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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5354_Библиотеки_им_академика_М_И_Перельмана
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FIGURE 2.8 Structures of beta- carboline possess different biological activities.
β- Carbolines
The synthetic antimalarial drug ciprooxacin is a member of the spiroindolone
family. Cipargamin is a synthetic antimalarial molecule that belongs to the
spiroindolone class. In 2006, a high- throughput phenotypic screen of natural
products led to the discovery of this compound as a potent inhibitor of Plasmodium
falciparum growth. Known by its brand name Cialis, the β- carboline Cialis is
effective against pulmonary arterial hypertension (PAH), benign prostatic hyperplasia (BPH), and erectile dysfunction (ED). The average onset time is 30 minutes,
and the maximum duration is 36 hours. Starting with (D)- tryptophan methyl ester
and piperonal, tadalal can be synthesized via a Pictet- Spengler reaction. The
diketopiperazine ring is then nished off via condensations with chloroacetyl
chloride and methylamine.
Abecarnil is a β- carboline anxiolytic medication. It is in a class of drugs called
nonbenzodiazepines, which share the benzodiazepine’s effects without the same
chemical structure. It functions as a partial agonist at the benzodiazepine site of the
GABA receptor. Abecarnil was originally developed as an antianxiety drug, but it has
yet to be commercially developed for human use, instead being primarily used for
research into the development of other new sedative and anxiolytic drugs. In Japan,
brovincamine fumarate was prescribed to people with normal- tension glaucoma
so as to increase blood ow to the brain, boost metabolism, and decrease platelet
aggregation via the cyclic AMP (Adenosine- 3’,5’- cyclic monophosphate) pathway.
Brovincamine is effective because it blocks calcium channels. Yohimbine is an
α2- adrenergic receptor antagonist that has been used in several studies. It is a veterinary
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medicine for canine and cervid sedation. Some mammals, including humans, nd
yohimbine to be sexually stimulating. It has been used to treat erectile dysfunction,
but the reported clinical benets have been minimal, and the PDE5 inhibitor drug
class has largely replaced it.
In combination with a thiazide diuretic or vasodilator, it is used to treat hypertension. Combining reserpine and a thiazide diuretic has been shown to reduce
hypertension- related mortality in large clinical trials. The ability of reserpine to
deplete catecholamines from peripheral sympathetic nerve endings is a major contributor to its antihypertensive effects. Small cell lung cancer is treated with a drug
called Zepzelca. Some of the most common unwanted effects include leukopenia,
anaemia, lymphopenia, low albumin, neutropenia, fatigue, vomiting, cough, low
magnesium, low appetite, high creatinine, high alanine aminotransferase, high aspartate aminotransferase, nausea, constipation, dyspnea, musculoskeletal pain, high glucose, low sodium, and diarrhoea.
Through its pyridine ring and indole moiety, nor- harmane belongs to the class of
indole alkaloids (Banoth et al. 2020). There are beta- carbolines in plants, animals,
foods, bacteria, and insects (Hamann et al. 2008). Many of these alkaloids have
been isolated from marine sources like soft hydroids, corals, and bryozoans, and
land plants belonging to the families Caryophyllaceae, Rutaceae, Amaranthaceae,
Zygophyllaceae, Simaroubaceae, and Rubiaceae (França et al. 2006; Rajesh and
Murugan 2019). There are a few illustrations in Figure 2.9.
Canthi- 6- one 39 is of the type 6H- indolo[3,2,1- de][1,5]naphthyridine and is
classied as a substituted indole alkaloid. In addition to its role as an antimycobacterial
agent, it also plays the role of a metabolite. It is a hetero- tetracyclic organic compound known as an indole alkaloid. Aerobic and nonmotile, genus members are
responsible for diseases like tuberculosis and leprosy (Dejos et al. 2014). The Beta-
carboline- 1- proponoic acid 40 alkaloid known as beta- carboline- 1- propionic acid has
been shown to have anti- Leishmania and anti- Leishmaniatic properties. Furthermore,
apoptotic Leishmania amazonensis (19.5%) and L. infantum (40.4%) promastigotes
were assessed after 5 hours of incubation with the alkaloid. It was also found that NO
production was suppressed in infected macrophages due to β- carboline- 1- propionic
FIGURE 2.9 Structures of beta- carboline derivatives extracts from plants.
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acid treatment, suggesting that intracellular amastigote elimination is not reliant on
nitrosative stress (Gabriel et al. 2019).
β- Carbolines
Both Eudistomin I 41 and Eudistomin- H 42 showed potent antimicrobial activity
against a wide variety of bacteria and viruses. The zone of inhibition for Eudistomin
I, at 100 μg/ disc, was 3– 7 mm, and for Eudistomin- H, it was 7 mm. The 0.49 μg/ ml
concentration of Eudistomin- H, also isolated from the same ascidian, shows promise
as an anticancer agent. These results provide supporting evidence for further investigation into Eudistomin- H and its derivative Eudistomin I as potential anticancer and
antibacterial agents (Rajesh and Murugan 2019). The phytochemistry of L. oridana
was the rst to report 1- methoxycanthinone 43 and its isomer 5- methoxycanthinone
44. The discovery of simaroubolides in the Leitneriaceae family is signicant because
this class of compound had been previously isolated from the Simaroubaceae family.
The 1- methoxycanthinone isolated from Leitneria oridana showed promising antiHIV activity and growth inhibition across multiple human tumour cell lines in in vitro
biological testing (Xu et al. 2000). Over a hundred different alkaloids and synthetic
compounds can be traced back to β- carboline, also known as 9H- pyrido[3,4- b]indole.
The Norharmane 8 substituent determines the properties of these chemicals. Natural
beta- carbolines typically have a neuroprotective effect but may also have other effects.
Analogues of beta- carboline that were created in a lab have recently been shown to
have neuroprotective, cognitive- enhancing, and anticancer effects (Casal 2015).
Plakortamine- A, Plakortamine- B, Plakortamine- C, Hyrtioerectin- A, PlakortamineD, Fascalpysin, and Manzamine- A are all examples of β- carboline compounds that are
used as pharmaceuticals. The examples of pharmacologically active, marine alkaloids
having beta- carbolines include 6- Deoxymanzamine- X, 8- Hydroxymanzamine- A,
Methoxymanzamine- A, and Thorectandramine.
Plakortamine- A 45, B 46, C 47 & D 48 has been synthesized using total synthesis
approach. β- Carboline was extracted from the deep- sea Palauan sponge Plakortis
nigra. Several of the metabolites were found to be cytotoxic to HCT- 116 (human
colon tumour) cells (Sandler et al. 2002). In 1986, the novel antitumor alkaloid
manzamine A was isolated from the Okinawa sponge; its IC50 value against P388
mouse leukaemia cells was determined to be 0.07 μg/ ml (Figure 2.10).
The unique bioactivity and structural complexity of manzamine A made its total
synthesis an alluring but challenging endeavour. Manzamine A’s total synthesis was
FIGURE 2.10 Different structure of Plakortamine.
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β- Carbolines as Antibacterial Agents
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rst reported in 1998 by Winkler and Axten. After being isolated for over a decade,
the antimalarial properties of manzamine A were nally uncovered. Both the P. falciparum D6 and W2 strains were found to be sensitive to manzamine A’s antimalarial
effects in vitro, with IC50 values of 4.5 and 8.0 ng/ ml (Ashok et al. 2015). There are
a plethora of Cdk inhibitors available, both in the form of biological proteins and
small molecules. All Cdks can be inhibited to varying degrees by small molecule
Cdk inhibitors; there are no Cdk4- specic inhibitors. Researchers discovered that the
red pigment fascaplysin 50, which is present in marine sponges, inhibits Cdk4 specifically in vitro. Antimicrobial- based compound were rst isolated from the sponge
Fascaplysinopsis sp. The authors resynthesized fascaplysin and used it to test its
effects as a Cdk4 inhibitor on cell lines derived from osteosarcoma, colon carcinoma,
and normal diploid broblasts (Soni et al. 2000).
The marine sponge Hyrtios erectus from the Red Sea yielded a new class of
alkaloids called hyrtioerectines A 51. Carbon- bond- linked moieties in hyrtioerectine
A include 6- hydroxy β- carboline and 6- hydroxyindole. Using Fukuzawa’s assay,
we determined that compound 51 was moderately cytotoxic to HeLa cells; its IC50
value was determined to be 10 µg/ mL (Youssef 2005). Antimalarial activity of 8methoxymanzamine- A 52 was high, on par with that of 8- hydroxymanzamine- A but
with higher cytotoxicity. The lowest antimalarial potency and absence of cytotoxicity
was observed for 8,12- diacetylmanzamine- A (IC50:1300 and 1200 ng/ ml against D6
and W2 strains, respectively) (Ashok et al. 2015). An unidentied sponge from the IndoPacic region was the source of the antimicrobial compounds 8- hydroxymanzamineA 53 and the manzamine dimer neo- kauluamine. Both compounds belong to the
manzamine family. The in vitro activity of manzamines against AIDS- opportunistic
infectious diseases, such as tuberculosis and toxoplasmosis, as well as their in vivo
activity as antimalarial agents with superior activity to that of the clinically used
drugs artemisinin and chloroquine, are some of the topics that are discussed in
this chapter (Ashok et al. 2015). Edrada and colleagues were able to extract new
manzamine alkaloids, 6- deoxymanzamine- X 54, from the Philippine marine sponge
Xestospongia ashmorica in the year 1996. These alkaloids exhibited low cytotoxicity
when tested on L5178y cell lines (Ashok et al. 2015). Recent research has shown that
the substance known as thorectandramine 55, which is a novel hexacyclic quaternary β- carbolinium derivative, possesses both antiproliferative and cytotoxic activity.
This compound was recently isolated from a Palauan collection of the sponge known
as Thorectandra sp. (Charan 2002). The chemical literature contains only a small
number of studies on the genus Thorectandra, most of which detail the isolation of
various sesterterpenes and sterols (Figure 2.11).
2.3 CHARACTERISTICS OF BETA- CARBOLINES
The bioactive components of raw materials and foods have been the subject of
extensive research in recent decades (Pfau & Skog 2004; Herraiz 2002, Laviță et al.
2016; De Meester 1995). Both harman and harmine, which differ from NH in that
they have different substituents on their rings, have been the subject of extensive
research. Carbolines’ biological and pharmacological activities span a wide spectrum
(including antitumor, antiviral, and antimicrobial activity) (Herraiz 2012; Li
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β- Carbolines
FIGURE 2.11 Different derivatives of carboline alkaloids.
et al. 2016). The β- carbolines H and NH are found naturally in mammalian tissues
and body uids (such as urine and platelets), and they are also stored in the organs of
living organisms. They can be produced endogenously in these environments (Zheng
et al. 2000). H is particularly interesting because it is stored in large quantities in the
brain. Due to the high lipophilicity of H, it is able to spread much more quickly in the
tissues of the brain and the peripheral nervous system, which results in levels that are
approximately 55 times higher there than in blood plasma. Carbolines are eliminated
in urine and faeces, with the majority of H passing out through the bowel movements.
2.4 OCCURRENCE OF BETA- CARBOLINES
The Nitrariaceae succulent P. harmala was the rst plant to produce β- carboline
compounds. From hallucinogenic plants like B. caapi and T. terrestris, harman can be
extracted. Smoke from cigarettes, tobacco leaves, and tobacco chewing all test positive for beta- carbolines (Alves et al. 2010; Poindexter Jr and Carpenter 1962). NH and
H have been discovered in processed and refrigerated foods by multiple investigations
(Wojtowicz et al. 2015; Totsuka et al. 1999; Allen and Holmstedt 1980). Cookies,
coffee (Herraiz 2004; Schultes 1982; Tsuchiya et al. 1999; Casal 2015; Alves et al.
2007; Zawirska- Wojtasiak et al. 2018) (particularly between the ages of 78 and 83),
bread, soy, barley, maize, coffee substitutes, and fermented alcoholic beverages are all
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β- Carbolines as Antibacterial Agents
examples of plant- derived foods that contain these compounds (Tsuchiya et al. 1996;
Adachi et al. 1991). H and NH have also been found in foods like meat, fruit, sh,
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vegetables, and fruit juices (Adachi et al. 1991). Many scientists have conjectured that
consumption of items containing NH and H in mammalian tissues may be connected
to increased levels of β- carbolines in biological uids and human tissues. Meat and
sh have been reported to contain β- carboline molecules, although the concentration
varies depending on the kind of meat and heat treatment. Beef, chicken, and mutton
were all found to contain H and NH after being ame- grilled, deep- fried, or baked
(Totsuka et al. 1999; Ogawa et al.1993). Herraiz discovered that H and NH levels
in raw beef and pork llets were below the detection limit (Herraiz and Galisteo
et al. 2003). After being heated, the amount of carbolines in meat varied depending
on the cooking technique used. Well- done best meat had the highest average value,
with H ranging from 20.7 to 32.1 ng/ g and NH from 36.4 to 128.1 ng/ g. Sausage
was found to have NH levels between 0 and 3.7 ng/ g, with undetectable being the
most common. Carbolines were nowhere to be found in raw sh. After processing,
NH concentrations in cooked sh ranged from 6.4% to 48.1% by weight, and H
concentrations from 0.7% to 4.3% by weight. No matter the method of preparation or
the type of sh, NH concentrations were always higher than H concentrations.
2.5 NATURAL PRODUCTS HAVING A SIMPLE Β- CARBOLINE
SKELETON
Norharman and 1- or 6- substituted β- carboline were synthesized in a single reaction,
thanks to work by Wang and coworkers (Scheme 2.1). The designed synthesis begins
with racemic tryptophan and other amino acids, and then moves through a series of
reactions and chemical transformations, including a decarboxylation, a deamination,
a Pictet- Spengler reaction, and an oxidation. Moreover, a number of alkaloids and
synthetic analogues were obtained by replacing specic amino acids in the original
product (Wang et al. 2018).
The high yield enantioselective synthesis of (S)- eleagnine(- )- tetrahydroharmane
was reported by Lood et al (Scheme 2.2). Their synthesis begins with a chirally correct
methyl ester of a modied amino acid. The amide of morpholine was synthesized by
reacting morpholine with t- BuMgCl. The amide was lithiated laterally, and then o-
toluidine that was Boc- protected was added to get the ketone. After reacting the ketone
with KHMDS (potassium bis(trimethylsilyl)amide), a mixture of diastereomeric
indoline- lactones was obtained by quenching the resulting potassium enolate with
ethyl bromoacetate. This diastereomeric mixture was treated with sulfuric acid in
SCHEME 2.1 Acid catalyzed one- pot synthesis of norharman.
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β- Carbolines
SCHEME 2.2 Synthesis of tetrahydroharmane.
SCHEME 2.3 Synthesis of β- carboline derivative.
MeOH to facilitate sequential lactone ring opening and Boc- cleavage to form indole.
The Pf- protecting group (phenyluorenyl group) was hydrogenolyzed, and the free
amine was treated with Na2CO3 base to produce lactam. Finally, an enantiomeric
excess of (S)- eleagnine was obtained through gram- scale synthesis using a LiAlH4
reducing agent (Lood et al. 2015).
Stolonine C, a new β- carboline alkaloid, was discovered and synthesized as a result
of chemical research into the marine tunicate C. stolonifera (Scheme 2.3). The PictetSpengler reaction of formaldehyde with L- tryptophan methyl ester is the rst step
in this synthesis, followed by C- ring dehydrogenation and ester group hydrolysis.
Taurine was used to convert the intermediate into an amide, which led to the nal
product (Tran et al. 2015).
Tryptamine and indole- 3- carbonitrile are used in a two- step alternative synthesis of the nal product, which also involves dehydrogenation of an intermediate
with carbonized palladium (Scheme 2.4) (Pakhare and Kusurkar 2015). To prepare
substituted 3,4- dihydro- carbolines in the presence of catalyst, Brányi- Balogh and
colleagues showed a microwave- assisted one- pot protocol. From tryptamine and
indole- 3- carboxylic acid, 50% isoeudistomin U alkaloid was synthesized using the
new method (Scheme 2.5) (Ábrányi- Balogh et al. 2016).
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SCHEME 2.4 Two- step synthesis of β- carboline using tryptamine and indole- 3- carbonitrile.
SCHEME 2.5 Microwave- assisted protocol for the preparation of 3,4- dihydro- carbolines.
SCHEME 2.6 Efcient method for preparing substituted β- carboline.
Alangiobussine and alangiobussinine were synthesized via the IBX (2-
Iodoxybenzoic acid)- mediated total synthesis pathway by oxidatively adding isocyanide to tryptoline. The reaction of tetrahydroisoquinolines and tryptolines with
isocyanides is a general method (Scheme 2.6) for preparing imino- carboxamides. The
natural product alangiobussine was successfully synthesized on a gram- scale using
the IBX- mediated oxidative addition technique. It was subsequently dehydrogenated
in the presence of CuBr and DBU (1,8- Diazabicyclo(5.4.0)undec- 7- ene) to yield
alangiobussinine (Ambule et al. 2019).
Komavine, a spiro- THC derivative, and several analogues with good functional
group tolerance were synthesized by Wang et al. using a new Pd- catalyzed cross-
annulation of phenols and tryptamine (Scheme 2.7). This alternative protocol for
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β- Carbolines
SCHEME 2.7 Pd- catalyzed cross- annulation reaction for the synthesis spiro- THC derivative.
SCHEME 2.8 Synthesis of marine natural product having β- carboline framework.
SCHEME 2.9 Pictet- Spengler reductive reaction approach for the synthesis of β- carboline.
synthesizing THC (tetrahydrocoumarin) derivatives involved cleaving the C- O bond
in phenol, activating the C- H bond in tryptamine, and forming the C- N/ C- C bond.
The yield was moderate to excellent. This work demonstrates a feasible strategy for
transforming the model monomers of phenolic lignin into compounds with commercial value (Wang et al. 2019).
The synthesis of shishijimicin A, a marine natural substance with exceptional
bioactivity activity, was broken down into 48 steps by Schott et al. (Schemes
2.8). By using their approach, the natural product is split into three signicant
intermediates. Using methods from the literature and functional group transformations, one of them, the β- carboline framework, was built in eight stages to prepare
the protected and iodine- functionalized critical intermediate in position 1 (Schott
et al. 2006).
Canthine, the framework of biologically active canthine- 6- ones, and harmicine
were successfully developed using the Pictet- Spengler reductive reaction (Scheme
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β- Carbolines as Antibacterial Agents
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SCHEME 2.10 Metal mediated approach for the synthesis of β- carbolines.
2.9). With 10% Pd/ C and H2, nitrile was utilized in place of the often- used aldehydes
in the reductive intramolecular cyclization technique. The nal product was formed
by further dehydrogenation of the C- ring with a 10% Pd/ C catalyst (Pakhare and
Kusurkar 2015).
Fandrick et al. invented the process of propargylation of cyclic aldimines by
copper catalysis (Scheme 2.10). With a high yield and stereoselectivity, (S)- harmicine
was synthesized by using a coupling agent, copper(II)isobutyrate, and a chiral ligand.
The ring closure and subsequent C= N bond reduction was catalyzed by titanium, and
the resulting compound was deprotected and transformed into the nal compound
(Fandrick et al. 2016).
3.10 SYNTHETIC ASPECTS OF BETA- CARBOLINES HAVING
ANTIBACTERIAL PROPERTY
Pictet- Spengler reaction of tryptamine with pyruvaldehyde in acid was the rst step
in the development of acetyl- carboline, which was then aromatized in situ using 10%
palladium on carbon. To get N- boc- 1- acetyl- carboline, di- tert- butyl dicarbonate was
used to shield the N- H group of 1- acetyl- carboline from oxidation in the presence
of dimethyl aminopropional (DMAP) (Scheme 2.11). In addition, Scheme 2.11
gave good- to- excellent yields of β- carboline chalcone analogues after reacting with
respective aldehydes in the presence of a 20% NaOH solution in aqueous ethanol
for 16 hours. Bromide salts (the nal product) were obtained from the N2- alkylation
of three β- carboline chalcones with various alkylbromides with a yield of over 80%
(Venkataramana Reddy et al. 2018).
Using Neamine derivatives rich in amino groups, the coupling reaction was
executed (Scheme 2.12). The substance was synthesized by reacting amines
with acids. Similarly, tetrahydro- 2H- pyran- 3,4- diyl dibenzoate was obtained by
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