體選擇性的C-C鍵。近年來,有機小分子催化的不對稱Michael反應(yīng)引起了化學(xué)家的廣泛興趣,大量的合成方法得到了發(fā)展。異羅丹寧骨架的具有廣泛的生物活性,然而,有機催化的不對稱合成異羅丹寧鮮見報道。為了高效的構(gòu)建p DOS庫,本課題組前期發(fā)展了發(fā)散性有機分子催化的串聯(lián)反應(yīng)策略(DOCA),通過簡單易得的噻唑烷二酮及其類似物與α,β-不飽和醛反應(yīng)得到了一系列多樣性分子骨架。其中以異羅丹寧為底物,通過Michael-環(huán)合串聯(lián)反應(yīng)合成了骨架不同的駢合硫代吡喃骨架�；谝陨涎芯�,異羅丹寧可以互變異構(gòu)化成烯醇式Michael供體,與二烯醛通過有機催化發(fā)生共軛加成反應(yīng),得到了一系列的高收率和中等到優(yōu)秀對映選擇性(ee值最高值99%)的4,5-雙取代的異羅丹寧目標(biāo)產(chǎn)物,該產(chǎn)物是快速合成手性異羅丹寧的構(gòu)建模塊,具有很好的應(yīng)用前景。因異羅丹寧具有多樣的生物活性,對4,5-雙取代的異羅丹寧目標(biāo)產(chǎn)物進行藥理活性研究將有助于藥物先導(dǎo)物的發(fā)現(xiàn),具有深入研究的價值。三、基于氧化還原-氨基化-芳構(gòu)化-Friedel-Crafts�；�(lián)反應(yīng)快速構(gòu)建吡咯[1,2-b]異喹啉-10(5H)-酮骨架及新型拓?fù)洚悩?gòu)酶抑制劑的發(fā)現(xiàn)吡咯[1,2-b]異喹啉酮骨架廣泛分布于許多天然產(chǎn)物中,但目前合成該骨架的方法非常有限。通過文獻調(diào)研,我們發(fā)展了一種新的氧化還原-氨基化-芳構(gòu)化-Friedel-Crafts�；�(lián)反應(yīng),快速構(gòu)建了吡咯[1,2-b]異喹啉-10(5H)-酮骨架。通過對反應(yīng)條件的優(yōu)化,確定了最優(yōu)反應(yīng)條件,并在此基礎(chǔ)上進行了底物適用性的探討。研究結(jié)果表明,該串聯(lián)反應(yīng)底物適應(yīng)性較好,目標(biāo)產(chǎn)物能夠通過一步反應(yīng)得到,最高收率為96%。抑酶活性實驗和體外抗腫瘤實驗研究發(fā)現(xiàn),化合物3h為Top1和Top2雙重抑制劑,可以作為抗腫瘤先導(dǎo)化合物值得進一步研究。四、總結(jié)綜上所述,本研究通過多種串聯(lián)反應(yīng)構(gòu)建了4種優(yōu)勢骨架,并設(shè)計合成了160個首次報道的新化合物,通過生物活性評價發(fā)現(xiàn)了3種全新結(jié)構(gòu)類型的抗腫瘤先導(dǎo)化合物。本論文將合成方法學(xué)與藥物化學(xué)結(jié)合,發(fā)現(xiàn)了抗腫瘤先導(dǎo)結(jié)構(gòu),為開發(fā)具有自主知識產(chǎn)權(quán)的抗腫瘤創(chuàng)新藥物奠定了基礎(chǔ)。
[Abstract]:Privileged-substructure-based diversity oriented synthesis (P DOS) based on dominant skeleton is an effective strategy for building a high quality small molecular compound library, and the key to the discovery and construction of a dominant skeleton with reactive activity is the key of this strategy. Drug precursors were found through phenotypic screening, including: (1) the antitumor framework and anti-tumor activity of new spironazolone were constructed by asymmetric tandem reaction based on organic small molecular catalysis. (2) an asymmetric Michael addition reaction of isorodenin to alpha and beta unsaturated aldehydes, catalyzed by organic small molecules, was used. A highly efficient method for constructing the chiral dominant skeleton 4,5- two to replace ISO rodenning was developed. (3) a rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone backbone and a novel topoisomerase inhibitor by redox - aminoaromatization and aromatization series reaction were developed and a new type of topoisomerase inhibitor was found. Study on the construction of novel spiral pyrazolone against tumor skeleton and its antitumor activity (1) asymmetric tandem reaction of organic small molecular catalysis construction of novel spiral pyrazolone and its antitumor activity relationship study on phenotypic screening in drug discovery. Compared with drug screening based on target, phenotypic screening can be direct. The high quality small molecule compound library is the material basis for phenotypic screening, combining the high quality small molecule library with the phenotypic screening in order to discover new drug precursors and clarify its mechanism, which has broad prospects for development. In order to construct high quality small fraction, By integrating the dominant skeleton of the drug molecules with the series of divergent organic catalysis, the asymmetric series reaction strategy of divergent organic catalysis (DOCA) was developed. The framework of the stereostructural diversity was synthesized by a simple and easy chiral pyrazole four pyran semi acetal. A new novel spironazolone antitumor skeleton was successfully found. Based on this, the new type of new spironazolone with different stereotyping was designed and synthesized. A high active antitumor compound was found. (two) a new type of pyrazole was constructed by the series reaction of organic small molecules. The skeleton of ketone cyclohexadienone and its antitumor activity study the anti-tumor skeleton of a new pyrazolone cyclohexadienone by simple and easy chiral pyrazole four thiopria acetal. The scope of the substrate was determined by the scope of application of the substrate. A preliminary anti swelling in vitro was selected to select the target product. The tumor activity test, in which compound 5S shows the best antitumor activity in vitro, can be used to develop new antitumor drugs, and has the value of deep research. Two, the asymmetric Michael addition reaction of small organic molecules catalyzes the asymmetric addition of isorodenning to alpha and beta unsaturated aldehydes to construct asymmetric reaction of organic small molecules catalyzed by chiral modules in drug molecules. It should be widely used in organic synthesis, it can be environmentally friendly and fast and efficient synthesis of bioactive molecules and natural products, especially asymmetric Michael addition can effectively construct a stereoselective C-C bond. In recent years, the asymmetric Michael reaction catalyzed by organic small molecules should cause extensive interest of chemists and a large number of compounds. The method has been developed. The isrodenning framework has a wide range of biological activities. However, the asymmetric synthesis of isorodenin by organic catalysis is rare. In order to construct the P DOS library efficiently, the series of divergent organic molecules catalyzed series reaction (DOCA) was developed, and the simple and easy thiazolidane two ketone and its analogues were used. A series of diversity molecular skeletons were obtained with alpha, beta unsaturated aldehydes, in which different Luo Danning cytoskeleton cytoskeleton was synthesized by Michael- cyclization. Based on the above study, isosardenning could be transformed into enol Michael donor and conjugated with dienaldehyde through organic catalysis. In addition, a series of 4,5- biosuenin target products with high yield and excellent enantioselectivity (EE value 99%) were obtained. The product is a construction module for rapid synthesis of chiral isrodenannin. It has a good application prospect. The isosenannin has a variety of biological activity and the 4,5- biosubstituted isorodenning The research on the pharmacological activity of the target product will be helpful to the discovery of drug precursors. Three, the rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone skeleton and the discovery of pyrrole [1,2-b] isoquinolone based on the redox - aminoaromatization -Friedel-Crafts acylation reaction The skeleton is widely distributed in many natural products, but at present, the method of synthesizing the skeleton is very limited. Through literature research, we developed a new redox - aminoaromatization -Friedel-Crafts acylation series reaction and rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone framework. On the basis of the optimal reaction conditions, the substrate suitability was discussed. The results showed that the substrate was adaptable and the target product could be obtained by one step reaction. The highest yield was 96%. inhibition activity test and in vitro antitumor experimental study. Compound 3H was a double inhibitor of Top1 and Top2. Further research on antineoplastic precursor compounds is worth further research. Four, in summary, this study constructs 4 dominant skeletons through a variety of tandem reactions and designs and synthesizes 160 new compounds reported for the first time. Through Bioactivity Evaluation, 3 new structural types of antitumor precursor compounds have been found. This paper will synthesize methods and drugs. The combination of chemical discovery and anticancer precursor structure has laid the foundation for developing innovative anti-tumor drugs with independent intellectual property rights.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R914
，
本文編號：2119420
[Abstract]:Privileged-substructure-based diversity oriented synthesis (P DOS) based on dominant skeleton is an effective strategy for building a high quality small molecular compound library, and the key to the discovery and construction of a dominant skeleton with reactive activity is the key of this strategy. Drug precursors were found through phenotypic screening, including: (1) the antitumor framework and anti-tumor activity of new spironazolone were constructed by asymmetric tandem reaction based on organic small molecular catalysis. (2) an asymmetric Michael addition reaction of isorodenin to alpha and beta unsaturated aldehydes, catalyzed by organic small molecules, was used. A highly efficient method for constructing the chiral dominant skeleton 4,5- two to replace ISO rodenning was developed. (3) a rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone backbone and a novel topoisomerase inhibitor by redox - aminoaromatization and aromatization series reaction were developed and a new type of topoisomerase inhibitor was found. Study on the construction of novel spiral pyrazolone against tumor skeleton and its antitumor activity (1) asymmetric tandem reaction of organic small molecular catalysis construction of novel spiral pyrazolone and its antitumor activity relationship study on phenotypic screening in drug discovery. Compared with drug screening based on target, phenotypic screening can be direct. The high quality small molecule compound library is the material basis for phenotypic screening, combining the high quality small molecule library with the phenotypic screening in order to discover new drug precursors and clarify its mechanism, which has broad prospects for development. In order to construct high quality small fraction, By integrating the dominant skeleton of the drug molecules with the series of divergent organic catalysis, the asymmetric series reaction strategy of divergent organic catalysis (DOCA) was developed. The framework of the stereostructural diversity was synthesized by a simple and easy chiral pyrazole four pyran semi acetal. A new novel spironazolone antitumor skeleton was successfully found. Based on this, the new type of new spironazolone with different stereotyping was designed and synthesized. A high active antitumor compound was found. (two) a new type of pyrazole was constructed by the series reaction of organic small molecules. The skeleton of ketone cyclohexadienone and its antitumor activity study the anti-tumor skeleton of a new pyrazolone cyclohexadienone by simple and easy chiral pyrazole four thiopria acetal. The scope of the substrate was determined by the scope of application of the substrate. A preliminary anti swelling in vitro was selected to select the target product. The tumor activity test, in which compound 5S shows the best antitumor activity in vitro, can be used to develop new antitumor drugs, and has the value of deep research. Two, the asymmetric Michael addition reaction of small organic molecules catalyzes the asymmetric addition of isorodenning to alpha and beta unsaturated aldehydes to construct asymmetric reaction of organic small molecules catalyzed by chiral modules in drug molecules. It should be widely used in organic synthesis, it can be environmentally friendly and fast and efficient synthesis of bioactive molecules and natural products, especially asymmetric Michael addition can effectively construct a stereoselective C-C bond. In recent years, the asymmetric Michael reaction catalyzed by organic small molecules should cause extensive interest of chemists and a large number of compounds. The method has been developed. The isrodenning framework has a wide range of biological activities. However, the asymmetric synthesis of isorodenin by organic catalysis is rare. In order to construct the P DOS library efficiently, the series of divergent organic molecules catalyzed series reaction (DOCA) was developed, and the simple and easy thiazolidane two ketone and its analogues were used. A series of diversity molecular skeletons were obtained with alpha, beta unsaturated aldehydes, in which different Luo Danning cytoskeleton cytoskeleton was synthesized by Michael- cyclization. Based on the above study, isosardenning could be transformed into enol Michael donor and conjugated with dienaldehyde through organic catalysis. In addition, a series of 4,5- biosuenin target products with high yield and excellent enantioselectivity (EE value 99%) were obtained. The product is a construction module for rapid synthesis of chiral isrodenannin. It has a good application prospect. The isosenannin has a variety of biological activity and the 4,5- biosubstituted isorodenning The research on the pharmacological activity of the target product will be helpful to the discovery of drug precursors. Three, the rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone skeleton and the discovery of pyrrole [1,2-b] isoquinolone based on the redox - aminoaromatization -Friedel-Crafts acylation reaction The skeleton is widely distributed in many natural products, but at present, the method of synthesizing the skeleton is very limited. Through literature research, we developed a new redox - aminoaromatization -Friedel-Crafts acylation series reaction and rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone framework. On the basis of the optimal reaction conditions, the substrate suitability was discussed. The results showed that the substrate was adaptable and the target product could be obtained by one step reaction. The highest yield was 96%. inhibition activity test and in vitro antitumor experimental study. Compound 3H was a double inhibitor of Top1 and Top2. Further research on antineoplastic precursor compounds is worth further research. Four, in summary, this study constructs 4 dominant skeletons through a variety of tandem reactions and designs and synthesizes 160 new compounds reported for the first time. Through Bioactivity Evaluation, 3 new structural types of antitumor precursor compounds have been found. This paper will synthesize methods and drugs. The combination of chemical discovery and anticancer precursor structure has laid the foundation for developing innovative anti-tumor drugs with independent intellectual property rights.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R914
，
本文編號：2119420
本文鏈接：http://www.lk138.cn/yixuelunwen/yiyaoxuelunwen/2119420.html
最近更新
教材專著
