含有糖基片段的DNA双插入剂和氨基糖有机锡羧酸酯的合成及活性研究
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摘要
本论文共分为三部分，分别为含有糖基片段的DNA双插入剂的合成和DNA结合活性研究，氨基糖有机锡羧酸酯的合成及抗肿瘤活性、造血干细胞毒性研究，糖修饰姜黄素类似物的设计合成。
DNA是生物体遗传信息的载体，是大多数抗癌、抗病毒试剂在体内的主要作用靶点。小分子物质与DNA通过分子识别、结合、修饰、剪切等方式发生作用，研究小分子物质与DNA的相互作用不仅对阐明抗肿瘤、抗病毒及致癌物的作用机理，而且对进一步设计合成以DNA为作用靶点的药物具有重要意义。
嵌插结合是小分子与DNA相互作用的重要形式之一。近年来合成的多种DNA双重嵌插试剂由于具有良好的DNA结合能力和一定的序列选择性引起了药学家的关注。单糖由于构型单一且含有丰富的官能团和反应位点，长久以来被用作生物活性物质的结构骨架。很多以DNA为作用靶点的抗生素和抗肿瘤药物均含有糖基片段，如蒽环类抗生素(Anthracyclines)，烯二炔类抗肿瘤抗生素(Enediyne antibiotics)等等。近年来，研究发现这些药物分子中的糖片段对DNA的识别及选择位点起着非常重要的作用。
由此做为出发点，本论文分别合成了含有D-吡喃葡萄糖、2-脱氧-2-氨基D-葡萄糖和D-吡喃葡萄糖醛酸等糖基片段的结构骨架，以喹啉、喹喔啉、吖啶、吲哚[3，2-b]喹啉类等含氮芳香环作为嵌插部分，合成了三个系列的DNA双重嵌插试剂。第一类为葡萄糖6位羟基与8-OH喹啉相连，一位分别以对苯二酚，乙二醇和三聚乙二醇等不同连接臂相连的化合物；第二类为2-氨基葡萄糖一位分别与不同的含氮芳香环如8-OH喹啉、9-羟乙基吖啶和吲哚[3，2-b]喹啉环相连，2位氨基与对苯二甲酰氯发生缩合反应的化合物；第三类是结构类似于棘霉素(Echinomycin)含有糖醛酸骨架的大环化合物，环上连有喹喔啉基团。所合成的化合物用核磁共振(~1H NMR，~(13)C NMR)、质谱(MS，HR-MS)进行了结构确认。并用紫外可见光谱法、荧光发射光谱和EB竞争结合DNA等手段，研究了化合物与小牛胸腺DNA(CT-DNA)的结合活性。研究结果表明部分化合物能够以嵌插的形式与DNA进行结合。
应用拼合原理，将对肿瘤细胞具有较好的杀伤作用，而对人体正常细胞毒性很小的D-氨基葡萄糖衍生物与氧化二正丁基锡反应合成了两个新的有机锡(Ⅳ)羧酸酯类化合物双-[顺-N-1，3，4，6-四-O-苯甲酰基-2-去氧吡喃葡萄糖基丁烯二酸单酰胺]-二正丁基锡酯(35b)和双-[顺-N-1，3，4，6-四-O-苯甲酰基-2-去氧吡喃葡萄糖基邻苯二甲酸单酰胺]-二正丁基锡酯(36b)，并经红外光谱(IR)，核磁共振(~1H NMR，~(13)C NMR)谱学研究，初步确定了其结构。体外抗肿瘤活性结果表明，化合物35b、36b对肿瘤细胞株小鼠白血病细胞株P388、人白血病细胞株HL-60、人肺癌细胞株A-549和人肝癌细胞株BEL-7402均显示出较强的细胞毒活性，其中化合物对P388和HL-60的IC_(50)值为0．06μM；克隆基因分析表明化合物有造血细胞毒性浓度为2．06μM。表明化合物35b、36b具有较高的肿瘤细胞毒性和较低的造血细胞毒性，是有开发前途的先导化合物。
姜黄素类化合物由于其广谱的抗癌活性、疗效确切和低毒性，备受人们的关注。由于该类化合物具有稳定性差，生物利用度低等缺点，限制了其成为药物的可能性。糖对先导化合物进行活性修饰后，可以降低化合物毒副作用，增加化合物的脂溶性和水溶性，增强靶向性。目前对姜黄素类化合物的糖修饰研究相对较少。本章研究并建立了一条简便可行的反应路线，以此来合成对姜黄素4位活泼亚甲基进行糖修饰的化合物。同时设计合成了一系列苯环以不同的取代基进行取代，姜黄素4位亚甲基上进行葡萄糖修饰的化合物，希望开发出稳定性好，药物安全性高，同时能增加抗肿瘤活性和水溶性的姜黄素类似物。所得到的8个化合物(39a-39h)用核磁共振(~1H NMR，~(13)C NMR)、质谱(MS，HR-MS)进行了结构确认。生物活性测试正在进行中。
This dissertation was divided into three parts,the first part is study on thesynthesis of DNA intercalators containing sugar skelecton and their DNA bindingproperties;the second part is the synthesis of novel dibutyltin carboxylates ofaminoglucosyl derivatives and their anti-tumor activity and myelotoxicity study;thethird part is the design and synthesis of curcumin derivatives containing sugarhybrids.
DNA is the carrier of genetic information and plays an important role in thecourse of genetic,which is the main target molecule that exists in anticancer andantiviral therapies.Small molecules that interact with DNA through recognition,binding,modification and cleavage have attracted great interests in the healthcarefield.
Intercalators are the most important group of compounds that interact reversiblywith the DNA double helix.In recent years,synthese of various bisintercalators hasbeen popularly studied for their higher DNA-binding capacity and substantialsequence selectivity.Monosaccharides have long been known as biologically relevantscaffolds.Advantages of using saccharides are that they display a high density offunctional groups,are available as single enantiomers and contain multiple sites forattachment of recognition groups.Carbohydrate also exists in many antitumorantibiotics which targeting in DNA helix,including Anthracyclines family andEnediyne antibiotics.And it has been found that the carbohydrate part in thesemoleculars play a crucial role in the DNA recognition and sequence selectivity.
According to this,we design and synthesis three series of DNA bisintercalators containing D-glucose,2-deoxy-2-amino-D-glucose and D-glucopyranuronic acidscatffold.For the chromophore part,we choose quinoline,quinoxaline,acridine andindol[3,2-b]quinoline ring as the intercalating agents.In the first series of compounds,8-hydroxy-quinoline is linked to the 6-CH_2OH group of glucose and the 1-OH groupof glucose was connected with different linkers including quinol,glycol andtriethylene glycol.The second series of the intercalators is based on the 2-aminoglucose which the amino group is coupled with terephthaloyl chloride and the 1-OHof the sugar is connected with different chromophores including 8-OH quinoline,9-hydroxyethyl acridine and indol[3,2-b]quinolin.The third part is the analogues ofEchinomycin based on D-glucopyranuronic acid which contains the macrocycles andquinoxaline group.All the synthesized compounds are characterized by ~1H NMR,~(13)CNMR,MS and HR-MS.Also their interactions with calf thymus DNA (CT-DNA)were also investigated with UV-absorption,fluorescence spectroscopy and EBdisplacement analysis.The primary results suggest that the binding mode betweensome compounds and calf thymus DNA might be intercalation.
D-amino glucose(2-amino-2-deoxy-D-glucose) is one of the most importantmonosaccharides in the glycosylprotein of higher animals and present in almost alltissues of human body.One of its interesting biological properties is that itsderivatives such as chitosan and glucosamine derivatives could kill the tumor cellswhile being less toxic to normal cells in human body.To take the advantage of thepositive biological properties of organotin (Ⅳ) compounds and D-amino glucose,wedesigned two dibutyltin complexes of aminoglucosyl derivative compoundsbis-{cis-4-[N-(1′,3′,4′,6′-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido]-4-oxo-2-butenoic acid]-di-n-butyltin} carboxylate (35b) and bis-{o-[N-(1′,3′,4′,6′-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl]benzoic acid]-di-n-butyltin}carboxylate(36b).These two compounds were then characterized by IR,NMR and MS.In vitrotests showed that both compounds have high cytotoxicity to four tumor cell lines(P388,HL-60,A549 and BEL-7402) while compound (36b) is more efficient to P388and HL-60 (IC_(50)=0.06μM).Clonogenic assays demonstrated that both compounds (35b) and (36b) have hematopoietic cell toxicity at 2.06μM.This indicates thatcompound 36b could be a potential leading compound for antitumor drugs.
Curcumin has attracted considerable attention due to its wide range of anticancerproperties,definitely curative effect and low toxicity.But poor water and plasmasolubility and easy decompose in water Caused by curcumin structure extremelylimited the use of curcumin.It has been found that whcn modified by carbohydrates,the lead compounds show lower toxicity and side effects,improved bioavailability.According to this,a series of carbohydrate modified compounds based on curcuminskelecton were designed and synthesized.And 4-methylene of the curcumin wassubstituted by 1-O-bromoethoxy glucose and the function groups in the two benzenerings are various.We postulated that the glycosylecurcuminoids derivatives mayincrease their stability,antitumor activity and water solubility.All the eightcompounds are novel and the structures are confirmed by ~1H NMR,~(13)C NMR,ESI-MS and HR-MS.The screening of their bioactivities is underway.
DNA是生物体遗传信息的载体，是大多数抗癌、抗病毒试剂在体内的主要作用靶点。小分子物质与DNA通过分子识别、结合、修饰、剪切等方式发生作用，研究小分子物质与DNA的相互作用不仅对阐明抗肿瘤、抗病毒及致癌物的作用机理，而且对进一步设计合成以DNA为作用靶点的药物具有重要意义。
嵌插结合是小分子与DNA相互作用的重要形式之一。近年来合成的多种DNA双重嵌插试剂由于具有良好的DNA结合能力和一定的序列选择性引起了药学家的关注。单糖由于构型单一且含有丰富的官能团和反应位点，长久以来被用作生物活性物质的结构骨架。很多以DNA为作用靶点的抗生素和抗肿瘤药物均含有糖基片段，如蒽环类抗生素(Anthracyclines)，烯二炔类抗肿瘤抗生素(Enediyne antibiotics)等等。近年来，研究发现这些药物分子中的糖片段对DNA的识别及选择位点起着非常重要的作用。
由此做为出发点，本论文分别合成了含有D-吡喃葡萄糖、2-脱氧-2-氨基D-葡萄糖和D-吡喃葡萄糖醛酸等糖基片段的结构骨架，以喹啉、喹喔啉、吖啶、吲哚[3，2-b]喹啉类等含氮芳香环作为嵌插部分，合成了三个系列的DNA双重嵌插试剂。第一类为葡萄糖6位羟基与8-OH喹啉相连，一位分别以对苯二酚，乙二醇和三聚乙二醇等不同连接臂相连的化合物；第二类为2-氨基葡萄糖一位分别与不同的含氮芳香环如8-OH喹啉、9-羟乙基吖啶和吲哚[3，2-b]喹啉环相连，2位氨基与对苯二甲酰氯发生缩合反应的化合物；第三类是结构类似于棘霉素(Echinomycin)含有糖醛酸骨架的大环化合物，环上连有喹喔啉基团。所合成的化合物用核磁共振(~1H NMR，~(13)C NMR)、质谱(MS，HR-MS)进行了结构确认。并用紫外可见光谱法、荧光发射光谱和EB竞争结合DNA等手段，研究了化合物与小牛胸腺DNA(CT-DNA)的结合活性。研究结果表明部分化合物能够以嵌插的形式与DNA进行结合。
应用拼合原理，将对肿瘤细胞具有较好的杀伤作用，而对人体正常细胞毒性很小的D-氨基葡萄糖衍生物与氧化二正丁基锡反应合成了两个新的有机锡(Ⅳ)羧酸酯类化合物双-[顺-N-1，3，4，6-四-O-苯甲酰基-2-去氧吡喃葡萄糖基丁烯二酸单酰胺]-二正丁基锡酯(35b)和双-[顺-N-1，3，4，6-四-O-苯甲酰基-2-去氧吡喃葡萄糖基邻苯二甲酸单酰胺]-二正丁基锡酯(36b)，并经红外光谱(IR)，核磁共振(~1H NMR，~(13)C NMR)谱学研究，初步确定了其结构。体外抗肿瘤活性结果表明，化合物35b、36b对肿瘤细胞株小鼠白血病细胞株P388、人白血病细胞株HL-60、人肺癌细胞株A-549和人肝癌细胞株BEL-7402均显示出较强的细胞毒活性，其中化合物对P388和HL-60的IC_(50)值为0．06μM；克隆基因分析表明化合物有造血细胞毒性浓度为2．06μM。表明化合物35b、36b具有较高的肿瘤细胞毒性和较低的造血细胞毒性，是有开发前途的先导化合物。
姜黄素类化合物由于其广谱的抗癌活性、疗效确切和低毒性，备受人们的关注。由于该类化合物具有稳定性差，生物利用度低等缺点，限制了其成为药物的可能性。糖对先导化合物进行活性修饰后，可以降低化合物毒副作用，增加化合物的脂溶性和水溶性，增强靶向性。目前对姜黄素类化合物的糖修饰研究相对较少。本章研究并建立了一条简便可行的反应路线，以此来合成对姜黄素4位活泼亚甲基进行糖修饰的化合物。同时设计合成了一系列苯环以不同的取代基进行取代，姜黄素4位亚甲基上进行葡萄糖修饰的化合物，希望开发出稳定性好，药物安全性高，同时能增加抗肿瘤活性和水溶性的姜黄素类似物。所得到的8个化合物(39a-39h)用核磁共振(~1H NMR，~(13)C NMR)、质谱(MS，HR-MS)进行了结构确认。生物活性测试正在进行中。
This dissertation was divided into three parts,the first part is study on thesynthesis of DNA intercalators containing sugar skelecton and their DNA bindingproperties;the second part is the synthesis of novel dibutyltin carboxylates ofaminoglucosyl derivatives and their anti-tumor activity and myelotoxicity study;thethird part is the design and synthesis of curcumin derivatives containing sugarhybrids.
DNA is the carrier of genetic information and plays an important role in thecourse of genetic,which is the main target molecule that exists in anticancer andantiviral therapies.Small molecules that interact with DNA through recognition,binding,modification and cleavage have attracted great interests in the healthcarefield.
Intercalators are the most important group of compounds that interact reversiblywith the DNA double helix.In recent years,synthese of various bisintercalators hasbeen popularly studied for their higher DNA-binding capacity and substantialsequence selectivity.Monosaccharides have long been known as biologically relevantscaffolds.Advantages of using saccharides are that they display a high density offunctional groups,are available as single enantiomers and contain multiple sites forattachment of recognition groups.Carbohydrate also exists in many antitumorantibiotics which targeting in DNA helix,including Anthracyclines family andEnediyne antibiotics.And it has been found that the carbohydrate part in thesemoleculars play a crucial role in the DNA recognition and sequence selectivity.
According to this,we design and synthesis three series of DNA bisintercalators containing D-glucose,2-deoxy-2-amino-D-glucose and D-glucopyranuronic acidscatffold.For the chromophore part,we choose quinoline,quinoxaline,acridine andindol[3,2-b]quinoline ring as the intercalating agents.In the first series of compounds,8-hydroxy-quinoline is linked to the 6-CH_2OH group of glucose and the 1-OH groupof glucose was connected with different linkers including quinol,glycol andtriethylene glycol.The second series of the intercalators is based on the 2-aminoglucose which the amino group is coupled with terephthaloyl chloride and the 1-OHof the sugar is connected with different chromophores including 8-OH quinoline,9-hydroxyethyl acridine and indol[3,2-b]quinolin.The third part is the analogues ofEchinomycin based on D-glucopyranuronic acid which contains the macrocycles andquinoxaline group.All the synthesized compounds are characterized by ~1H NMR,~(13)CNMR,MS and HR-MS.Also their interactions with calf thymus DNA (CT-DNA)were also investigated with UV-absorption,fluorescence spectroscopy and EBdisplacement analysis.The primary results suggest that the binding mode betweensome compounds and calf thymus DNA might be intercalation.
D-amino glucose(2-amino-2-deoxy-D-glucose) is one of the most importantmonosaccharides in the glycosylprotein of higher animals and present in almost alltissues of human body.One of its interesting biological properties is that itsderivatives such as chitosan and glucosamine derivatives could kill the tumor cellswhile being less toxic to normal cells in human body.To take the advantage of thepositive biological properties of organotin (Ⅳ) compounds and D-amino glucose,wedesigned two dibutyltin complexes of aminoglucosyl derivative compoundsbis-{cis-4-[N-(1′,3′,4′,6′-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido]-4-oxo-2-butenoic acid]-di-n-butyltin} carboxylate (35b) and bis-{o-[N-(1′,3′,4′,6′-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl]benzoic acid]-di-n-butyltin}carboxylate(36b).These two compounds were then characterized by IR,NMR and MS.In vitrotests showed that both compounds have high cytotoxicity to four tumor cell lines(P388,HL-60,A549 and BEL-7402) while compound (36b) is more efficient to P388and HL-60 (IC_(50)=0.06μM).Clonogenic assays demonstrated that both compounds (35b) and (36b) have hematopoietic cell toxicity at 2.06μM.This indicates thatcompound 36b could be a potential leading compound for antitumor drugs.
Curcumin has attracted considerable attention due to its wide range of anticancerproperties,definitely curative effect and low toxicity.But poor water and plasmasolubility and easy decompose in water Caused by curcumin structure extremelylimited the use of curcumin.It has been found that whcn modified by carbohydrates,the lead compounds show lower toxicity and side effects,improved bioavailability.According to this,a series of carbohydrate modified compounds based on curcuminskelecton were designed and synthesized.And 4-methylene of the curcumin wassubstituted by 1-O-bromoethoxy glucose and the function groups in the two benzenerings are various.We postulated that the glycosylecurcuminoids derivatives mayincrease their stability,antitumor activity and water solubility.All the eightcompounds are novel and the structures are confirmed by ~1H NMR,~(13)C NMR,ESI-MS and HR-MS.The screening of their bioactivities is underway.
引文
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