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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5874_Библиотеки_им_академика_М_И_Перельмана
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Wang, J.; Gong, F.; Liang, T.; Xie, Z.; Yang, Y.; Cao, C.; Gao, J.; Lu, T.; Chen, X., A review
β- Carbolines
of synthetic bioactive tetrahydro- β- carbolines: A medicinal chemistry perspective.
European Journal of Medicinal Chemistry 2021,225, 113815.
WHO. World malaria report 2017. (2017, November 29). www.who.int/ teams/ glo bal- mala ria-
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WHO. World malaria report 2018. (2018, November 19). www.who.int/ teams/ glo bal- mala ria-
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WHO. World malaria report 2019. (2019, December 4). www.who.int/ teams/ glo bal- mala ria-
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WHO. World Malaria Report 2020. (2020, November 30). www.who.int/ teams/ glo bal- mala
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WHO. World malaria report 2021. (2021, December 6). www.who.int/ teams/ glo bal- mala ria-
progra mme/ repo rts/ world- mala ria- rep ort- 2021
Zhang, M.; Sun, D., Recent advances of natural and synthetic β- carbolines as anticancer agents.
Anti- Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal ChemistryAnti- Cancer Agents) 2015,15 (5), 537– 547.
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β- Carbolines
7
as Antioxidant
Synthesis and
Biological Study
Chetna Ameta, Monika Kumawat,
Dharmendra, and Mukesh Kumar
7.1 INTRODUCTION
The synthesis of organic molecules derived from renewable natural resources for
diverse applications, particularly in the elds of biology and pharmaceuticals, is a
burgeoning trend in contemporary synthetic chemistry. Over the past two decades,
an array of alkaloids has been extracted from natural sources, with their signicance
in biological and pharmaceutical domains under rigorous examination. Research has
unveiled that a wide spectrum of natural alkaloids are endowed with bioactivity, and
they have been harnessed in the treatment of various pathogenic ailments. One noteworthy class of these natural compounds is the β- carbolines, which have garnered
attention due to their potential antioxidant properties. These compounds can be
naturally found in a variety of plants, foods, and beverages and have been the subject of investigation regarding their potential health- enhancing attributes. A welldocumented member of the β- carboline family is harmine, present in plants such as
Peganum harmala (Syrian rue) and Banisteriopsis caapi (a vine used in Ayahuasca
preparations).
Antioxidants serve as defenders of our cells against oxidative stress by neutralizing harmful free radicals. Oxidative stress is closely associated with a range of
health concerns, including the aging process, inammation, and chronic diseases.
Consequently, antioxidants can play a pivotal role in mitigating oxidative damage and
promoting overall well- being. Research into the antioxidant potential of β- carbolines
is an ongoing endeavor, and the available evidence suggests that some of these
compounds may indeed exhibit antioxidant effects. For instance, harmine has been
demonstrated to possess antioxidant and free radical- scavenging properties in various
studies. Nonetheless, it is vital to recognize that the effectiveness of these compounds
as antioxidants can be inuenced by factors such as their concentration, the specic
type of β- carboline, and the experimental conditions in which they are assessed.
Carbolines are among the most fascinating alkaloids and are categorized based on
their ABC skeleton as α- , β- , γ- , or δ- carbolines (Figure 7.1) (Smirnova et al. 2012).
179DOI: 10.1201/9781351058032-7
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β- Carbolines
FIGURE 7.1 Structural diversity of carbolines.
FIGURE 7.2 SARs analysis of β- carbolines.
7.2 PHARMACOLOGICAL ACTIVE β- CARBOLINES
Molecules based on the β- carboline skeleton exhibit remarkable structural diversity. First isolated in 1841, β- carboline (9H- pyrido[3,4- b]indole), also known as
nor- harmane, is a nitrogen- containing heterocycle. It falls into the category of indole
alkaloids and features a pyridine ring fused with an indole backbone. The structure
of β- carboline resembles tryptamine, with the ethylamine chain reconnected to the
indole nucleus through an additional carbon atom, resulting in a three- ringed structure (Figure 7.2) (Goebel 1841).
β- carboline alkaloids have been successfully extracted from a diverse array of
sources, primarily encompassing plants (particularly in Rutaceae (Domenech- Carbo
et al. 2017), Simaroubaceae (Ohishi et al. 2015), Amaranthaceae (Agrawal et al.
2013), Caryophyllaceae (Chen et al. 2010), Rubiaceae (Figueiredo et al. 2014), and
Zygophyllaceae (Wang et al. 2016), as well as marine organisms such as hydroids
(Skropeta and Wei 2014), bryozoans (Till and Prinsep 2009), soft corals (Gao
et al. 2013), and sponges (Tanaka et al. 2014). Furthermore, these alkaloids have
been identied in microorganisms (Savi et al. 2015), insects (Marques et al. 2005),
various food products (Kim et al. 2016), alcoholic beverages (Tsuchiya et al. 2016),
tobacco smoke (Sari and Khalil 2015), and in various human tissues and bodily uids
(Lamounier et al. 2015).
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β-Carbolines as Antioxidant
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FIGURE 7.3 Biological activities of β- carboline alkaloids.
In addition to broad occurrence, (Figure 7.3) they exhibit a wide array of remarkable actions, including sedative (Smith et al. 2013), anxiolytic (Stephens 2013), hyp notic (Baldwin and Tiwari 2015), anticonvulsant (Pogosyan et al. 2007), antineoplastic
(Zheng et al. 2014), antiviral (Formagio et al. 2009), antiparasitic (Gooyit et al. 2015),
antimicrobial (Zhang et al. 2015), and more. These attributes have garnered signicant attention from both the academic and industrial sectors. To date, it is noteworthy
that some β- carboline- based remedies (Figure 7.4) have been successfully brought to
the commercial market.
Human oxygen consumption is estimated at approximately 250 mL per min, with
about 2– 4% of this oxygen being altered into various reactive oxygen species (ROS)
(Pless et al. 1999). Among these species, the hydroxyl radicals are considered to be
the most toxic, and they can be engendered in vivo via the Fenton reaction, often
originating from the endogenous production of hydrogen peroxide within the brain
(Sinet et al. 1980). Hydroxyl radicals can trigger degenerative reactions, including
lipid peroxidation in cell membranes. Neurons are particularly vulnerable to damage
from free radicals due to their low levels of antioxidant enzymes and limited free
radical scavenger concentrations (Kedziora and Bartosz, 1988). This susceptibility
has been associated with the development of neurodegenerative diseases, including
Alzheimer’s disease (Pappolla et al. 1997), Parkinson’s disease (Götz et al. 1994), and
mental deterioration in Down’s syndrome.
An antioxidant treatment is a logical approach, and well- established antioxidant
substances like ascorbic acid (vitamin C) and vitamin E are commonly recommended
and utilized. However, recent literature suggests that beyond these vitamins,
β- caroline derivatives also exhibit antioxidant properties, despite earlier discussions
about their potential for producing ROS and phototoxicity (Larson et al. 1988; Pari
et al. 2000).
The formation of free radicals and ROS is an inherent aspect of human metabolism. Maintaining a balance between the rate of ROS formation and the activity of
antioxidant systems is crucial for homeostasis. This balance hinges on the interplay
of low- molecular- weight antioxidants and proteins. Any increase in the rate of ROS
formation or inhibition of antioxidant mechanisms can lead to oxidative stress, a pivotal factor in the pathogenesis of various diseases, including neurodegenerative and
mental disorders. Research in this area focuses on specic low- molecule components,
whose activity or concentration may correlate with the progression of free radical
reactions. β- carboline derivatives are potential ligands for 5- HT1A and 5- HT2A
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β- Carbolines
FIGURE 7.4 β- carboline drugs and their pharmacological activity.
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β-Carbolines as Antioxidant
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FIGURE 7.5 The Structure- afnity relationship of β- carboline binding to BzR.
receptors. The pro- or antioxidant properties of this compound group may have a
direct impact on the overall antioxidant balance. Consequently, it is imperative to
investigate whether β- carboline derivatives inuence the levels of free radicals or
ROS. A inclusive assessment of the antioxidant activity of β- carboline derivatives can
shed light on their role in nonenzymatic systems that counteract ROS malfunction or
formation (Figure 7.5) (Pless et al. 1999).
7.3 ANTIOXIDANT ACTIVITY OF β- CARBOLINES
7.3.1 TeTrAhyDro- β- cArboliNes
Several tetrahydro- β- carboline alkaloids in fruits were identied and the occurrence
of these biologically active substances in such products assessed. It has been found
that these alkaloids detected in fruit products may act as antioxidants (Herraiz
and Galisteo 2003). A role of these compounds as protective agents against free
radicals is suggested. Four tetrahydro- β- carboline alkaloids, 1,2,3,4- tetrahydro- β-
carboline- 3- carboxylic acid, 1- methyl- 1,2,3,4- tetrahydro- β- carboline- 3- carboxylic
acid, 1- methyl- 1,2,3,4- tetrahydro- β- carboline, and 6- hydroxy- 1- methyl- 1,2,3,4tetrahydro- β- carboline, have bee found as naturally occurring substances in some
fruit and fruit juices. These compounds occur in the µg/ g level in those products, and
a characteristic and distinct prole appears to exist depending on the type of fruit and
juice involved. For example, 1- methyl- 1,2,3,4- tetrahydro- β- carboline may appear in
tomato, tomato juice, and kiwi; 6- hydroxy- 1- methyl- 1,2,3,4- tetrahydro- β- carboline
in bananas, pineapple, tomato, and their corresponding juices; and 1- methyl- 1,2,3,4tetrahydro- β- carboline- 3- carboxylic acid in oranges and grapefruits, although it
also occurs in most juices. Fruit- occurring tetrahydro- β- carboline alkaloids acted as
antioxidants and free radical scavengers in the ABTS assay when compared with
ascorbic acid and Trolox. This indicates that tetrahydro- β- carboline alkaloids might
act as antioxidants when absorbed and accumulated in the body, contributing to the
antioxidant effect of fruit products containing these compounds (Table 7.1).
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TABLE 7.1
β- Carbolines
Tetrahydro- β- carboline derivatives
R
1
CH
3
H COOH H 1,2,3,4- tetrahydro- β- carboline- 3- carboxylic acid
CH
3
CH
3
R
2
R
3
Compound
H OH 6- hydroxy- 1- methyl- 1,2,3,4- tetrahydro- β- carboline
COOH H 1- metyl- 1,2,3,4- tetrahydro- β- carboline-
3-carboxylic acid
H H 1- methyl- 1,2,3,4- tetrahydro- β- carboline
TABLE 7.2
Tetrahydro derivatives of β- carboline from garlic extracts
(1R,3S)- MTCC H CH
(1S,3S)- MTCC CH
(1R,3S)- MTCdiC COOH CH
(1S,3S)- MTCdiC CH
In their study, Ichikawa et al. (2006) employed a hydrogen peroxide scavenging
assay to explore the antioxidant compounds derived from ripened garlic extract. This
is made by immersing carved garlic in an ethanolic solution for a period of 10 months.
During their investigation, four distinct 1,2,3,4- tetrahydro- β- carboline derivatives
(THbCs), namely 1- methyl- 1,2,3,4- tetrahydro- β- carboline- 3- carboxylic acid and 1-
methyl- 1,2,3,4- tetrahydro- β- carboline- 1,3- dicarboxylic acid (MTCdiC), originating
from both diastereoisomers, were successfully isolated and recognized using LCMS
(liquid chromatography- mass spectrometry).
Remarkably, these exhibited robust scavenging activities against hydrogen peroxide and effectively inhibited 2,2’- azobis(2- amidinopropane) hydrochloride-
induced lipid peroxidation. Notably, among them, (1S,3S)- MTCdiC demonstrated the
most potent scavenging activity against hydrogen peroxide, surpassing even ascorbic
R
1
3
3
R
2
3
H
3
COOH
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β-Carbolines as Antioxidant
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FIGURE 7.6 Various derivatives of β- carboline.
TABLE 7.3
IC50 of DPPH antioxidant assay of pure 6- methoxy scaffold
β- carboline v/ s BHT and quercetin
DPPH antioxidantt assay
Type of standard/ pure compound
Quercetin 0.20 ± 0.00 0.66
BHT 0.28 ± 0.00 1.27
BEN 2.92 ± 0.04 10.50
ANI ND ND
ACE ND ND
VAN 1.74 ± 0.02 5.37
IC50(ug/ mL) IC50 uM
acid. Furthermore, (1R,3S)- and (1S,3S)- MTCdiC demonstrated the ability to inhibit
LPS- induced nitrite production at concentrations ranging from 50– 100 mmol/ L and
10– 100 mmol/ L, respectively.
Notably, THbCs (short for thiosulnates, a class of compounds) were absent in
both raw garlic and various processed garlic products. Surprisingly, they only came
into existence and their concentrations rose as part of the inherent aging progression
in garlic extraction. These discoveries strongly indicate that THbCs, originating during
this natural aging process, manifest themselves as robust antioxidants within aged garlic
extract. Consequently, these compounds offer great potential for future applications in
the prevention of diseases linked to oxidative harm (Table 7.2 and Figure 7.6).
The scavenging capacities of DPPH (diphenyl picrylhydrazyl) radical at 4 μg/ mL
concentration were as follows: VAN (58.30 ± 1.65%), BEN (56.43 ± 1.86%), ANI
(39.78 ± 1.35%), and ACE (39.23 ± 1.22%) (Table 7.3). The inhibition order ranked
is quercetin > BHT > VAN > BEN > ANI > ACE. Signicantly, VAN exhibited higher
inhibition (p < 0.05) compared to BEN, while BEN demonstrated superior DPPH inhibition compared to ANI and ACE. This activity can be ascribed to its hydrogen- donating
capability (Herraiz and Galisteo, 2004), with its β- carboline core acting as an efcient
free radical inhibitor, promptly reacting with DPPH radicals (Prakash et al. 2012).
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β- Carbolines
FIGURE 7.7 dl- 1- (4- hydroxybenzyl)- 1,2,3,4- tetrahydro- β- carboline.
Notably, the substances BEN (6- methoxy- 1- phenyl- 2,3,4,9- tetrahydro-
1H- pyrido[3,4- b]indole), ANI (6- methoxy- 1- (4- methoxyphenyl)- 2,3,4,9- tetrahydro-
1H- pyrido[3,4- b]indole), ACE (6- methoxy- 1- methyl- 2,3,4,9- tetrahydro- 1H- pyrido
[3,4- b]indole), and VAN (2- methoxy- 4- (6- methoxy- 2,3,4,9- tetrahydro- 1H-
pyrido[3,4- b]indol- 1- l)phenol) exhibited the most signicant antioxidant properties,
as evidenced by their IC50 values of 1.74 ± 0.02 and 2.92 ± 0.04 ppm, correspondingly. Conversely, ACE and ANI’s IC50 values could not be determined because they
displayed less than 50% inhibition even at a concentration of 4 ppm, although antioxidant activity of quercetin (IC50 = 0.20 ± 0.00 ppm) and BHT (IC50 = 0.28 ±
0.00 ppm) was higher than that of VAN (as shown in Table 7.3). Earlier studies have
reported IC50 values for various fruits such as orange (IC50 = 5.40 ± 1.30 ppm),
guava (IC50 = 2.11 ± 0.63 ppm), and star fruit (IC50 = 3.80 ± 2.10 ppm) (Duh 1998).
In a study by Qais and Jahan, a new tetrahydro- β- carboline (i.e., dl- 1- (4-
hydroxybenzyl)- 1,2,3,4- tetrahydro- β- carboline) was synthesized using the BischlerNapieralsky reaction (Qais and Jahan 2020). This synthesis involved the usage of
ZnCl2 with POCl3 as a dehydrating agent. The product underwent evaluation for its
antioxidant and analgesic activities (Figure 7.7). The antioxidant activity of the compound was assessed through the DPPH assess, and the IC50 value obtained was 48.42
ppm, while the standard ascorbic acid showed a signicantly lower IC50 value of
2.83 ppm in comparison (Table 7.4).
7.3.2 β-cArboliNe AlKAloiDs
Experiments and computer simulations determined that different substances (i.e.,
harmine, harmaline, harmalol, harmane, and 1,2,3,4- tetrahydroharmane- 3- carboxylic
acid) can act as antioxidants.
In the laboratory- based research, harmine exhibited the highest hydrogen peroxide
scavenging activity at 27.63 ± 1.74%, notably surpassing the performance of ascorbic
acid (8.02 ± 0.58%). 1,2,3,4- tetrahydroharmane- 3- carboxylic acid also displayed
substantial hydrogen peroxide scavenging activity, reaching 11.52 ± 0.82%, and
both compounds outperformed the reference standard, ascorbic acid. Additionally,
TABLE 7.4
newgenrtpdf
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Antioxidant activity (IC50) of synthesized compound and standard ascorbic acid
Conc. of
Absorbance
of blank
0.732 500
Standard/ test
sample (ug/ ml)
250
125
62.5
31.25
15.625
7.813
3.906
1.953
0.977
Absorbance of
standard
0.017
0.018
0.020
0.022
0.029
0.054
0.071
0.315
0.505
0.659
Aborbance of
test sample
0.046
0.102
0.280
0.376
0.521
0.565
0.625
0.634
0.660
0.688
Inhibition of
standard (%)
97.70
97.50
97.30
96.90
96.90
92.60
90.30
56.90
31.00
9.90
Inhibition of
test sample (%)
93.70
86.00
61.70
48.60
28.80
22.80
14.60
13.40
09.80
06.00
IC50 (ug/ ml) of
standard
IC50 (ug/ ml)
of test sample P value
2.83 48.42 0.0169
β-Carbolines as Antioxidant
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