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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
SCHEME 1.7 Synthesis of β- carboline- 3- carboxyl- Trp- Trp- AA- OBzl compounds.
For pharmaceutical action, the outcomes were compared to the reference standard
using cyclophosphamide (CTX). At dosages of 30 and 40 mg/ kg, certain compounds
showed tumor inhibition rates of 50.8% and 56.2% against mice with Lewis lung
cancer, CT- 26 colon cancer, and H22 liver cancer, respectively, against these mice
(Shi et al. 2013).
Chen et al. reported synthesis of tripeptide benzyl ester by condensation of a
number of amino acids, and then assessing the biological properties of the unique
β- carboline linked tripeptide. Compound 18 (Scheme 1.7) is prepared by 1- (4-
hydroxy- 3- methoxyphenyl)- tetrahydro- β- carboline- 3- carboxylate 16 interacts
with selenium oxide in the presence of acetic acid, subsequently 1- (4- hydroxy- 3methoxyphenyl)- β- carboline- 3- carboxylic acid 17 is produced by hydrolyzing the
reaction with NaOH. Employing the MTT (3- [4,5- dimethylthiazol- 2- yl]- 2,5 diphenyl
tetrazolium bromide) assay on the cancer cell lines HT- 29, A- 549, K- 562, and HL- 60,
all 18 prepared compounds were assessed; the outcomes showed moderate activity.
While certain compounds showed the highest efcacy in the in vivo study when
tested on S- 180 mice, displaying tumor inhibition of 63.4% and 62.9%, respectively,
which was comparable to the positive control, adriyamycin (61.1%), an anticancer
drug. These compounds operate by DNA intercalation. β- carboline and Trp- Trp,
the two structural units, both have planar polycyclic aromatic pharmacophore that
can stack at the DNA pairs’ intercalation sites. The process in which the β- carboline
derivatives synthesized in this study intercalated with the DNA of calf thymus (CT)
was examined. A variety of well- known, simple, yet accurate procedures were used in
spectroscopy, including relative viscosity tests with and without CT DNA and other
data indicating intercalative binding of the β- carboline derivatives to DNA (Chen
et al. 2014).
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β- Carbolines as Anti-Cancer Agents
1.3.1.2 DNA Groove- binding Agents
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Numerous DNA- interactive C3- tethered 1, 2, and 3- triazolo- β- carboline motifs were
synthesized via the click reaction, and their cytotoxicity was examined in vitro.
Compound 19 reacted with sodium azide in DMF via Cu(I)- catalyzed azide- alkyne
cycloaddition (CuAAC), and then it reacted with different alkynes to form C- 3 linked
1,2,3- triazolo- β- carboline hybrids motifs 20 (Scheme 1.8). Each of the 20 compounds
was evaluated for its in vitro cytotoxicity against the gastric cancer cell line HGC- 27,
PC- 3, HeLa, MCF- 7, and HT- 29. Only a few of the compounds exhibited IC50 values
less than 10 µM. Compound 20a was shown to be the most potent against HT- 29, with
an IC50 value of 3.67 µM. Molecular docking studies revealed that these drugs were
actually bound to a tiny groove in DNA. Experiments such as circular dichroism,
uorescence titration, UV- visible titration, and viscometrical titration corroborated
the previous results and demonstrated that compound 20 exhibits a strong electrostatic bond with DNA (Shankaraiah et al. 2016).
By IC50 value of 0.13 µM, compound 19e from this new series was discovered
to have potential cytotoxic property against the triple- negative breast tumor cell line
(MDA- MB- 231). Notably, the DCFDA assay revealed that 19e promoted the production of ROS. Moreover, identifying 19e moiety JC- 1 enables to observe the breakdown
of the mitochondrial membrane potential. Furthermore, 19e was found to suppress
colony pattern and cell migration in a dose- reliant manner in clonogenic and wound
healing experiments. The typical intercalation of 19e with CT- DNA with a binding constant of 1x105 M
- 1
was then identied by molecular modeling and DNA binding afnity
experiments using relative viscosity, circular dichroism, and UV- visible spectroscopy.
The cytotoxic activity of 3- (1H- benzo[d] imidazole- 2- yl)- β- carboline metal complex was tested by Jin et al. using cisplatin as the standard reference. The metal
β- carboline complexes 22 to 25 shown in Scheme 1.9 were produced as a result of the
reaction between the β- carboline imidazole amalgam 21 and a number of metal salts.
When compared to the usual cisplatin treatment, the anticancer evaluation report
against several cancer cell lines was unsatisfactory (Jin et al. 2014).
The structural unit of naturally occurring eudistomin compounds contains
β- carboline and exhibits a numerous biological attributes. The prepared eudistomin
K derivative showed excellent efcacy when tested against numerous malignant
cell lines, including LI- 210, Molt- 4F, MT- 4, and P- 388 leukemic cells. Successful
overall synthesis of Eudistomin U was noted and its cytotoxicity examined. A Suzuki
SCHEME 1.8 Synthesis of C3- tethered triazolo- β- carboline derivatives.
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β- Carbolines
SCHEME 1.9 Synthesis of β- carboline complexes with 3- (1H- benzo[d] imidazole- 2yl)- metal.
SCHEME 1.10 Synthesis of eudistomin U.
cross- coupling reaction among β- carboline and indoleboronic acid followed by
DDQ- mediated oxidation of lactum 26 produced compound 27, which was then
transformed into the desired product 28 in the presence of a base (Scheme 1.10). The
prepared compound has IC50 value of 15.6 M against the C19 cancer cell line when its
potency was evaluated using the MTT cell viability test (Rinehart et al. 1984; Schupp
et al. 2003).
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.11 Synthesis of novel nickel (II) complex of 6- methoxy- 1- pyridine- β- carboline.
Jing- Mei Yang et al. fabricated a novel nickel (II) complex of 6- methoxy- 1-
pyridine- β- carboline 33, which is depicted in Scheme 1.11. The intermediate 31
was prepared from commercially available 5- methoxytryptamine 29 and pyridine- 2-
carbaldehyde 30 by using Pictet– Spengler cyclization (Yang et al. 2018). 6- Methoxy-
1- pyridine- β- carboline 32 was found from intermediate 31 by dehydrogenation,
which was catalyzed by Pd/ C. Finally nickel (II) complex of 6- methoxy- 1- pyridine-
β- carboline 33 was made by hydrothermal synthesis in 12:1 methanol/ DMSO using
Ni((II)NO3)2•6H2O and 6- methoxy- 1- pyridine- β- carboline 32.
The produced complex is subjected to cytotoxicity evaluations against six cancer
cell lines (MGC- 803, Hep G2, T24, OS- RC- 2, NCI- H460, and SK- OV- 3) as well as
the human normal liver cell line HL- 7702. Compared to ligand 32 and cisplatin, the
IC50 values of MGC- 803, Hep G2, T24, OS- RC- 2, NCI- H460, and SK- OV- 3 were
generally lower, falling within the micromolar range (3.77– 15.10 μM).
Ramya Tokala et al. reported production of novel β- carboline- thiazolidinedione
hybrids motifs and evaluated for in vitro cytotoxicity possibilities against certain
human cancer cell lines, specically, PC- 3, A549, MG- 63, HCT- 15, MDA- MB231, A431, and PANC- 1 along with a normal human cell line (L- 132) (Tokala et al.
2018). β- carboline- linked 2,4- thiazolidinedione hybrids motifs 39 were prepared by
a parallel synthesis principal used in the Knoevenagel condensation reaction. The
condensation reaction between 1- aryl- 9H- pyrido[3,4- b]indole- 3- carbaldehydes
36 and various substituted 2,4- thiazolidinediones was performed (Scheme 1.12).
Readily available L- tryptophan 34 esteried using thionyl chloride in methanol gives
L- tryptophan ester 35, which subjected to Pictet– Spengler reaction with different
aldehydes by with catalytic quantity of TFA produces diastereomers 36. The compound 36 aromatized by means of KMnO4 to afford 37 followed by reduction of ester
group with LiAlH4 offers the consequent alcohols 38. Activated MnO2 then converted
these alcohols to their related aldehydes 39.
Through the Pictete– Spengler condensation of L- tryptophan with formaldehyde,
the free ligand Norharman was generated quickly and then reuxed in ethanol to
produce Ru1 through Ru4 (Chen et al. 2013). These ndings showed that the 2- N
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SCHEME 1.12 Synthesis of novel β- carboline- thiazolidinedione hybrids motifs.
β- Carbolines
atoms on Norharman are coupled with ruthenium. The DFT approach was used to
optimize the complexes Ru1 through Ru4 geometries depicted in Figure 1.2.
According to Siyu Zhu et al., new β- carboline- fused imidazolium motifs 45 were
synthesized, based on the fascaplysin structure, and tested for cytotoxicity (Zhu et al.
2022). The 3- (4,5- dimethylthiazol- 2- yl)- 2,5- diphenyltetrazolium bromide (MTT)
assay was used to assess the cytotoxicity of 45 in lung carcinoma (A549), gastric carcinoma (BGC- 823), murine colon carcinoma (CT- 26), liver carcinoma (Bel- 7402),
and breast carcinoma (MCF- 7) cell lines. The ndings demonstrated that the majority
of the target compounds exhibited outstanding activity against one or more cancer
cell lines. The compounds’ strong inhibitory effect on VEGFR2 was conrmed by
docking studies because it bound to the important amino acids in the active site
(Ile892, Leu889, and Asp1046) and interacted hydrophobically with the hydrophobic pocket of the receptor. Scheme 1.13 depicts the target novel β- carboline- fused
imidazolium derivatives synthesis processes. L- tryptophan was used as the starting
material for synthesis of harmane using Pictet– Spengler cyclization, which was then
followed by oxidation and decarboxylation in one step with the help of active manganese dioxide (MnO2). The key intermediates, β- carboline- 1- carboxaldehydes 43, were
produced by rst synthesizing the N9- alkylation products 41 from the harmane 40.
The methyl group at position 1 of the compounds 41 was then further oxidized to its
corresponding carboxaldehyde using selenium dioxide (SeO2) in anhydrous dioxane.
Finally, the required β- carboline N- fused imidazolium 44, 45 was synthesized by
reacting 43 with the appropriate primary amine, formaldehyde, and acetyl chloride
while utilizing anhydrous alcohol as a solvent.
As reported by Dighe et al., the Mannich reaction between methyl 1-
(dimethoxymethyl)- 9H- pyrido[3,4- b]indole- 3- carboxylate 46, formaldehyde, and
primary amines synthesized a number of new N- heterocyclic carbenes based on
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β- Carbolines as Anti-Cancer Agents
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FIGURE 1.2 Geometries of complexes Ru1, Ru2, Ru3 and Ru4.
SCHEME 1.13 Synthesis of β- carboline- fused imidazolium motifs.
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β- Carbolines
SCHEME 1.14 Synthesis of N- heterocyclic carbenes based on β- carbolines.
β- carbolines 49 as shown in Scheme 1.14 (Dighe et al. 2015). Using human breast
cancer and lung cancer cell lines, the antiproliferative effectiveness of each synthesized
β- carboline motif was evaluated. After 24 hours of treatment, three motifs of 49
displayed IC50 values of less than 10 μM against human breast cancer MDA- MB- 231
cells. However, owing to their great afnity for HSA, which was examined spectroscopically with compound 3h, these analogs had no in vivo effect in animal models.
The starting compound methy- 1- formyl- 9H- carboxylate 46 react with formaldehyde
and aniline in ethanolic HCl solvent in situ by replacing HCl with AcCl, this reaction
condition gave a product 49 in 92% yield.
By introducing various alkylamino(methyl) groups into the 1,3,4- oxadiazole unity
of 50, Savariz et al. reported the synthesis and anticancer activity assessment of many
new Mannich bases (Savariz et al. 2010) 51 (Scheme 1.15). The aim of the current
report is to synthesize six series of β- carboline derivatives employing the Mannich
bases formation reaction and to investigate the effects of various 3- alkylamino
(methyl) substituents on the oxadiazole ring with the expectation that performing so
will improve their antitumor activity. More particularly, the production and anticancer
action in vitro of 3- alkylamino(methyl)- 2- thioxo- 1,3,4- oxadiazol- 5- yl groups at C- 3
on β- carboline derivatives 51. The antibacterial properties of Mannich bases 51 and
50 were also assessed.
1.3.1.3 Topoisomerase Inhibitors
Sathish et al. outlined the synthesis of podophyllotoxin- linked β- carboline motifs for
potential applications as DNA topoisomerase II inhibitors and anticancer medicines
(Sathish et al. 2018). Compounds 53 are produced when β- carboline acids 52 react
with 4- amino- podophyllotoxin in the presence of the coupling mixture of EDCI and
HOBt as shown in Scheme 1.16. Using the MTT approach, the in vitro cytotoxicity
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.15 Synthesis Mannich base based β- carboline derivatives.
of all synthesized podophyllotoxin linked β- carboline motifs against several human
cancer cell lines, including A- 549, DU- 145, MDA MB- 231, HT- 29, and HeLa, was
assessed. Most of the 30 motifs exhibited excellent cytotoxicity and selectivity against
DU- 145 cells as compared to doxorubicin, etoposide, and podophyllotoxin, with an
IC50 value ranging from <10 μM to <5 μM.
Additionally, Kamal et al. prepared a dithiacarbamate with β- carboline motifs
that have the ability to block DNA topoisomerase II and induce apoptosis (Kamal
et al. 2015). The compound 54 has been transformed into the expected compound
55, depicted in Scheme 1.17, through the addition of carbon disulde, alkyl halides
such as methyl iodide, allyl bromide, and benzyl bromide, as well as TEA in pyridine. The cytotoxic effects of all the produced compounds on a variety of cancer cell
lines, namely A- 549, MCF- 7, DU- 145, and HeLa, were studied. These synthesized
compounds 55 were then tested for their ability to induce apoptosis using Annexin
V- FITC, Hoechst staining assays, and DNA- binding studies. It was found that these
compounds bind to DNA more strongly and inhibit topoisomerase II, which causes
cell death.
The impact of Harman and norharmanon on the functions of DNA topoisomerases
was studied by Funayama et al. It was found to inhibit DNA topoisomerase I activity,
with corresponding ED50 values of 23.8 and 34.4 mg/ ml (Funayama et al. 1996).
However, topoisomerase II- mediated stability of the complex that can be broken as
well as topoisomerase II inhibitory action were not seen with these drugs. Scheme
1.18 depicted the synthesis route of amino acid functionalized β- carboline motifs.
1.3.1.4 Combilexins
One of these compounds, called combilexin, has the ability to attach to DNA in two
different ways: by binding to the DNA minor groove and by intercalating DNA.
A set of substituted phenyl and chalcone/ (N- acetyl)- pyrazole moiety containing
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β- Carbolines
SCHEME 1.16 Synthesis of podophyllotoxin linked β- carbolines.
SCHEME 1.17 Synthesis of dithiacarbamate containing β- carbolines.
β- carboline hybrid motifs 62 were synthesized by Kamal et al. Using the 3- (4,5-
dimethylthiazol- 2- yl)- 2,5- diphenyl tetrazolium bromide (MTT) assay (Scheme 1.19),
all the prepared hybrid products 62 and 63 were evaluated against several cancer
cell lines, including A- 549, DU- 145, MCF- 7, HeLa, ACHN, and HEK- 293 celllines.
Doxorubicin and harmine served as positive controls. When some compounds were
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.18 Synthesis of amino acid functionalized β- carbolines.
SCHEME 1.19 Synthesis of Combilexin.
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