四氢-β-咔啉衍生物的设计、合成及抗氧化性能研究

doi:10.6023/cjoc202301007

摘要/Abstract

四氢-β-咔啉类化合物(THBCs)是吲哚类生物碱的重要结构单元, 大多具有显著的抗炎、抗病毒、抗癌、抗菌及抗氧化等生物特性. 以3-(2-甲基氨基乙基)吲哚和醇为起始原料, 发展了一种钳形锰催化剂催化的氧化Pictet-Spengler反应. 该反应体系具有良好的底物适用性, 以芳香醇和脂肪醇为底物合成了12种THBCs产物, 收率为43%~99%. 并采用¹H NMR、¹³C NMR和HRMS等方法对产物的结构进行确认和表征. 同时通过清除ABTS^＋•和DPPH•实验研究了此类化合物的抗氧化能力. 结果表明, 在2个测试体系中, 12种化合物均具有一定的自由基清除能力, 说明这些化合物是一类潜在的抗氧化剂. 其中, 1-(4-氟苯基)-2-甲基-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3c)、2-甲基-1-(2-萘基)-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3e)、1-丁基-2-甲基-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3h)、(E)-2-甲基-1-(3-戊烯基)-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3j)、2-甲基-1-(2-吡啶-3-乙基)-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3l)清除ABTS^＋•效果最佳, 1-环己基-2-甲基-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3i)、2-甲基-1-(2-噻吩-2-乙基)-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3k)稍弱, 2-甲基-1-苯基-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3a)、2-甲基-1-(4-甲硫苯基)-2,3,4,9-四氢-1H-吡啶- [3,4-b]吲哚(3b)、1-(2-呋喃基)-2-甲基-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3d)、2-甲基-1-(3-吡啶基)-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3f)、2-甲基-1-(2-噻吩基)-2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚(3g)次之, IC₅₀可达0.073 mg•mL^－1及以上. 目标化合物清除DPPH•的能力以化合物3a、3c、3e、3h的效果最佳, 3d、3i、3j、3l次之, 3b、3f、3g效果最差. 综上, 化合物3c、3e、3h对ABTS^＋•和DPPH•均有较好的清除能力, 3b、3f、3g对2,2'-偶氮-双(3-乙基苯并噻唑啉-6-磺酸)二铵盐自由基(ABTS^＋•)以及2,2'-偶氮-双(3-乙基苯并噻唑啉-6-磺酸)二铵盐自由基(DPPH•)的清除能力均较差.

关键词: 四氢-β-咔啉, 锰催化剂, 醇, Pictet-Spengler反应, 抗氧化

Tetrahydro-β-carbolines (THBCs) are important structural units of indole alkaloids, most of which have significant biological properties, such as anti-inflammatory, antiviral, anticancer, antibacterial, and antioxidant properties. Herein, a Pictet-Spengler oxidation reaction with 3-(2-methylaminoethyl) indole and alcohols as starting materials was developed over the pincer manganese catalyst. The reaction system showed good substrate applicability, 12 kinds of THBC products were synthesized from aromatic alcohols and aliphatic alcohols with the yields of 43%~99%. The structures of the products were confirmed and characterized by ¹H NMR, ¹³C NMR, IR and HRMS. The antioxidant activity of these compounds were investigated by scavenging ABTS^＋• and DPPH•. The results showed that in the two test systems, all of those compounds had good free radical scavenging ability, indicating that those compounds are a class of potential antioxidant. Among them, 1-(4-fluoro- phenyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3c), 2-methyl-1-(naphthalen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido- [3,4-b]indole (3e), 2-methyl-1-propyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(3h), 2-methyl-1-propyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole (3j) and 2-methyl-1-(2-(pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3l) showed the best effect on scavenging ABTS^＋•, while 1-cyclohexyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3i) and 2-methyl- 1-(2-(thiophen-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3k) were slightly weaker, followed by 2-methyl-1-phe- nyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3a), 2-methyl-1-(4-(methylthio)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]- indole (3b), 1-(furan-2-yl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3d), 2-methyl-1-(pyridin-3-yl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole (3f) and 2-methyl-1-(thiophen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3g), and IC₅₀could reach 0.073 mg•mL^－1 or above. Among of the target compounds, 3a, 3c, 3e and 3h had the best effect on scavenging DPPH•, followed by 3d, 3i, 3j and 3l, and 3b, 3f and 3g had the worst effect. In conclusion, compounds 3c, 3e and 3h had good scavenging ability on ABTS^＋• and DPPH•, while compounds 3b, 3f and 3g had poor scavenging ability on 2,2'-azino- bis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS^＋•) and 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH•).

Key words: tetrahydro-β-carbolines, manganese catalysis, alcohols, Pictet-Spengler reaction, antioxidation

引用此文

张晓雨, 李欣燕, 崔冰, 邵志晖, 赵铭钦. 四氢-β-咔啉衍生物的设计、合成及抗氧化性能研究[J]. 有机化学, 2023, 43(8): 2885-2894.

Xiaoyu Zhang, Xinyan Li, Bing Cui, Zhihui Shao, Mingqin Zhao. Design, Synthesis and Antioxidant Activity of Tetrahydro-β-carbolines[J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2885-2894.

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图/表 9

图1. 含有四氢-β-咔啉(THBC)骨架的天然产物或药物分子

Figure 1. Examples of natural products or drugs containing the tetrahydro-β-carbolines (THBC) scaffold

图式1. Ru和Ni催化合成THBCs

Scheme 1. Synthesis of THBCs catalyzed by Ru and Ni catalysis

图2. 催化剂结构

Figure 2. Catalyst structure

表1. 不同反应条件对目标化合物3a合成产率的影响

Table 1. Effects of reaction conditions on the synthesis of the target compound 3a

表2. 锰催化3-(2-甲基氨基乙基)吲哚与不同醇的脱氢偶联合成四氢-β-咔啉化合物

Table 2. Manganese-catalyzed dehydrogenative coupling of 3-(2-methylaminiethyl) indole with various alcohols to synthesis THBCs

图式2. 锰催化3-(2-甲基氨基乙基)吲哚与醇脱氢偶联的可能反应机理

Scheme 2. Proposed reaction mechanism for dehydrogenative coupling of 3-(2-methylaminiethyl) indole with alcohol

图3. THBCs和Vc对ABTS＋?清除能力

Figure 3. ABTS＋? scavenging ability of of THBCs and Vc

Compound	Structure	IC₅₀/(mmol•mL^－1)
Compound	Structure	ABTS^＋•	DPPH•
3a		0.170	1.621
3b		0.192	>10
3c		0.114	1.115
3d		0.168	2.737
3e		0.115	1.115
3f		0.165	>10
3g		0.166	>10
3h		0.102	1.090
3i		0.137	8.581
3j		0.109	4.275
3k		0.126		9.476
3l		0.111		6.141
Vc		0.099		1.003

表3. 目标化合物的抗氧化活性

Table 3. Antioxidant activity of compounds

图4. 目标化合物和Vc对DPPH?清除能力

Figure 4. DPPH? scavenging ability of THBCs and Vc

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