天然β-咔啉衍生物合成及其活性研究
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摘要
恶性肿瘤（癌）为细胞性病变，它是严重危害人民生命健康的常见病。拓扑
异构酶抑制剂是一类重要的抗肿瘤药物。近年来，作为拓扑异构酶抑制剂的嵌入
剂是一个研究热点。嵌入剂是由平面多芳环体系，以及连接于母核的碱性边链组
成的化合物，母核的平面结构可以嵌入DNA 碱基对之间，而碱性边链在亲和力
和选择性方面起着重要作用。γ-咔啉衍生物是目前研究中的、从天然抗肿瘤活
性物质—鱼藤碱的结构简化而得的嵌入剂。而一些β-咔啉结构天然产物可与拓
扑异构酶结合，但它们并没有稳定DNA-嵌入剂-拓扑异构酶Ⅱ三元复合物的能
力，可能与它们缺少碱性侧链相关。因而，我们设计、改造了一系列天然β-咔
啉衍生物，组成具有碱性边链取代的衍生物。
本文化学合成工作中：
1. 以吡啶为原料，经过氧化、硝化、重排、氨基化合物取代等八步反应，
合成了1-（3-二甲氨丙基）氨基-γ-咔啉衍生物, 对一些合成条件进行了改进。
2. 以丙二酸二乙酯和丙烯氰为原料，经缩合、Raney Ni催化氢化、重排、
DDQ 氧化、氨基化合物取代等八步反应，合成了两个取代的1-氨基-β-咔啉衍
生物。
3. 以1，3-溴氯丙烷和丙二酸酯为起始原料，经Japp-Klingemann反应和
Fischer吲哚重排等反应制备了色胺，它分别与甲醛、乙醛、呋喃甲醛、5-乙酰氧
甲基呋喃甲醛进行Pictet-spengler环合反应合成四氢-β-咔啉，再经过N-酰化保
护、DDQ 氧化、无水肼肼解，合成了四个系列的1-取代-4-氨基-β-咔啉，并进
行了一系列的衍生物合成。总共合成了17个4-氨基-β-咔啉系列化合物，9个
1-甲基-4-氨基-β-咔啉系列化合物，4个1-（呋喃-2-基）-4-氨基-β-咔啉系列化
合物，2个1-（5-羟甲基呋喃-2-基）-4-氨基-β-咔啉系列化合物。
4. 根据逆合成分析，设计了一条国内外未见报道的1，3-二甲基-4-氨基-β
-咔啉衍生物的路线。以硝基甲烷与乙醛经缩合、氧化制备硝基丙酮；邻甲苯胺
通过重氮化反应、氧化、水解制备邻溴苯甲醛。把它们作为原料经Hantzsch反
应、氧化、还原、酰化、分子内Goldberg反应，环合得1,3-二甲基-4-乙酰氨基-β-
咔啉，再用浓盐酸处理得1，3-二甲基-4-氨基-β-咔啉。总共合成了七个1，3-
二甲基-4-氨基-β-咔啉衍生物。
5. 设计了一条以吲哚为原料，经Mannish反应等六步反应合成了4-甲基-β
-咔啉-1，3-二羧酸二甲酯的反应路线，并将其转化为带有类似上述边链的酰胺化
合物。
7
复旦大学博士论文
本文共合成各种类型的目标化
Malignant tumor (cancer) is the pathological changes. It causes serious harm to
the health of the human being. The inhibitors of topoisomerase Ⅱplay an important
role in the treatment of cancer. Recently, many studies are focusing on intercalators as
a potent inhibitors of topoisomerase Ⅱ.
Intercalating agents share a common planar polyaromatic system. These agents
bind to DNA base pairs by insertion. The chromophores are linked to basic chains that
might also play an important role in the affinity and selectivity of their action.
γ-carboline derivatives are recently subjects to many investigations. They
represent a class of anticancer drugs that are related to the natural product ellipticine
by deletion of an aromatic ring. β-carboline structures are present in many naturals
products. These compounds effect on DNA topoisomerases, but they don.t stabilize
the cleavable complex mediated by topoisomerase. This is might be due to the lack of
the basic side chains in this class of compounds. For this reason, we designed and
synthesized a series of β-carbolines compounds bearing a basic side chain .
Our chemical work consisted in the following routes:
1-(3-dimethylaminopropyl)amino-γ-carboline was obtained by using pyridine
as starting material via an eight-step sequence, such as oxidation, nitration,
rearrangement and amino-substitution.
According to the reported methods, two derivatives of 1-amino-β-carboline
were synthesized, using acrylonitrile and diethyl malonate as starting materials
through an eight-step sequence, such as condensation, Raney Ni catalyst,
rearrangement and DDQ oxidation.
Tryptamine was synthesized by using 1-bromo-3-chloropropane and diethyl
malonate as starting materials, via Japp-Klingemann reaction and Fischer indole
rearrangement. The obtained tryptamine was condensed with aldehydes
(formaldehyde, acetaldehyde, furfural, 5-(hydroxymethyl) furfural) to give tetrahydro-
β-carboline. Protecting amine to amide, DDQ oxidation, then treated with hydrazine
gave four series of 1-substituted 4-amino-β-carboline. In total, 17 derivatives of
4-amino-β-carbolines, 9 derivatives of 4-amino-1-methyl-β-carbolines, 4
derivatives of 4-amino-1-furanyl-β-carbolines and 2 derivatives of 4-amino-1-
(5-hydroxymethylfuranyl)-β-carbolines were synthesized.
9
复旦大学博士论文
A synthetic route of 4-amin
异构酶抑制剂是一类重要的抗肿瘤药物。近年来，作为拓扑异构酶抑制剂的嵌入
剂是一个研究热点。嵌入剂是由平面多芳环体系，以及连接于母核的碱性边链组
成的化合物，母核的平面结构可以嵌入DNA 碱基对之间，而碱性边链在亲和力
和选择性方面起着重要作用。γ-咔啉衍生物是目前研究中的、从天然抗肿瘤活
性物质—鱼藤碱的结构简化而得的嵌入剂。而一些β-咔啉结构天然产物可与拓
扑异构酶结合，但它们并没有稳定DNA-嵌入剂-拓扑异构酶Ⅱ三元复合物的能
力，可能与它们缺少碱性侧链相关。因而，我们设计、改造了一系列天然β-咔
啉衍生物，组成具有碱性边链取代的衍生物。
本文化学合成工作中：
1. 以吡啶为原料，经过氧化、硝化、重排、氨基化合物取代等八步反应，
合成了1-（3-二甲氨丙基）氨基-γ-咔啉衍生物, 对一些合成条件进行了改进。
2. 以丙二酸二乙酯和丙烯氰为原料，经缩合、Raney Ni催化氢化、重排、
DDQ 氧化、氨基化合物取代等八步反应，合成了两个取代的1-氨基-β-咔啉衍
生物。
3. 以1，3-溴氯丙烷和丙二酸酯为起始原料，经Japp-Klingemann反应和
Fischer吲哚重排等反应制备了色胺，它分别与甲醛、乙醛、呋喃甲醛、5-乙酰氧
甲基呋喃甲醛进行Pictet-spengler环合反应合成四氢-β-咔啉，再经过N-酰化保
护、DDQ 氧化、无水肼肼解，合成了四个系列的1-取代-4-氨基-β-咔啉，并进
行了一系列的衍生物合成。总共合成了17个4-氨基-β-咔啉系列化合物，9个
1-甲基-4-氨基-β-咔啉系列化合物，4个1-（呋喃-2-基）-4-氨基-β-咔啉系列化
合物，2个1-（5-羟甲基呋喃-2-基）-4-氨基-β-咔啉系列化合物。
4. 根据逆合成分析，设计了一条国内外未见报道的1，3-二甲基-4-氨基-β
-咔啉衍生物的路线。以硝基甲烷与乙醛经缩合、氧化制备硝基丙酮；邻甲苯胺
通过重氮化反应、氧化、水解制备邻溴苯甲醛。把它们作为原料经Hantzsch反
应、氧化、还原、酰化、分子内Goldberg反应，环合得1,3-二甲基-4-乙酰氨基-β-
咔啉，再用浓盐酸处理得1，3-二甲基-4-氨基-β-咔啉。总共合成了七个1，3-
二甲基-4-氨基-β-咔啉衍生物。
5. 设计了一条以吲哚为原料，经Mannish反应等六步反应合成了4-甲基-β
-咔啉-1，3-二羧酸二甲酯的反应路线，并将其转化为带有类似上述边链的酰胺化
合物。
7
复旦大学博士论文
本文共合成各种类型的目标化
Malignant tumor (cancer) is the pathological changes. It causes serious harm to
the health of the human being. The inhibitors of topoisomerase Ⅱplay an important
role in the treatment of cancer. Recently, many studies are focusing on intercalators as
a potent inhibitors of topoisomerase Ⅱ.
Intercalating agents share a common planar polyaromatic system. These agents
bind to DNA base pairs by insertion. The chromophores are linked to basic chains that
might also play an important role in the affinity and selectivity of their action.
γ-carboline derivatives are recently subjects to many investigations. They
represent a class of anticancer drugs that are related to the natural product ellipticine
by deletion of an aromatic ring. β-carboline structures are present in many naturals
products. These compounds effect on DNA topoisomerases, but they don.t stabilize
the cleavable complex mediated by topoisomerase. This is might be due to the lack of
the basic side chains in this class of compounds. For this reason, we designed and
synthesized a series of β-carbolines compounds bearing a basic side chain .
Our chemical work consisted in the following routes:
1-(3-dimethylaminopropyl)amino-γ-carboline was obtained by using pyridine
as starting material via an eight-step sequence, such as oxidation, nitration,
rearrangement and amino-substitution.
According to the reported methods, two derivatives of 1-amino-β-carboline
were synthesized, using acrylonitrile and diethyl malonate as starting materials
through an eight-step sequence, such as condensation, Raney Ni catalyst,
rearrangement and DDQ oxidation.
Tryptamine was synthesized by using 1-bromo-3-chloropropane and diethyl
malonate as starting materials, via Japp-Klingemann reaction and Fischer indole
rearrangement. The obtained tryptamine was condensed with aldehydes
(formaldehyde, acetaldehyde, furfural, 5-(hydroxymethyl) furfural) to give tetrahydro-
β-carboline. Protecting amine to amide, DDQ oxidation, then treated with hydrazine
gave four series of 1-substituted 4-amino-β-carboline. In total, 17 derivatives of
4-amino-β-carbolines, 9 derivatives of 4-amino-1-methyl-β-carbolines, 4
derivatives of 4-amino-1-furanyl-β-carbolines and 2 derivatives of 4-amino-1-
(5-hydroxymethylfuranyl)-β-carbolines were synthesized.
9
复旦大学博士论文
A synthetic route of 4-amin
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97
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