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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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β- Carbolines
FIGURE 5.2 Number of publications with the keyword “β- carboline” between 2010 and
2022 pointed in the PubMed® and Scopus® databases.
A number of reviews and book chapters published in the last ve years systematize the synthetic possibilities for the design of natural products based on
β- carbolines (Chundawat 2020), including the most recent advances in the synthesis of β- carboline alkaloids with improved procedures for their synthesis (Devi
et al. 2018; Dai et al. 2018) and their pharmacological potential (Szabó et al.
2021; Ayipo et al. 2021с; Thatikayala et al. 2022); the presence of β- carbolines in
foodstuffs and prevention of neurodegenerative diseases (Piechowska et al. 2019);
combination of the β- carboline core with various pharmacophores and screening
of the products for anticancer properties (Soni et al. 2021; Sanctis et al. 2022; Luo
and Song 2021; Aaghaz et al. 2021; Sahoo et. Al. 2019); metal complexes with
β- carboline- based ligands (Ayipo et al. 2021b); and also studies of the fungicidal
(Dai et al. 2022), antimicrobial (Almeida et al. 2021), antimalarial (Kamboj
et al. 2021), and antileishmanial (Banoth et al. 2020) activities. There are also
publications that systematize the syntheses of the 1,2,3,4- tetrahydro- β- carboline
core with various pharmacological properties (Wang et al. 2021a; Maity et al.
2019), including their use as effective pesticides (Song et al. 2021). A recent review
addresses the structure– activity relationships of β- carbolines in SAR analysis
(Abinaya et al. 2022). Numerous β- carboline alkaloids were proposed as potential
agents for the treatment of nervous and mental disorders (Ayipo et al. 2021a), in
particular Alzheimer’s disease (Beato et al. 2021).
The growth of research interest in the synthesis and unique biological properties of
the β- carboline core is conrmed by the increasing number of relevant publications
in reference databases such as PubMed® (2023) and Scopus® (2023) (Figure 5.2).
However, to our knowledge, no systematic reviews on the sulfur- containing
β- carboline derivatives are currently available from the scientic literature. This
chapter describes the advances made in the last two decades in the synthesis of
sulfur- containing β- carboline scaffolds and elucidation of their biological activities.
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Sulfur- containing β- Carbolines
The literature search was mainly performed using the Scopus®, Pub Med®, and SciFinder® databases (2022).
5.2 SULFUR- CONTAINING β- CARBOLINE: SYNTHESIS AND
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DRUG DESIGN
Sulfur- containing compounds represent an important class of functional molecules,
including active pharmaceutical intermediates (APIs) and materials. The most
common groups of organosulfur compounds are classied, depending on the sulfur
oxidation state and type of bonding, into thioethers, disuldes, trisuldes, sulfoxides,
sulfones, sulfonates, sulfates, sulfonamides, sulfamates, thioesters, thioamides,
isothiocyanates, thiazoles, and thiazolines (Wang et al. 2020). All of these compounds
can serve as building blocks for the preparation of pharmacologically active products.
The sulfur atoms present in biological molecules as sulde or thiol groups (allicin and
amino acids – methionine, cysteine, and taurine) exhibit antibacterial and antioxidant
properties, while the S- CH3 thiomethyl groups incorporated in coenzymes participate in the methyl transport and xation (e.g., S- adenosylmethionine) (Parcell 2002).
Recently, high potential of sulfanyl azoles for the design of molecules with multiple
biological activity was demonstrated (Akhmetova et al. 2022).
In continuation of the studies into the chemistry of sulfur- containing compounds,
we addressed a biologically active class of carboline heterocycles that rank high in the
medical and biological properties.
The S- derivatives of β- carbolines are most often formed by replacement of
hydrogen atoms by the S atom in the C- (1,3) and N- (2) positions of the pyridine ring
(routes a, b, and с) or in the С- (6,7) and N(9) positions of the indole moiety (routes
d, e, f). The preferable way is to introduce the sulfur atoms via Spacers, which
are represented by methylene or ethylene units, or aromatic rings (Figure 5.3). It
FIGURE 5.3 The design of β- carboline S- derivatives.
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β- Carbolines
is noteworthy that studies on thiomethylation or thiolation of the β- carboline core
are virtually missing from the literature. Most studies are devoted to the design of
S- containing β- carbolines via bulky Spacers (Figure 5.3). The atom numbering in
the carboline core corresponded to the International Union of Pure and Applied
Chemistry rules (Abramovitch and Spenser 1964). The material in the review is
arranged in terms of the methods used for functionalization of β- carboline, depending
on the position of S- containing substituent in the ring. In some cases, quite a few
examples of β- carboline synthesis that are beyond the scope of this chapter are deliberately omitted.
An important circumstance is that a number of sulfur β- carboline derivatives were
isolated from natural compounds (metabolites present in marine organisms); their
structures were proven and the strategies for their synthesis were developed. Most
of the presented compounds exhibit versatile biological activities (Figure 5.4). For
example, Gesashidine A has an antibacterial activity against Micrococcus luteus
(MIC = 16.6 µg/ mL) (Suntornchashwej et al. 2005), while Hyrtimomines D, E, J
show an inhibitory activity against Candida albicans (IC50, 4 and 8 lg/ mL; IC50, 2
μg/ mL) and Cryptococcus neoformans (IC50 = 4 and 8 lg/ mL, respectively) (Tanaka
et al. 2013; Tanaka et al. 2014). Meanwhile, the compounds Hyrtimomine H and K
exhibit no antimicrobial activities (Tanaka et al. 2014). Other Dragmacidonamine A,
B derivatives were isolated from the sponge Dragmacidon; only Dragmacidonamine
A had a moderate cytotoxic activity against the L5178Y mouse lymphoma cells
(Ebada et al. 2008; Pedpradab et al. 2004). Mention should be made of Lurbinectedin,
which was used to treat metastatic small cell lung cancer and was found to be cytotoxic
against other types of cancer (He et al. 2019; Li et al. 2022a). The Orthoscuticellines
E metabolite showed a moderate antiplasmodial activity against Plasmodium fal-
ciparum (Prinsep et al. 1991; Kleks et al. 2020). Eudistomidin J, isolated from the
marine tunicate Eudistoma glaucus, showed cytotoxic activity in vitro against P388
(IC50 = 0.043 µg/ mL) and L1210 (IC50 = 0.047 µg/ mL) mouse leukemia cells and
against human epidermoid carcinoma KB cells (IC50 = 0.063 µg/ mL) (Suzuki et al.
2011; Rashid et al. 2001). Stolonine C taurinamide derivatives, isolated from the
marine tunicate Cnemidocarpa stolonifera, exhibited a moderate cytotoxicity against
the PC3 prostate cancer cells when present in concentration of 20 µM (Tran et al.
2015). Shishijimicin A, which was obtained from the ascidian Didemnum proliferum,
deserves special attention. Testing of this compound as an innovative antitumor antibiotic revealed anticancer properties against the P388 leukemia cells (IC50 = 0.48
pg/ mL) (Nicolaou et al. 2015; Oku et al. 2003). Didemnoline A- D metabolites,
differing in the N- substitution of the β- carboline core, were isolated from the tunicate Didemnum and identied (Palanisamy et al. 2017). Ishigadine A, a new indole
alkaloid with a moderate cytotoxic activity against the L1210 mouse leukemia cells,
was isolated from the Okinawa sea sponge Hyrtios sp. (Takahashi et al. 2018).
5.2.1 syNThesis of hybriD β- cArboliNes MoDifieD iN The c- 1 posiTioN by
ThioNe, sulfoNe groups AND beNzoThiopheNe frAgMeNT
In order to prepare molecules with potential fungicidal properties, targeted synthesis
of β- carboline derivatives 12 containing a thione group was carried out (Wang et al.
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Sulfur- containing β- Carbolines
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FIGURE 5.4 Sulfur- containing β- carboline moieties in the composition of natural metabolites.
2021b) (Scheme 5.2). The series of products was tested for the antiviral (against the
tobacco mosaic virus) and fungicidal activities (Fusarium oxysporium, Cercospora
arachidicola Hori, Physalospora piricola, Rhizoctonia cerealis, Alternaria solani,
Pyricularia grisea, Phytophthora capsici, Sclerotinia sclerotiorum). Among this
series of compounds, the highest activity against the tobacco mosaic virus exceeding
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β- Carbolines
SCHEME 5.2 Design of hybrid molecules 12 based on β- carboline scaffold with thiohydrazide
substituent in C- 1 position.
the activity of ribavirin (protective effect = 40 ± 1%) was found for the compounds
containing benzyl and para- bromophenyl substituents at the terminal nitrogen atom
of the thiourea moiety, tested in 500 μg·mL−1concentration (protective effects of 58 ±
3% and 60 ± 2%, respectively). Compounds containing butyl, para- methoxyphenyl,
and benzyl substituents present in concentrations of 50 μg·mL−1 showed >97% selectivity of the fungicidal action against the phytopathogenic fungi Physalospora piricola
and Rhizoctonia cerealis.
Recently, a regioselective method was proposed for the synthesis of mono- ortho-
sulfonamide β- carboline derivatives 15 by the ruthenium- catalyzed reaction of arylsubstituted β- carbolines 13 with sulfonyl azides 14 (Scheme 5.3). This reaction can
take place both with electron- withdrawing and with electron- donating substituents
in the benzene ring of the C- 1- aryl substituent. The synthetic pathway involves the
formation of intermediate ruthenium complex A of N- ligand 13 and azide 14. The
elimination of N2 affords the target ortho- sulfonamides 15. The primary screening
of the antiproliferative action against the cancer cells – HCT- 116 (human colorectal
carcinoma) and A549 (human lung carcinoma) – showed that the compounds provide
a high percentage of inhibition of HCT- 116 cells, being more active than harmine
(Bora et al. 2021).
In 2022, Singh’s research team developed a facile and efcient synthesis of
β- carboline- linked 2- acylbenzothiophenes 18 in the KI– DMSO system (Singh
et al. 2022). This approach is implemented by the crotonic condensation of
1- acetyl- β- carboline 15 with 2- nitrobenzaldehyde 16, which gives the intermediate
2- nitrochalcone- β- carboline 17. The thiophene ring is formed via the reaction of chalcone
17 with elemental sulfur in the presence of an equimolar amount of KI (Scheme 5.4).
5.2.2 DesigN of N(2)- subsTiTuTeD β- cArboliNes wiTh s- fuNcTioN
The effect of N(2)- modication of the tetrahydro- β- carboline scaffold on the
antileishmanial activity was considered in relation to Leishmania donovani
promastigotes and axenic amastigotes (Manda et al. 2014). The target N- alkylated
β- carbolines 20 and 22 were prepared by the condensation of tetrahydro- β- carboline
3 with thienylalkyl(acyl) halides 19 and 21 in the presence of bases (Scheme 5.5).
Among the series of thienyl(thiazole)- substituted tetrahydro- β- carbolines, the highest
activity against promastigotes (IC50 = 9.1 μM) was exhibited by the compound
containing a methyl- 5- chlorothienyl moiety; however, this compound showed no
activity against axenic amastigotes. The same derivative 20 had an antitrypanosomal
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SCHEME 5.3 Ruthenium(II)- catalysed ortho- sulfonamidation of 1- aryl- β- carbolines.
SCHEME 5.4 KI promoted synthesis of 2- acylbenzothiophene- β- carbolines 18 based on the
condensation between 1- acetyl- β- carbolines 15, 2- nitrobenzaldehyde 16 and elemental sulfur.
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β- Carbolines
SCHEME 5.5 Synthesis of N(2)- substituted tetrahydro- β- carbolines.
SCHEME 5.6 Gold(III)- catalyzed cycloisomerization of indole- substituted N-
propargylamides 25 in the design of 2,9- dihydro- β- carboline- 1- ones 26.
activity against Trypanosoma brucei (IC50 = 8.9 μM). There is a single example of
the synthesis of tetrahydro- β- carbolinesulfonamide 24; the synthesis includes the
reaction of tetrahydro- β- carboline 3 with 4- uorobenzenesulfonyl chloride 23 in the
presence of triethylamine (Ren et al. 2022). The authors note that this functionalization
increases the solubility and polarity of the target molecule 24 (Scheme 5.5).
A convenient method for the design of substituted 2,9- dihydro- β- carbolin- 1- ones
26 was developed by Padwa and co- workers (2010). The essence of the method is
the intramolecular cyclization of indole- substituted N- propargylamides 25 in the
presence of gold(III) chloride (Scheme 5.6).
5.2.3 С- 3 fuNcTioNAlizATioN of β- cArboliNes wiTh sulfANyl- , ThioNe- ,
sulfoNe groups via spAcers
Analysis of the data published over the past few years showed a considerable interest
in the design of molecules containing sulfur atoms of different valence: divalent
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sulfur in thioethers and thiones; hexavalent sulfur in sulfates and sulfonic acids, their
salts, and amides. A recent review addresses S- containing scaffolds (ve- , six- , and
seven- membered heterocycles) as important structural elements for the drug design
related to sulfur- containing molecules with cytotoxic properties (Laxmikeshav et al.
2022). According to this concept, β- carboline hybrid molecules were obtained as
multipurpose antitumor agents.
5.2.3.1 Sulfanyl Derivatives of β- Carbolines
In order to block the С- 1 position of β- carbolines, the C- 1 atom was substituted with
the 3- hydrophenyl pharmacophore moiety, which is a structural unit of the monastrol
drug (Abdelsalam et al. 2018). First, key hydrazide 27 was obtained in four preparative steps from tryptophan 7 and 3- hydroxybenzaldehyde. The presence of the
active functional group in the side chain enabled subsequent transformations to prepare a series of sulfur- containing thiosemicarbazide 28 and benzosulfohydrazide 29
derivatives and various heterocyclic systems (thiazolidinone 30 and thiazoline 31,
mono- and bis- 1,3,4- oxadiazole- 2- thiones 28, 30, 31). The range of sulfur- containing
β- carbolines was investigated for anticancer activities against MCF- 7 (breast cancer)
and A- 549 (lung cancer) cells using colorimetric MTT assay with vinblastine as the
reference compound. Screening of the cytotoxic activity in vitro revealed two groups
of most active 3- hydroxyphenyl- 9H- β- carbolines in terms of the IC50 values: these are
compounds containing a thiosemicarbazide moiety at С- 5 and 4- bromophenyl or tolyl
substituent at nitrogen and the S- methyl sulfanyloxadiazole derivative (Scheme 5.7).
Enzyme inhibition assay in relation to topo- I and KSP/ Eg5 ATPase demonstrated
high inhibitory activity of 4- bromophenyl- substituted thiosemicarbazide derivative
SCHEME 5.7 С- 3- Functionalization of 3- hydroxyphenyl- β- carbolines.
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β- Carbolines
SCHEME 5.8 Diversication of sulfur- containing β- carbolines as multi- target anticancer
agents.
28 against both enzymes (IC50 = 5.90 μM for topo- I and IC50 = 13.37 μM for KSP-
ATPase) exceeding that of camptothecin (IC50 = 6.90 μM for topo- I) and monastrol
(IC50 = 16.62 μM for KSP- ATPase), while S- methyl sulfanyloxadiazole derivative 29
showed twice higher inhibitory activity against KSP/ Eg5- ATPase (IC50 = 8.73 μM)
compared with the monastrol activity.
Notably, the bioisosteric replacement of the 1,3,4- oxadiazole moiety by the 1,2,4triazole- 3- thione moiety resulted in a higher anticancer activity in the single- dose
NCI in vitro assay (Abdelsalam et al. 2018). Experiments for studying the mechanism
of cytotoxicity in relation to MDA- MB- 435 melanoma cells showed that lead compound 32 containing a tolyl substituent in position N- 4 causes Pre- G1 apoptosis and
arrests the cell cycle in the G2/ M phase by dual inhibition of both topo- I and KSPATPase, with its inhibitory activity being twice as high as those of camptothecin or
monastrol used as reference compounds (Scheme 5.8).
Later (Barbosa et al. 2016), β- carboline- 4- thiazolidinones were tested for the
anticancer activity in vitro against human cancer cell lines and for the antiviral
activity against the herpes simplex virus type 1 (HSV- 1). It was found that the nature
of the 4- thiazolidinone moiety and substitutions in the β- carboline С- 3 and С- 1
positions determine the biological activity. The presence of 4- dimethylaminophenyl
group in the С- 1 position and N- (2- aryl- 4- thiazolidinone)- carboxamide moiety in
the С- 3 position of β- carboline 37 endows the molecule with enhanced anti- HSV- 1
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FIGURE 5.5 Structures of 4- thiazolidinone- β- carbolines 37- 39 exhibiting anticancer and
antiviral activity.
FIGURE 5.6 C- 3 Functionalization of the β- carboline skeleton by diversication in the
thiazolidinedione moiety.
activity (EC50 = 0.80 ± 2.000 µM). Meanwhile, compound 39, which has the same
С- 1- substituent, but N’- (2- ylidene- 4- thiazolidinone)- 3- carbohydrazide moiety at
С- 3, demonstrates anticancer activity in vitro with GI50 below 5 μM against any of the
tested cell lines (U251, MCF- 7, NCI/ ADR- RES, 786- 0, NCI- H460, OVCAR- 3, and
HT- 29) (Figure 5.5).
In 2018, Tokala et al. obtained a series of novel hybrid molecules 40 containing a
thiazolidinedione moiety in the С- 3 position of β- carboline; in other words, the sulfur
atom in these compounds is linked via a vinyl spacer (Figure 5.6). Cytotoxic activity
assays in vitro using PC- 3 (prostate cancer cells), A549 (lung cancer cells), MG- 63
(osteosarcoma cells), HCT- 15 (colon cancer cells), MDA- MB- 231 (breast cancer cells),
A431 (skin cancer cells), PANC- 1 (pancreatic cancer cells), and L- 132 normal human
lung epithelial cells demonstrated that the molecule containing a para- chlorophenyl
substituent in the carboline С- 1 position and a morpholinethiazolidinedione moiety
in the С- 3 position has the highest activity against the MDA- MB- 231 breast cancer
cells (IC50 = 0.97±0.13 mM). The half- maximal inhibitory concentration of doxorubicin
used as the reference is IC50 = 1.18 ± 0.06 mM. Although this compound has
high cytotoxicity against cancer cells, it is also toxic (IC50 = 3.33 ± 0.93 mM) against
the conditionally normal L- 132 cells, which attests to non- specic action of this
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