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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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β- Carbolines
exposed to UV light, pBR322 plasmid DNA was observed to be cleaved. DNA fragmentation testing, Hoechst staining, and Annexin V- FITC analysis all supported the
malignant cells apoptosis. A few compounds had topoisomerase I inhibitory action in
addition to combilexin characteristics. From molecular docking and binding, it was
found that topoisomerase I inhibition was mostly caused by the development of a
ternary complex of DNA and topo I as well as a bimodal contact with DNA (Kamal
et al. 2014; Luo et al. 2009).
As DNA binding and topoisomerase inhibitors, β- carboline- bis- indole motifs were
synthesized by via Amberlite IR- 120H as a reusable heterogeneous catalyst in reux
conditions (Kovvuri et al. 2018). Dess- Martin periodinate was employed to mediate
the oxidation of 64 to produce methyl- β- carboline- 3- carboxaldehyde 65, which was
then treated with various substituted indoles in a water- methanol solvent to produce
66 (Scheme 1.20).
Through the use of the MTT assay, all of the prepared β- carboline- bis- indole
motifs were tested for their ability to inhibit the proliferation of a number of
human cancer cell lines, including A- 549, DU- 145, HeLa, and MCF- 7. These
compounds demonstrated moderate- to- good anticancer activity, with doxorubic
serving as the positive control and IC50 values in the scale of 1.80 to 44.20 μM.
Following the 4- methyl (66a) substitution, the compound with the 4- fluoro
(66b) substitution on the phenyl ring at C1 position displayed tremendous
antiproliferative action against DU- 145 cells. The anticancer activity was significantly affected by the quantity of methoxy groups on the phenyl moiety.
SCHEME 1.20 Synthesis of β- carboline- bisindole derivatives.
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.21 Synthesis of bivalent β- carboline derivatives.
When the 4- methyl group 66a on the phenyl ring was replaced with an added
electron- rich methoxy group, the activity against DU- 145 was reduced by
1.4 times. These compounds interact with DNA topoisomerase I to produce a
ternary enzyme- DNA- ligand complex structure, which inhibits it, according to
molecular docking and binding studies.
Du H et al. reported the synthesis of novel bivalent β- carboline derivatives and
investigated their impacts on the cell cycle, apoptosis induction, and antiproliferative
action on a group of cancer cell lines (Du et al. 2016). The investigation showed that
bivalent β- carbolines are more effective at inhibiting cell proliferation than monomer.
Additionally, the antiproliferative effects of bivalent β- carbolines were enhanced
when a methyl or benzyl group was added to position- N9. Harmine 67 was isolated
from Peganumharmala L., and from harmine, N9- substituted analogues 68 and 69
were prepared. Then, based on monomeric β- carbolines chain varying from n as 4
to 8, the bivalent β- carbolines 69 were synthesized by reacting with the appropriate
dibromoalkane in ethyl acetate (Scheme 1.21). These compounds have various groups
as spacers between the nitrogens of the pyridine ring.
1.3.1.5 Scission
Al- Allaf et al. documented the fabrication of trans- palladium complex 70 and harmine
67, along with a cytotoxic evaluation against P388, L1210, and K562. In order to
produce the palladium complex 70, PdCl2 was added to DMSO and heated to 90°C
for two hours in order to completely dissolve. Following the ltration of the reaction
mixture, the ltrate was mixed with the HCl solution and allowed to cool to ambient
temperature in order to carry out the whole precipitation process. Furthermore, the
multifaceted trans- [Pd(DMSO)2Cl2] 70 was dissolved in gently heated DMSO, and
harmine 67 was added slowly while being violently agitated. Once the mixture
cooled, drops of a cold HCl solution were applied until the entire required component
71 (Scheme 1.22) precipitated.
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β- Carbolines
SCHEME 1.22 Synthesis of harmine trans- palladium complex.
SCHEME 1.23 Synthesis of β- carbolines with terminal guanidinium.
Compound 71 had a signicant cytotoxic impact (IC50 value ranging in between
0.364– 0.38 μM) in comparison to platinum- containing drugs such as carboplatin and
cisplatin (Al- Allaf and Rashan 1998). A number of platinum (II) and palladium (II)
complexes with different β- carbolines, such as harmaline, harmalol, harmine, and
harman, were additionally prepared and described for their antiproliferative effects
against three tumor cells, with IC50 values ranging from 0.2 to 2.0 mg/ mL (Al- Allaf
et al. 1990). According to Yu et al., the reaction of 72 with S- Methyl urea in sodium
hydroxide base yielded β- carboline motifs with terminal guanidinium changeover 73
(Scheme 1.23). On tat- TAR, compound 73 displayed inhibitory effects. The capillary
electrophoresis assay demonstrated that these drugs also have the ability to block
tat- TAR interactions in addition to their TAR- binding characteristics (Yu et al. 2004).
β- carboline- carbohydrate hybrid motifs synthesis and anticancer efcacy were
reported by Toshima et al. Trimethylsilyl triuoromethane sulfonate was used in the
reaction between compound 74 and carbohydrate derivatives to yield compound 75
(Scheme 1.24). It was found that when exposed to long- wavelength UV radiation, a
β- carboline- carbohydrate cross molecule containing 2, 6- dideoxy sugars cleaves DNA
at the guanine site. Since many naturally occurring DNA binding anticancer drugs
have different forms of 2,6- dideoxy sugars, many 2,6- dideoxy sugars were employed
as the source of carbohydrates for the design of such hybrid motifs. Furthermore,
these compounds 52 displayed increased DNA cleaving ability due to the hydrophobicity of sugar molecule that has been found to be favorable for binding to DNA
grooves (Toshima et al. 2002).
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.24 Synthesis of β- carboline- carbohydrate hybrid.
1.3.2 KiNAses As TArgeT
By phosphorylating amino acids with ATP, protein kinases control the biological
activity of proteins. This process converts proteins from their inactive state to their
active state by generating conformational changes. Protein kinase inhibitors are now
acting as prospective targets for the treatment of cancer because kinases play a signicant role in modulating a variety of cell processes, including apoptosis, proliferation,
DNA damage and repair, cell motility, etc. Therefore, occasionally they function as
cogenesis. Novel forms of 7, 8- dichloro- 1- oxo- β- carboline motifs have been produced
and their ability to inhibit kinases tested. The main reason for the inherent afnity of
kinase inhibitors for kinases is their ATP- mimetic binding to the kinase hinge section.
However, the substituted 7, 8- dichloro- 1- oxo- β- carboline motifs have unique struc-
tural properties of the alkaloid bauerine C, whose kinase inhibitory effect is independent of the standard ATP- mimetic hinge interactions. The presence of halogen
bonds with kinase backbone residues and an unexpected, inverted binding mode
were both revealed by the cocrystal. Compound 76 was cyclized with sodiumhydride
(NaH), and after reacting with N- Boc- 4- piperidone using methyl iodide, compound 77
was produced. Compound 78 was then produced by performing out the deprotection
reaction in the presence of TFA (Scheme 1.25). The substances exhibit exceptional
selectivity against a variety of human protein kinases as inhibiting specic kinases
like PIM1. These motifs were suggested to be useful conceptual frameworks for the
synthesis of some kinase inhibitors, such as the PIM family, CLKs, DAPK3 (ZIPK),
BMP2K (BIKE), etc., by biochemical and structural studies (Huber et al. 2012).
1.3.2.1 Haspin Kinase Inhibitors
Haspase kinase inhibitors engage in recreation in the treatment of cancer and are
among the best probes for illuminating the cellular functions of proteins. It was
communicated to Cuny et al. who evaluated β- carboline as a potential haspase kinase
inhibitor (Cuny et al. 2012). In stronger base NaOH, compound 79 was reacted with
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β- Carbolines
SCHEME 1.25 Synthesis of 7,8- dichloro- 1- oxo- β- carbolines.
SCHEME 1.26 Synthesis of β- carboline derivatives.
phthalimide- protected alkylamines to form compound 80, which was then deprotected
with hydrazine hydrate to yield compound 81 (Scheme 1.26). High- throughput
screening (HTS) was used to determine the synthetic β- carboline motifs ability to
inhibit haspase- kinase at various concentrations. A compound with an IC50 value of
0.10 μM was discovered to be the most active of those that had potential activity. It
was discovered that the substance with amine at position N- 9 signicantly lowered
the power of the enzyme when tested against human DYRK2.
As B- Raf inhibitors, Xin et al. synthesized a number of 1- carboxamide- and
6- sulfonamide- substituted β- carboline motifs that play a crucial role in the MAPK
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β- Carbolines as Anti-Cancer Agents
signal- transduction conduit that controls cell proliferation, differentiation, and survival (Xin et al. 2012). Starting with the indole derivative 82, compound 83 was
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prepared through cyclization reaction, and on esterication yielded compound 84,
which on dehydrogenated with the use of the potassium permanganate to form aromatic ester 85. Ester 85 on direct amidation by methanolic ammonium hydroxide
yields compound 86, which on a reaction with chlorosulfonic acid at 0 0C temperature
gives compound 87. Compound 87 treated with different amines gives target motifs
88 (Scheme 1.27). The IC50 values for all the produced compounds ranged from
1.62 to 91.55 μM, indicating extremely strong inhibitory effects. One- carboxamide6- (N- (3- (dimethylamino) propyl)- sulfamoyl)- β- carboline 88a, which contains two
dimethyl aminopropyl groups and has an IC50 value of 1.62 μM, was found to be
the most powerful compound. With an IC50 value of 2.81 μM, it was shown that substituting diethyl aminopropyl for both dimethyl aminopropyl groups led to a reduction in activity. With wild- type B- Raf kinase, molecular docking studies were carried
out to determine the binding model of these drugs. With the hinge backbone carbonyl oxygen and amide of CYS531, respectively, H- bonding between the NH of
the carboxamide and the nitrogen atom of pyridine was seen when the most effective
molecule, 88a, was docked with B- Raf kinase. Additionally, the NH and nitrogen
atoms of sulfonamide may form two hydrogen bonds with the amide and carbonyl
oxygen of ASP593, and the oxygen atom of sulfonamide can establish two hydrogen
bonds with the amine of LYS482. This is identical to the binding models found in
the crystal structures of the DFG loop and hinge region in association with the BRaf inhibitors Sorafenib and PLX4032, respectively. It was then decided that new
B- Raf inhibitors may be constructed using the β- carboline ring as the hinge binder.
The innovative synthesis protocol of 1- carboxamide and 6- sulfonamide- substituted
β- carboline drug 91 is shown in Scheme 1.28.
1.3.2.3 Cyclin- dependent Kinase Inhibitors
Cyclin- dependent kinases (CDKs) are heterodimeric protein kinases that control cell
cycle succession through phosphorylation. It has been demonstrated in numerous
cases that CDKs are frequently dysregulated in human cancers; as a result, CDK
inhibitors are given to stop cell proliferation during cancer treatment. ATP- Mg
and CDK inhibitors ght for the ATP- binding site of CDKs. When harmine and
1- substituted β- carboline motifs were made and their anticancer efcacy assessed,
5- methylimidazol- 4- yl 92 (Figure 1.3) was found to have the most CDK inhibitory
activity, inhibiting CDK5 by 94% at a concentration of 50 μM and CDK2 by 89% at
the same concentration (Lo and Zhang, 2012).
Iridium complex is a new anticancer drug that improves focus by inducing apoptosis and interacts with DNA or protein kinase. Liang et al. reported the preparation
of two cyclometalated iridium (III) complexes with 2- (2- thienyl) pyridine (thp) 93
and β- carbolines alkaloids as functional ligands 94 (Figure 1.4). Two equivalents of
β- carboline and the corresponding dimer of cyclometalated Ir(III) were reuxed in a
mixture of DCM and MeOH (2:1) before being subjected to an anion exchange reaction using NH4PF6. Complexes 69 and 70 were tested against the A- 549, A- 549cisR,
cisplatin- resistant A- 549, HepG2, HeLa, and LO2 cancer cells (He et al. 2014)
2+
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β- Carbolines
SCHEME 1.27 Synthesis of 1- carboxamide- 6- sulfonamide substituted β- carbolines.
SCHEME 1.28 Synthesis of β- carbolines 91.
1.3.3 TubuliN/ MicroTubule As A TArgeT
The synthesis of 1- substituted 1, 2, 3, 4- tetrahydro 95 and 3, 4- dihydro β- carboline
96 motifs was carried out by Shen et al. with starting indole derivative 82 (Scheme
1.29). The Pictet– Spengler reaction method was employed to synthesize the desired
compounds 95, which were then subjected to DDQ oxidation to produce compounds
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β- Carbolines as Anti-Cancer Agents
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FIGURE 1.3 Structure of iridium (III) biquinoline complex.
FIGURE 1.4 Structures of the Ir(III) complexes 93 and 94.
SCHEME 1.29 Synthesis of β- carbolines.
96. The anticancer efcacy of the produced compounds was tested against the human
tumor cell lines KB- 16, A- 549, and HT- 29 as well as the murine P- 388 tumor cell
line86. Compound 96 demonstrated great activity because it has a planar structure
due to this double bond between C- 1 and C- 2, which is essential for cytotoxicity and
may make it easier to intercalate with the DNA molecule (Shen et al. 2005).
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1.3.4 KiNesiN (eg5) iNhibiTors
β- Carbolines
Based on the known structure of the Eg5 inhibitor HR22C16, Shankaraiah et al.
described the preparation and anticancer assessment of a variety of hybrid tetrahydro-
β- carboline- hydantoin motifs. Compound 97 yields hydration- fused tetrahydro-
β- carbolines 98 after its treatment with different isocyanates (Shankaraiah et al.
2014). Favorable cis product was produced in the current reaction, and it was easily
transformed into trans- hydantoin- fused tetrahydro- carbolines 99 during basecatalyzed epimerization at the C11 position in reux conditions using acetonitrile
and K2CO3 (Scheme 1.30). Through the MTT assay, the in vitro cytotoxicity of all
the synthesized compounds was assessed against the cell lines A549, ME- 180, HeLa,
MCF- 7, and PC- 3. The compounds reported IC50 values of fewer than 20 mM against
the PC- 3, A549, and MCF7 cell lines, exhibiting equipotent action to that of the reference standard etoposide. It effectively binds to the Eg5 motor proteins allosteric site,
which is predominantly made up of the residues Glu116, Gly117, Glu118, Trp127,
Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215, according to molecular
docking studies. One compound showed high specicity towards prostate cancer cells
and its IC50 was ve times higher in normal prostate epithelial cells (RWPE) than the
standard drug. Other compounds were discovered to be extremely active against PC- 3
cell lines and were subsequently screened for in vitro cytotoxicity on ordinary RWPE.
1.3.5 hDAc iNhibiTors
As HDAC inhibitors, Ling et al. reported the synthesis of β- carboline hydroxamic
acid. When compound 100 is treated with NH2(CH2)nCOOMe, a Curtius rearrangement occurs to produce compound 101. Compound 101 then reacts with NH2OK
SCHEME 1.30 Synthesis of tetrahydro- β- carboline- hydantoin hybrids.
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SCHEME 1.31 Synthesis β- carboline/ hydroxamic acid hybrids.
in MeOH to yield hydroxamic acid derivatives 102 (Scheme 1.31). The effectiveness
of each produced drug was tested against an HDAC- enriched HeLa cell nuclear
extract. Typically, HDAC inhibitors have three domains: the zinc binding group, the
hydrophobic aromatic substitution on the cap group, and the saturated or unsaturated
linker domain. In this instance, the zinc binders cap group was identied by
the β- carboline ring and hydroxamic acid fragments. The compounds ability to
block an enzyme when it contains one or two methylene units was minimal, whereas
compounds with more than two methylene units displayed increased inhibitory efcacy (Ling et al. 2015). A series of β- carboline and N- hydroxycinnamamide hybrid
motifs were described by Ling et al. as potential HDAC inhibitors for the treatment of
drug- resistant hepatocellular cancer. In the presence of a base, compound 103 reacted
with methyl bromoethylcinnamate to yield compound 104, which was then treated
with NH2OK in methanol (Scheme 1.32). Compound 104a demonstrated potent and
precise antiproliferative effects on HepG2, Bel7402, and drug- resistant Bel7402/ 5FU
cells. In Bel7402/ 5FU cells, it controlled the appearance of proteins associated with
apoptosis and signicantly increased autophagic ux activity (Ling et al. 2019).
Ji Liu et al. reported the synthesis of a number of new hydroxamate derivatives
111 based on β- carboline that were used as HDAC inhibitors depicted in Scheme
1.33 (Liu et al. 2017). The majority of these inhibitors were shown to have strong
histone deacetylase inhibitory effects as well as superior antiproliferative activity
among IC50 in the low micromole range. In line with its effective HDAC inhibition,
compound 111k also led to a rise in the acetylation of histone H3 and α-
tubulin. Importantly, compound 111 caused hypochromism through an electrostatic
contact with CT- DNA, which raises the possibility of causing DNA damage.
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