五环三萜环磷酸酯缓释前药和2-吲哚基环戊烷并吲哚衍生物的设计、合成与活性研究
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摘要
一、五环三萜类天然产物在自然界中分布广泛，具有保肝抗炎、抗肿瘤、抗病毒、抗溃疡及抗过敏等多种药理活性，是当前药物研发的热点。但是五环三萜普遍存在体内代谢过快，半衰期过短的缺陷。对五环三萜进行结构改造以维持稳定的血药浓度、延长体内保留时间，是目前学界研究的重点课题之一。而环磷酸酯肝靶向基团有潜在的缓释活性，有制成缓释前药的可能。
本论文首次将五环三萜类化合物与环磷酸酯基团连接，设计并合成了一类新型五环三萜环磷酸酯缓释前药。首先以取代苯乙酮为起始原料，经酮酯缩合、还原、硅醚化、缩酮化及手性拆分、酸水解、磷酯化、酯交换等7步反应，得到了甘草次酸、齐墩果酸、熊果酸三类共39个立体专一的五环三萜环磷酸酯衍生物，均为未见文献报道的新化合物；并对关键的酯交换反应进行了研究，确定了最优的碱性试剂为N,N-二异丙基氨基锂，用量为5倍当量，建立了一种有效的合成方法。随后对P16R、P16S、P17R和P17S四个化合物进行了体外释药和体内缓释实验，结果显示前药能够在36h或更长时间内持续释放原药，延长甘草次酸的半衰期和体内保留时间，具有良好的缓释活性，具有进一步研究的价值和较高的成药潜力。
二、月橘碱是一种具有抗着床活性和抗肿瘤活性的双吲哚生物碱，其结构改造和药理活性研究是当前研究较多的课题。月橘碱的基本骨架2-吲哚基环戊烷并吲哚是抗肿瘤活性的必需结构，也是合成双吲哚生物碱类化合物的重要中间体，可以通过3-烯基吲哚的立体选择性环二聚反应合成。3-烯基吲哚环二聚反应是一种较新颖的[3+2]环加成反应，目前研究较少，可能成为立体专一的双吲哚生物碱的有效合成方法，具有较高的研究价值。
本论文以一系列不同取代基取代的3-烯基吲哚衍生物为原料，通过酸介导的立体选择性环二聚反应，设计并合成了11个含有2-吲哚基环戊烷并吲哚骨架的月橘碱类似物，除Y01外均为未见文献报道的新化合物；并通过测试酸试剂、取代基电性、空间位阻、时间、温度等因素对反应的影响，对3-烯基吲哚的立体选择性环二聚反应进行了深入研究，首先确定了TFA为最优的酸试剂，CH2Cl2为适合的反应溶剂，并确定了较优的反应条件，随后对反应的影响因素和机理进行了研究，提出了一种分步反应机理，为此类双吲哚生物碱的立体选择性合成提供了一种有效的合成策略；最后对部分化合物进行了体外抗肿瘤活性测试，初步结果显示，Y03、Y06和Y08三个化合物表现出较好的肿瘤细胞增殖抑制活性，具有进一步研究和改造的价值，目前正在进行更深入的活性测试。
1. Pentacyclic triterpenes, which have a wide distribution in nature, have variouspharmacological activities, such as hepatoprotective, anti-inflammatory, anti-tumor,anti-virus, anti-ulcer and anti-allergy activity. This kind of natural product is one of the drugresearch hotspots. However, the quick metabolism in vivo limits its clinical applicationas drugs. The structural modification of pentacyclic triterpenes is an effective methodto prolong the mean retention time (MRT) and maintain a stable blood concentration.1,3-cyclic propanyl phosphate ester, a liver-targeted group, has been found havingpotential sustained-release activity. This group may be an appropriate method to alterthe metabolism of pentacyclic triterpenes.
In this thesis, a new class of potential prodrugs,1,3-cyclic propanyl phosphateesters of pentacyclic triterpenes, has been designed and synthesized. First,39stereospecific derivatives of18β-glycyrrhetic acid (GA), oleanolic acid (OA) andursolic acid (UA) has been synthesized using substituted acetophenone as startingmaterial via condensation, reduction, trimethyl silylation, ketalization, chiralseparation, hydrolysis, esterification and transesterification. All synthesizedcompounds are new compounds and their structure have been confirmed by NMR,HRMS and polarimetry techniques. Meanwhile, the key step of synthesis,transesterification reaction, has been studied to establish an efficient synthetic method ofthis prodrug. Lithium diisopropylamide (LDA) has been found best alkaline catalystand the optimal ratio is5times of pentacyclic triterpene. has been established. Then,4compouds (P16R, P16S, P17R and P17S) have been chosen to investigate the drugrelease properties in vitro and the sustained-release properties in vivo. The resultsshow that the pentacyclic triterpenes can be released from the prodrugs at a steady rate in rats and the plasma concentrations of GA were nearly stable in36h or even longer.This result indicated that1,3-cyclic propanyl phosphate esters of pentacyclictriterpenes have good sustained-release properties to avoid the quick metabolism ofGA. This kind of prodrugs is highlighted as a hopeful new strategy to improvepentacyclic triterpenes metabolism.
2. Bisindole alkaloids form an important family of alkaloids and show importantbioactivities. Yuehchukene is a tetrahydrocyclopenta[b]indole-type bisindole alkaloidwith anti-implantation activity and antitumor activity. The total synthesis, structuralmodification and bioactivity study of this kind of alkaloids have become activeresearch topics. As the core skeleton of yuehchukene,3-indolyl cyclopent[b]indolewhich has potential antitumor activity is a useful bisindole intermediate in thesynthesis of a number of biologically active bisindole alkaloids.[3+2]cyclodimerization reaction is a noval [3+2] cycloaddition reaction, and graduallybecome an efficient method to synthesize many heterocyclic compounds. So thederivatives of3-indolyl cyclopent[b]indole may also be synthesized bycyclodimerization reaction of3-vinylindoles.
In this thesis, a new class of2-indolyl cyclopent[b]indoles was designed andsynthesized, and acid mediated cyclodimerization of3-vinylindoles to2-indolylcyclopent[b]indoles was investigated. First, the catalysts and conditions of reactionhave been tested. Trifluoroacetic acid (TFA) carries out to be the best acid reagent, CH2Cl2is an appropriate solvent, and the optimum reaction condition is confirmed. And11stereospecific derivatives of2-indolyl cyclopent[b]indole have been synthesized usingsubstituted3-vinylindoles as starting material via TFA mediated cyclodimerizationreaction. The reaction showed moderate to good yields and high stereoselectivity. Allsynthesized compounds are new compounds except Y01, and their structures havebeen confirmed by NMR, HRMS. Then, the electronic effect of substituent groups,steric hindrance, time, temperature and other influences has been investigated, and astepwise mechanism are given. This reaction provides an efficient synthetic strategy forthe stereoselective synthesis of this kind of bisindole alkaloids. Finally, the inhibition activity of3-indolyl cyclopent[b]indoles on the growth of HL-60cells has been testedand compound Y03, Y06and Y08show moderate activity. The derivates of2-indolylcyclopent[b]indoles is worth further research.
本论文首次将五环三萜类化合物与环磷酸酯基团连接，设计并合成了一类新型五环三萜环磷酸酯缓释前药。首先以取代苯乙酮为起始原料，经酮酯缩合、还原、硅醚化、缩酮化及手性拆分、酸水解、磷酯化、酯交换等7步反应，得到了甘草次酸、齐墩果酸、熊果酸三类共39个立体专一的五环三萜环磷酸酯衍生物，均为未见文献报道的新化合物；并对关键的酯交换反应进行了研究，确定了最优的碱性试剂为N,N-二异丙基氨基锂，用量为5倍当量，建立了一种有效的合成方法。随后对P16R、P16S、P17R和P17S四个化合物进行了体外释药和体内缓释实验，结果显示前药能够在36h或更长时间内持续释放原药，延长甘草次酸的半衰期和体内保留时间，具有良好的缓释活性，具有进一步研究的价值和较高的成药潜力。
二、月橘碱是一种具有抗着床活性和抗肿瘤活性的双吲哚生物碱，其结构改造和药理活性研究是当前研究较多的课题。月橘碱的基本骨架2-吲哚基环戊烷并吲哚是抗肿瘤活性的必需结构，也是合成双吲哚生物碱类化合物的重要中间体，可以通过3-烯基吲哚的立体选择性环二聚反应合成。3-烯基吲哚环二聚反应是一种较新颖的[3+2]环加成反应，目前研究较少，可能成为立体专一的双吲哚生物碱的有效合成方法，具有较高的研究价值。
本论文以一系列不同取代基取代的3-烯基吲哚衍生物为原料，通过酸介导的立体选择性环二聚反应，设计并合成了11个含有2-吲哚基环戊烷并吲哚骨架的月橘碱类似物，除Y01外均为未见文献报道的新化合物；并通过测试酸试剂、取代基电性、空间位阻、时间、温度等因素对反应的影响，对3-烯基吲哚的立体选择性环二聚反应进行了深入研究，首先确定了TFA为最优的酸试剂，CH2Cl2为适合的反应溶剂，并确定了较优的反应条件，随后对反应的影响因素和机理进行了研究，提出了一种分步反应机理，为此类双吲哚生物碱的立体选择性合成提供了一种有效的合成策略；最后对部分化合物进行了体外抗肿瘤活性测试，初步结果显示，Y03、Y06和Y08三个化合物表现出较好的肿瘤细胞增殖抑制活性，具有进一步研究和改造的价值，目前正在进行更深入的活性测试。
1. Pentacyclic triterpenes, which have a wide distribution in nature, have variouspharmacological activities, such as hepatoprotective, anti-inflammatory, anti-tumor,anti-virus, anti-ulcer and anti-allergy activity. This kind of natural product is one of the drugresearch hotspots. However, the quick metabolism in vivo limits its clinical applicationas drugs. The structural modification of pentacyclic triterpenes is an effective methodto prolong the mean retention time (MRT) and maintain a stable blood concentration.1,3-cyclic propanyl phosphate ester, a liver-targeted group, has been found havingpotential sustained-release activity. This group may be an appropriate method to alterthe metabolism of pentacyclic triterpenes.
In this thesis, a new class of potential prodrugs,1,3-cyclic propanyl phosphateesters of pentacyclic triterpenes, has been designed and synthesized. First,39stereospecific derivatives of18β-glycyrrhetic acid (GA), oleanolic acid (OA) andursolic acid (UA) has been synthesized using substituted acetophenone as startingmaterial via condensation, reduction, trimethyl silylation, ketalization, chiralseparation, hydrolysis, esterification and transesterification. All synthesizedcompounds are new compounds and their structure have been confirmed by NMR,HRMS and polarimetry techniques. Meanwhile, the key step of synthesis,transesterification reaction, has been studied to establish an efficient synthetic method ofthis prodrug. Lithium diisopropylamide (LDA) has been found best alkaline catalystand the optimal ratio is5times of pentacyclic triterpene. has been established. Then,4compouds (P16R, P16S, P17R and P17S) have been chosen to investigate the drugrelease properties in vitro and the sustained-release properties in vivo. The resultsshow that the pentacyclic triterpenes can be released from the prodrugs at a steady rate in rats and the plasma concentrations of GA were nearly stable in36h or even longer.This result indicated that1,3-cyclic propanyl phosphate esters of pentacyclictriterpenes have good sustained-release properties to avoid the quick metabolism ofGA. This kind of prodrugs is highlighted as a hopeful new strategy to improvepentacyclic triterpenes metabolism.
2. Bisindole alkaloids form an important family of alkaloids and show importantbioactivities. Yuehchukene is a tetrahydrocyclopenta[b]indole-type bisindole alkaloidwith anti-implantation activity and antitumor activity. The total synthesis, structuralmodification and bioactivity study of this kind of alkaloids have become activeresearch topics. As the core skeleton of yuehchukene,3-indolyl cyclopent[b]indolewhich has potential antitumor activity is a useful bisindole intermediate in thesynthesis of a number of biologically active bisindole alkaloids.[3+2]cyclodimerization reaction is a noval [3+2] cycloaddition reaction, and graduallybecome an efficient method to synthesize many heterocyclic compounds. So thederivatives of3-indolyl cyclopent[b]indole may also be synthesized bycyclodimerization reaction of3-vinylindoles.
In this thesis, a new class of2-indolyl cyclopent[b]indoles was designed andsynthesized, and acid mediated cyclodimerization of3-vinylindoles to2-indolylcyclopent[b]indoles was investigated. First, the catalysts and conditions of reactionhave been tested. Trifluoroacetic acid (TFA) carries out to be the best acid reagent, CH2Cl2is an appropriate solvent, and the optimum reaction condition is confirmed. And11stereospecific derivatives of2-indolyl cyclopent[b]indole have been synthesized usingsubstituted3-vinylindoles as starting material via TFA mediated cyclodimerizationreaction. The reaction showed moderate to good yields and high stereoselectivity. Allsynthesized compounds are new compounds except Y01, and their structures havebeen confirmed by NMR, HRMS. Then, the electronic effect of substituent groups,steric hindrance, time, temperature and other influences has been investigated, and astepwise mechanism are given. This reaction provides an efficient synthetic strategy forthe stereoselective synthesis of this kind of bisindole alkaloids. Finally, the inhibition activity of3-indolyl cyclopent[b]indoles on the growth of HL-60cells has been testedand compound Y03, Y06and Y08show moderate activity. The derivates of2-indolylcyclopent[b]indoles is worth further research.
引文
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