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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5596_Библиотеки_им_академика_М_И_Перельмана
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β- Carbolines
SCHEME 8.26 Synthesis of β- carboline analogs.
SCHEME 8.27 Tetrahydro- β- carbolines (tryptolines).
Bischler– Napieralski designed a novel method for the preparation of 1,3-
diarylated 3,4- dihydro- β- carbolines. Using this process, benzophenone imimine is
selectively hydrolyzed, then classic Bischler- Napieralski (Ji et al., 2021) cyclization
is performed to produce 1,3- diarylated DHBCs. Corresponding β- carbolines are then
obtained through oxidation (Scheme 8.28).
Tetrahydro- β- carbolines were synthesized using an environmentally safe and
effective approach that involved the dehydrogenative coupling of alcohols with
tryptamines in the presence of a weak base and a catalytic quantity of Mn catalyst (Zhihui et al. 2023). This procedure produces good to outstanding yields of the
desired products for a range of benzylic and aliphatic alcohols with distinct functional
groups. Numerous medicinal compounds, including harman, harmaline, and harmine,
were effectively synthesized using this method (Scheme 8.29).
Wu and his co- workers devised a microwave- assisted technique to synthesize
1,2,3,4- tetrahydro- β- carbolines using a soluble polymer support system (Wu et al.
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SCHEME 8.28 Proposed Strategy for the Construction of 1,3- Diaryl DHBCs and
β- Carbolines.
SCHEME 8.29 Synthesis of tetrahydro- β- carbolines by coupling of alcohols.
2002). The loading of F- moc protected L- tryptophan on the soluble polymer support
in the presence of the coupling agent DCC/ DMAP marked the beginning of this synthetic approach. First, the F- moc group was deprotected in the presence of piperidine,
and then the Pictet– Spengler cyclization with carbonyl compounds produced 1,2,3,4-
tetrahydro- β- carbolines. Treatment of the cyclized product with 1% potassium
cyanide in methanol was used to separate the polyethylene glycol support, resulting
in the production of 1,2,3,4- tetrahydro- β- carbolines (Scheme 8.30).
An innovative technique for creating stereoselective tetrahydro- carbolines with
fused hydantoin under microwave irradiation on the molecular support of soluble
biarm hydroxy polymer (polyethylene glycol- 400) was reported by Chang
et al. (2006). The easily available NHBoc protected L- tryptophan was reacted with
polyethylene glycol- 400 in the presence of DCC/ DMAP to produce the Boc (tert-
Butyloxycarbonyl) protected intermediate. The following stage involves deprotecting
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β- Carbolines
SCHEME 8.30 Microwave assisted synthesis of 1,2,3,4- tetrahydro- β- carbolines.
SCHEME 8.31 Oxo and thio hydantoin fused tetrahydro- β- carboline.
the Boc group under microwave irradiation, followed by cyclization with aldehydes
to produce tetrahydro- β- carbolines in a cis/ trans isomer ratio of 1:1 Yeh et al. (2007)
reported the second diversity, which was developed by applying for the terminal
thiohydantoin moiety through the N- 2/ C- 3 bond of the tetrahydro- β- carboline frame.
The process of cyclization takes place in between the polymer- attached tetrahydro-
β- carboline and substituted isothiocyanates to produce tetrahydro- β- carbolines
(Scheme 8.31).
Balogh and co- workers developed a novel one- pot protocol for the synthesis of
substituted 3,4- dihydro- β- carbolines (DHβCs) in the presence of T3P (Abranyi-
Balogh et al. 2016). The synthesis of isoeudistomin alkaloid, which involves the
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SCHEME 8.32 Synthesis of substituted 3,4- dihydro- beta carboline.
SCHEME 8.33 Synthesis of N- Tosyl- β- carbolinones.
reaction of tryptamine and indole- 3- carboxylic acid, was also carried out using this
approach (Scheme 8.32).
In another protocol, Verniest and colleagues devised a procedure for N- Tosyl- β-
carboline synthesis that involves the reaction of indole substituted N- propargylamides
in the AuCl3 and followed by the 6- exo- dig cyclization under milder reaction reactions
(Verniest et al. 2010). Easily available as starting materials for the aforesaid synthesis is the acylation of N- tosylpropargylamines, which is generated in situ using
N- benzyl- 1H- 2- indolecarbonyl chloride (Scheme 8.33).
8.3 β- CARBOLINE AS ANTIDEPRESSANT AGENTS
Both the chemistry and functionality of the brain are affected by depression.
Depression is a major mental disorder, which often manifests as exhaustion, apathy,
low spirits/ thoughts, lack of concentration, anorexia, sleeplessness. etc. (Bakim et al.
2012). Patients with long- term illnesses like Alzheimer’s, Parkinson’s, and HIV frequently exhibit depressive symptoms (Skalisz et al. 2002). Mortality and morbidity
are brought on by major depressive illnesses, which include post- traumatic stress
disorder (PTSD), generalized anxiety, obsessive- compulsive disorder (OCD), and
irritability (Muhammad et al. 2013). Many factors are involved in depression such as
genetic, psychosocial, physical, biological, etc. Imbalance in the concentration levels
of various monoamine neurotransmitters such as serotonin/ 5- hydroxytryptamine
(5- HT), norepinephrine/ noradrenaline (NA), dopamine, and their metabolites is the
major cause of depression (Ferraz et al. 2019). Medically, tricyclic antidepressants
(TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake
inhibitors (SSRIs), serotonin- norepinephrine reuptake inhibitors (SNRIs), and
other serotonergic synthetic or herbal remedies are frequently used to maintain the
pathophysiological effects of depression (Hamid et al. 2017). The primary cause of
depression is monoaminergic activity in the brain. The concentration levels of amine
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neurotransmitters in the central nervous system are modulated by MAO enzyme,
which serves as a catalyst for neurotransmitter oxidative deamination (Herraiz et al.
β- Carbolines
2018). Thus, inhibition of MAO is essential to maintain balanced levels of 5- HT,
dopamine, and norepinephrine/ noradrenaline (NA) neurotransmitters in the brain by
preventing their degradation and reuptake. An imbalance of dopamine in the brain
causes symptoms of depression such as feelings of sadness and hopelessness, while
an imbalance of serotonin affects the processing of emotions. Dopamine, norepinephrine, and serotonin are the three neurotransmitters linked to depression. The main
purpose of an antidepressant is to treat depression. By changing the networks and
chemicals that transmit signals through nerve pathways to the brain, antidepressants
are helpful in treating depression The ve main categories of antidepressants are as
follows:
[a] Selective serotonin reuptake inhibitors (SSRIs)
[b] Serotonin and nor- epinephrine reuptake inhibitors (SNRIs)
[c] Tricyclic antidepressants (TCAs)
[d] Monoamine oxidase inhibitors (MAOIs)
[e] Atypical antidepressants
The neurochemical effects of antidepressants vary depending on the moieties such
as aromaticity, functional groups, chain conformations, etc., with varying degrees
of SAR (Ayoob et al. 2017). β- Carboline analogues have distinctive pharmacophore
characteristics that express their interactions with the depressive syndromes- related
processes. The beta- carboline alkaloids like harmine, harman, and nor- harman
(e) are MAO inhibitors present in a wide variety of plant products, including foods,
medicines, and narcotics. For example, 6- methoxy- 1,2,3,4- tetrahydro- β- Carboline
(pinoline) lowers depression symptoms by competitively blocking the function of
the MAO- A and by directly binding to the serotonin transporter, avoiding serotonin
absorption into the brain’s synaptosomes and platelet (Jiang et al. 2009). Through
the restriction of MAO- A and 5- HT reuptake and related selective serotonin reuptake
inhibitor- binding process, pinoline functions as an antidepressant (Pähkla et al.
2000). The possible antidepressant effects of β- carboline derivatives are outlined in
Table 8.1, along with the mechanisms of action shown in both in vivo and in vitro
investigations.
The β- Carboline scaffolds have a signicant role in biological function. When
different positions 1, 3, 5, 6, 7, 8, and 9 are substituted, several physiologically
active molecules with a broad spectrum of pharmacological actions are produced
(Thatikayala et al. 2022). (Figure 8.7).
The main biochemical theory of depression disorders is the monoamine hypothesis. It was rst put forth in the 1950s (Freis et al. 1954) and explains depression as
the result of a change in the levels of one or more monoamines, such as serotonin
(5- HT), dopamine (DA), and noradrenaline (NA). Noradrenergic, serotoninergic,
and dopaminergic neurons are widely distributed throughout the central nervous
system.
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TABLE 8.1
Pharmacological movements of β- Carboline scaffolds against depression
S.N. β- Carbolines Compound Mechanism of action Ref.
1. Encourage of hippocampal neurotransmitter generation. (Morales- García et al. 2017)
β-Carbolines as Anti- inflammatory and Antidepressant Agents
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2. Obstruct of MAO- A and Inverse agonism on benzodiazepine
3. Prevention of MAO- B and inverse agonism on benzodiazepine
4. Inhibition of MAO- A, 5- HT reuptake, and afnity to SSRI
receptors.
receptors to modulate glutamate/ GABA levels.
binding sites.
(Aricioglu et al. 2003; Farzin et al.
2006)
(Ebrahimi- Ghiri et al. 2019)
(Pahkla et al. 2000)
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β- Carbolines
FIGURE 8.7 Structure activity relationship (SAR) of β- Carboline scaffolds.
In general, NA affects how the prefrontal cortex works, how working memory is
processed, and how behavior and attention are controlled. The most cohesive network
of neurotransmitters in the brain is 5- HT, which is essential for controlling mood,
emotion, and motor function. Depressive behaviors may be inuenced by hypo- or
hyperserotoninergic states, indicating that this monoamine plays a critical role in regulating
other neurotransmitters that are also connected to depressive disorders. Lastly, DA
regulates working memory, attention, reward and motivation processes, and motor coordination (Jesulola et al. 2018; Hamon et al. 2013; Belzung et al. 2015; Dean et al. 2017;
Goldberg et al. 2014). This means that many behavioral signs of depression, including
low mood, alertness, decreased motivation, exhaustion, aggressiveness, impaired focus,
and cognitive performance, may be caused by monoaminergic system failure (Jesulola
et al. 2018). Because of this, the majority of antidepressant drugs function by raising
monoamine levels in synaptic clefts and subsequently regulating the corresponding
neurotransmission systems. Numerous investigations have shown that by inhibiting MAO
(Kim et al. et al. 1997) and 5- HT reuptake (McIsaac et al. 1972), β- carbolines raise the
extracellular concentration levels of these monoamines in various brain areas. The oxidative deamination of monoamines is catalyzzed by MAOs, a family of avin- containing
amine oxidoreductases that are typically found within the outer mitochondrial membrane.
MAO- A and MAO- B are two isoforms of MAO that have different substrate
preferences. MAO- A primarily breaks down 5- HT molecules, while MAO- B has a
stronger afnity for phenylethylamine and phenylamine. DA and NA are normally
metabolized by both isoforms (Corbineau et al. 2017; Fisar et al. 2016). Previous
studies have shown that β- carboline increases 5- HT levels in the synapse by preferentially inhibiting MAO- A.
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FIGURE 8.8 Molecular mechanisms involved in the antidepressant effects of β-
carbolines (βCB).
It is interesting to note that these alkaloids can interact with a variety of cell- surface
receptors, including 5- HT2A receptors (Glennon et al. 2000), which are connected to
the pharmacology of antidepressants. 5- HT2A, which are G- protein coupled receptors,
are found in the brain's thalamus, amygdala, hippocampal, and cortical areas.
Once activated, these receptors can regulate neuronal excitation implicated in
depression through modulation of glutamatergic and GABAergic postsynaptic
neurons, thereby producing antidepressant effects (Guiard et al. 2015). β- carbolines
interact with GABAA receptors in addition to serotoninergic receptors. In this situation, an inverse- agonistic mechanism is at work, which lowers inhibitory postsynaptic
signals and subsequently modies the antidepressant- like effects of monoamines,
such as 5- HT. Since certain carbolines serve as reverse agonists of GABAA receptors
they directly affect the 5- HT system by inhibiting MAO- A and 5- HT reuptake process (Herraiz et al. 2010).
Figure 8.8 demonstrate the primary chemical processes that underlie the
antidepressant- like effects of β- carbolines.
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8.4 β- CARBOLINE AS ANTI- INFLAMMATORY AGENTS
The β- carboline derivatives with diversied substitution at positions like 1, 2, 3, 6,
7, and 9 showcase a variety of biological activities. According to Medzhitov et al.
β- Carbolines
(2008), inammation is an adaptive reaction brought on by unpleasant stimuli and
circumstances including infection and tissue damage. The majority of the cellular and
molecular pathophysiology of inammation is mediated by proinammatory cells,
primarily activated macrophages, which produce a variety of inammatory mediators,
such as reactive oxygen species (ROS), nitric oxide (NO), interleukin- 6 (IL- 6), prostaglandin E2 (PGE2), and tumor necrosis factor- a (TNF- a) (Laskin et al. 2011; Kang
et al. 2012). Many diseases, including sepsis, rheumatoid arthritis, atherosclerosis,
and even cancer, are mediated or made worse by an excess or uncontrolled synthesis
of these mediators (Tabas et al. 2013). Nuclear factor erythroid 2- related factor 2
(Nrf2) is a transcription factor involved in the regulation of inammation. Through
consensus sequences known as antioxidant- response elements, Nrf2, a member
of the basic- leucine zipper transcription factor, controls the expression of many
detoxifying and antioxidant genes, including heme oxygenase- 1 (HO- 1), NAD(P)
H:quinone oxidoreductase (NQO1), glutathione S- transferases, and g- glutamyl cysteine synthetase catalytic subunit (GCLC) (Jaramillo et al. 2013). When Nrf2 is bound
to the Kelch- like ECH- associated protein (Keap1), it enters the Keap1- Cul3- E3 ubiquitin ligase complex, which subsequently ubiquitinates and degrades Nrf2 (Jaramillo
et al.). In response to oxidative stress, Nrf2 is released from Keap1, moves to the
nucleus, forms a heterodimer with the tiny Maf protein, and binds to sites associated
with antioxidants in the promoter regions of genes that are cytoprotective and antioxidant (Jaramillo et al. 2013).
β- carboline’s anti- inammatory properties were attained by inhibiting the generation of nitric oxide and tumor necrosis factor (TNF)- alpha in lipopolysaccharidestimulated murine RAW264 and human THP- 1 cells. In RAW264 cells, β- carboline
exhibited more potent TNF- alpha suppression effects compared to butein and reference polyphenol. It was also discovered that β- carboline inhibited the production of
interleukin- 6 in RAW264 cells (Yamazaki et al. 2011). Furthermore, another way that
Nrf2 might be activated is by phosphorylation. It has been demonstrated that several
kinases are involved in the phosphorylation of Nrf2, including mitogen- activated protein kinases (MAPKs) including extracellular signal- regulated kinases (ERK), c- jun
N- terminal kinases (JNK), and p38 kinases (Aleri et al. 2008). Neurodegenerative
disorders, aging, diabetes, photooxidative stress, cardiovascular disease, inammation, pulmonary brosis, acute pulmonary damage, and cancer have all been
demonstrated to be protected against by activating the Nrf2 defense response (Boutten
et al. 2011).
According to Paine et al. (2010), HO- 1 is the main antioxidative and anti-
inammatory enzyme that is controlled by activating Nrf2. The rate- limiting enzymatic phase of heme breakdown is catalyzed by heme oxygenase (HO), which also
generates carbon monoxide, ferrous iron, and biliverdin. Biliverdin reductase then
converts biliverdin into bilirubin (Paine et al. 2010). HO- 1 and HO- 2 are two known
genetically different HO isozymes (Paine et al. 2010). The constitutive isoform is
represented by HO- 2 (Paine et al. 2010). On the other hand, a variety of triggers,
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FIGURE 8.9 Anti- inammatory drug.
such as inammatory mediators and factors associated with oxidative stress, signicantly upregulate the inducible isoform HO- 1 (Maines et al. 2001). According to
Abraham et al. (2008), HO- 1 preserves cellular homeostasis and is crucial for tissue
protection by lowering oxidative damage and lowering the inammatory response. In
activated macrophages, the expression of HO- 1 or carbon monoxide therapy inhibits
the production of proinammatory cytokines and chemokines (Choo et al. 2015).
Accordingly, using natural phytochemicals to target the Nrf2/ HO- 1 pathway may be a
useful tactic for the management or prevention of inammatory illnesses (Motterlini
et al. 2014).
In Southeast Asian nations, Eurycoma longifolia Jack (Simaroubaceae) is a signicant medicinal plant (Bhat et al. 2010). Quassinoids, canthin- 6- one, β- carboline
alkaloids, and other bioactive components found in the plant are responsible for
E. longifolia’s efcacy (Bhat et al. 2010). According to a recent study (Tran et al.
2014), some quassinoids and β- carboline alkaloids from E. longifolia exhibit strong
NF- kB inhibitory effects when TNF- a is present. Nevertheless, not much research
has been done on E. longifolia’s anti- inammatory properties. Searching further for
Nrf2 activators in herbal medicinal plants, they discovered a strong Nrf2 activator
in 7- MCPA, a β- carboline alkaloid isolated from E. longifolia hairy- root cultures.
In this work, we used RAW264.7 cells to examine the anti- inammatory properties of 7- MCPA as well as its underlying processes. Here, we demonstrated how
7- MCPA prevented mice from developing septic shock from lipopolysaccharide
(LPS)- induced inammation in vivo by activating the Nrf2/ HO- 1 pathway through a
ROS- dependent p38 MAPK pathway. Strongly inhibiting the generation of NO, the
anti- inammatory chemical (E)- 3- (7- methoxy- 9H- pyrido[3,4- b]indol- 1- yl)acrylic
acid was isolated from the hairy- root cultures of Eurycoma longifolia (Ngoc et al.
2016) (Figure 8.9).
8.5 CONCLUSION
This current review chapter summarizes the modern synthetic routes and in vitro
and in vivo anti- inammatory, antidepressant properties of β- carbolines. β- carbolines
have also been investigated for other biological purposes, but most of the clinical
studies are supercial and did not employ detailed experimental studies or molecular
mechanisms. More and more techniques are being discovered that are based on ringclosing metathesis, cyclization, condensation, oxidative C- N coupling, and palladium catalyzed reductive N- hetero annulation for the synthesis of β- carbolines. The
synthetic diversity of the proposed mechanisms and the action of these compounds
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