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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 4.5 Various β- carbolines with signicant CDK inhibitory activity.
trials. The CDK4 inhibitory activity of compounds 15 and 16 was demonstrated with
IC50 values of 0.38 μM and 6.51 μM, respectively. The anti- HCT116 activity of 15 and
16 was observed to be potent in in vitro investigations, including mitigation of colony
formation, intrusion and migration, initiation of apoptosis, and cell cycle blockage in
G1 phase. According to the studies conducted in silico, it has been illustrated that they
display favorable biological effects and possess acceptable physicochemical properties
and ADME (absorption, distribution, metabolism, excretion) predictions. These
ndings suggest that compounds 15 and 16 could be promising candidates for further
advancement and preclinical investigation as anticancer drugs that target CDK4 (Li
et al. 2022).
A study using budding yeast as a model system found that 17, a β- C derivative,
inhibited yeast growth and blocked the cell cycle initiation by inhibiting CDK activity.
Laboratory- based studies have indicated that β- C drugs suppressed the kinase activity
of Cdk2/ Cyclin A. This suggests that the CDK inhibition mediated by β- C drugs
could be responsible for their potential antitumor effects (Li et al. 2007).
Inhibitory activity against CDK1/ cyclinB was assessed for a group of compounds
known as pyrrolo[2,3- a] carbazole analogs. The compound 18 was discovered to
be the most powerful inhibitor, with an IC50 in the low micromolar range and producing 90% inhibition at higher doses. Two potential binding modes of 18 in the
ATP- binding cleft were revealed through computational modelling of the CDK1- 18
binding interaction. These modes include interactions with enzyme residues Thr14,
Lys130, and Asp146. Based on the results, it appears that compound 18 has the potential to develop as a CDK1/ cyclin B inhibitor (Fousteris et al. 2008).
An anticancer agent fascaplysin (19) based β- C was examined for biological activities and it was found that they specically inhibit CDK4 more effectively than CDK2.
The most successful compound in the series was 20, which had an IC50 (CDK4- cyclin
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β-Carbolines as Kinase Inhibitors
D1) of 11 µmol, indicating strong inhibitory activity against CDK4- cyclin D1 (García
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et al. 2006).
A set of tryptamine and tetrahydro- β- C biphenyl derivatives were produced with
the use of Suzuki- Miyaura reaction, showcasing exibility of this crucial procedure.
The outcome of this study indicated that most of the compounds displayed notable
selectivity for CDK4/ cyclin D1 as opposed to CDK2/ cyclin A. Moreover, the parabiphenyl variants of the tryptamine and tetrahydro- β- C compounds exhibited better
biological activity when compared to their ortho- and meta- biphenyl analogs. This
observation suggested that the inhibitor’s biphenyl moiety tends to align in a preferred orientation in the “Phe 93 pocket” of the enzyme. The most potent compounds
identied, namely 21, 22, and 23, displayed IC50 values of 9.2 μM, 11.2 μM, and 9
μM, respectively. These biphenyls with parasubstituents contain t- butyl or methyl in
the 4th position. The potent binding mode of these compounds was attributed to their
strong lipophilic component and the suggested p- stacking interaction of the inhibitors
that occurs between them and the “Phe 93 pocket,” which might be the reason for
the observed inhibition properties of the inhibitors against CDK4/ cyclin D1 (Jenkins
et al. 2008).
In a study, two new cyclometalated Ru(II) complexes, 24 and 25, were developed
and their antiproliferative activities were evaluated. The complexes showed lower
IC50 values compared to other noncyclometalated Ru(II)- β- C complexes and cis-
platin. The interaction of Ru(II) polypyridyl moieties with 1- Ph- β- C resulted in a
higher degree of anticancer activity. The hydrophobicity of 24 and 25 was found
to be closely associated with their ability to enter cells and their efcacy in inducing cytotoxicity in tumor cells. Studies on absorption and distribution indicated
that the complexes were primarily conveyed into the cells via the clathrin- mediated
endocytosis route and accumulated within the cell nuclei. It was discovered that
both efciently triggered cell death in HeLa cells by causing mitochondrial impairment, accumulating intracellular reactive oxygen species as ROS, and inducing DNA
damage through ROS. Compound 24 prompted cell cycle inhibition at the G0/ G1
checkpoint by preventing the CDK2/ 4 kinases through downregulation of the expression of CDC25A. The studies uncovered valuable information for formulating and
creating novel cyclometalated Ru(II) compounds with powerful anticancer properties
(Chen et al. 2017).
A wide range of Ru (II)- containing arene entities with a β- C derivative, having
potential CDK inhibitory qualities, were synthesized and investigated for their
anticancer activity. Stability studies revealed that the hydrolysis behavior of these
complexes was signicantly affected by the nature of β- C ligand, and hydrolysis was
restrained at high chloride concentrations. These complexes displayed high potency
against several cancer cell lines, particularly 26 and 27, which showed less cytotoxicity against normal lung broblasts. The mechanism investigations revealed that
these compounds triggered cell death by disrupting mitochondrial function through
a pathway that involved the generation of ROS. Moreover, these complexes inhibited
CDK1 activity and activated G2M phase arrest, suppressing the level of expression of
CDK1 and cyclin B1, an essential regulator gene at the G2/ M boundary. The effectiveness of these complexes as antitumor was observed to have a positive correlation
with their ability to inhibit CDK1/ cyclin B. Additionally, the alliance of Ru (II)- arene
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β- Carbolines
complexes with β- C alkaloids appears to be a promising approach for developing
targeted antineoplastic agents that can overcome cisplatin resistance. According to a
study on the structure- relationship of these complexes, it was found that their stability
in water and capacity for hydrogen bonding with protein targets are crucial factors
(He et al. 2013).
A study revealed that two cyclometalated Ir (III) complexes inhibited a higher
level of anticancer activity against various cancer cell lines. These complexes
demonstrated an anticancer mechanism that was distinct from that of cisplatin. In
contrast to cisplatin, which stimulates apoptotic cell death in A549 cells and initiates
autophagy as a cytoprotective reaction, the mechanism of action of compound 28
involved autophagy- mediated apoptosis that was caspase- independent and ROSmediated, without inducing apoptosis. The activation of autophagy is triggered by
mTOR signaling by compound 28. Furthermore, compound 28 exhibited a strong
inhibitory effect on CDK2 and mild activity against mTOR and CDK1. The distinct
mechanism of action exhibited by these cyclometalated Ir (III) complexes has been
found to make them highly effective against A549 cells that are resistant to cisplatin.
This unique antitumor mechanism suggested that these complexes have the ability to
act as therapeutics for the cancer treatment that are apoptosis decient and/ or resistant
to cisplatin (He et al. 2014).
Based on the research ndings, it is evident that marine sponges produce several secondary metabolites as defense mechanisms against predation. Among these,
menzamine A (8) is a pentacyclic alkaloid fused with β- C, which exhibits anticancer
activity against pancreatic cancer. Nevertheless, its cytotoxicity against other tumors
and the mechanism by which it exerts its antineoplastic effects have yet to be fully
understood. This study demonstrated that manzamine A was effective against colorectal cancer (CRC) cell lines by reducing cell proliferation. To understand the
molecular regulation of manzamine A gene expression analysis was performed by
using microarray technology. The analysis revealed dysregulation in pathways related
to the steps: rst cell cycle, second DNA repair, then mRNA metabolism, and lastly
apoptosis. Moreover, manzamine A has been demonstrated to induce the arrest of
cell cycle at the G0/ G1 phase by inhibiting cyclin- dependent kinases through p53/
p21/ p27, and to trigger caspase- mediated apoptotic cell death by depleting mitochondrial transmembrane potential. In addition, it suppressed the epithelial- mesenchymal
transition process and mesenchymal transcription elements (e.g., snail, slug and
twist), leading to the acquisition of an epithelial- like phenotype and the inhibition of
migration.
In summary, manzamine A exhibited potential as an effective anticancer drug
against metastatic CRC. Based on the ndings of this research, it showed that
manzamine A has the potential to be used as a foundation for creating a cancer- ghting
medication that could be utilized in the treatment of metastatic CRC. Therefore, the
results offered a groundwork for additional studies aimed at exploring the potential of
manzamine A and its derivatives of cancer treatments (Lin et al. 2018).
An array of 3- substituted 6- aminosulfonyl- β- Cs was produced, and their mode of
interaction to cyclin- dependent kinase 2 was examined through molecular docking
and uorescence measurements to determine their binding mode. The investigation demonstrated that replacing the 3- cyclohexylmethoxy group with a different
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moiety resulted in an enhancement of interaction between hydrophobic residues
and the intense hydrophobic pocket of CDK2, thereby leading to an increase in the
afnity. Compound 29, which contained 3- (cyclohexyl methoxy) group, exhibited the
strongest binding capacity to CDK2. The outcome indicated that compound 29 has
the potential to function as a CDK2 inhibitor, and additional assessments regarding its
antitumor efcacy are necessary to ascertain the likelihood of these novel compounds
being employed as potential CDK2 inhibitors (Wang et al. 2012).
The β- C alkaloid, Harmaline (HAR) (3), is a naturally occurring compound found
in Peganum harmala seeds, and has demonstrated signicant antitumor effects.
A study assessed the possible antitumor impacts of HAR on stomach cancer by
conducting experiments in both in vitro and in vivo, with a particular emphasis on
the supression of CDK. The outcomes revealed that HAR successfully repressed the
proliferation process of cells in SGC- 7901 cancer cell lines, causing G2/ M cell cycle
arrest and boost in cell death. HAR stimulated the activation of proteins involved in
cell cycle regulation, such as p- Cdc2, p21, p- p53, and Cyclin- B, while suppressing the
activation of p- Cdc25C. Furthermore, the research indicated that HAR enhanced the
expression of Fas/ FasL, and the activation of Caspase- 8 and Caspase- 3, suggesting
that Fas/ FasL- mediated mechanisms were engaged in the induction of cell death by
HAR. The antitumor efcacy of HAR was further validated in vivo using a 15 mg/
kg/ day dosage that also resulted in cell cycle arrest. Based on this, it was suggested
that HAR has the capacity to function as a CDK inhibitor, and that it may serve as
a basis for future research into its antitumor activity (Wang, et al. 2015). In general,
β- C and their derivatives have exhibited promising potential as CDK inhibitors in the
management of several diseases, including cancer. However, additional investigation
is needed to fully comprehend their mode of operation and to maximize their therapeutic capabilities.
4.2.2 The role of β- c As iNhibiTors of DuAl- specificiTy TyrosiNe
phosphorylATioN- regulATeD KiNAses (DyrKs)
DYRKs refer to a group of protein kinases that are evolutionarily conserved. These
kinases possess both tyrosine and serine/ threonine kinase activities and are involved
in the regulation of many cellular functions, like cell division, differentiation, and
cell death (Yuan et al. 2022). Among the four members of this family (DYRK1A,
DYRK1B, DYRK2, and DYRK3), DYRK1A has been studied thoroughly due to
its involvement in the regulation of brain development and its association with the
neurodegenerative diseases including Down syndrome and Alzheimer’s disease
(Becker and Sippl 2011). Different β- C analogs with potential DYRK activity are
illustrated in Figure 4.6.
Because of their connection to Down’s syndrome and neurodegenerative
disorders, DYRKs have received proper attention in the eld of medical research.
To gain a deeper understanding related to structure- activity relationship, a combination of ligand- based pharmacophore analysis and protein/ ligand docking was
utilized with MOE (molecular operating environment) software. This approach
facilitated the synthesis of some novel β- C derivatives to validate the theoretical
framework. As a result, a slightly modied lead compound (30) was identied with
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β- Carbolines
FIGURE 4.6 Different β- carboline derivatives with excellent DYRK inhibitory activity.
potent DYRK1A inhibitory activity (IC50 of 130 nM) and notable specicity against
monoamine oxidase A (MAO- A), DYRK2, DYRK3, and DYRK4, along with CLK2
(Drung et al. 2014).
The potential therapeutic application of harmine was hindered through its unintended impact on MAO- A, which has an impact on various nervous system targets.
This study utilized an optimized time- dependent uorescence energy transfer- based
methodology for DYRK1A to screen for potential inhibitors in a high- throughput
manner using a 384- well format. The screening discovered harmine (1) and other four
related complexes as potent DYRK1A inhibitors. In summary, the study found that
harmol (6) showed better selectivity for DYRK1A than MAO- A and demonstrated a
better therapeutic window in a glioma tumour xenograft model compared to harmine.
The position of modications in harmine analogs affected the DYRK1A inhibition
but not the MAO- A inhibition. These results present insights into the potential development of β- C compounds as therapeutic molecules for the treatment of diseases
related to DYRK1A inhibition. Further research is required to explore the curative
potential of these entities in vivo and optimize their selectivity and potency (Tarpley
et al. 2021).
A different research investigation discovered that harmine (1) was identied as
a powerful and particular repressor of DYRK1A both in cultured cells and in vitro.
Harmine inhibited the substrate phosphorylation by DYRK1A more effectively
compared with different kinases in the DYRK family. A greater concentration was
required to completely restrain DYRK1A tyrosine autophosphorylation within a
bacterial in vitro translation system. Harmine hindered the phosphorylation of the
particular substrate from DYRK1A in cultured cells without negative effects on cell
viability. Furthermore, harmine was found to interfere with the neuritogenesis in
cultured hippocampal neurons, providing evidence for the participation of DYRK1A
in the control of neurite formation. These ndings suggest that harmine or other betacarboline alkaloids may have potential therapeutic applications in conditions where
DYRK1A is implicated, such as Down syndrome and neurodegenerative diseases
(Göckler et al. 2009).
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Investigations have shown that DYRK1A is involved in phosphorylating a protein
called tau, which is associated with Alzheimer’s disease. Inhibiting DYRK1A may
therefore be a potential strategy for preventing or slowing down the growth of tau
pathology in Alzheimer’s disease. During a study, harmine and other β- C derivatives
were assessed to control tau phosphorylation in cell culture screenings and in- vitro
phosphorylation screenings. The ndings indicated that these complexes can decrease
the expression of all three phosphorylated forms of tau protein and inhibited the phosphorylation of tau protein on serine 396 by DYRK1A. Additionally, certain functional
groups that can inuence the efcacy of β- C compounds in inhibiting tau phosphorylation were identied by researchers (Frost et al. 2011).
Harmine not only acts as an inhibitor of the kinase activity of DYRK1A, but it
also inhibits its auto- phosphorylation on tyrosine, thereby preventing the formation of the active enzymes. DYRK1A phosphorylates caspase 9 at an inhibitory site,
which can prevent caspase 9 from activating the apoptotic pathway at Thr125, which
serves as an inhibitory region and denes a standard for the activation of caspase 9
via basal inhibitory phosphorylation of this protease. The inhibitory phosphorylation
of caspase 9 at Thr125 by DYRK1A has great importance in apoptosis regulation
during development and pathogenesis. Harmine can block the DYRK1A- dependent
phosphorylation of Thr125, indicating its potential role in modulating the apoptotic
pathway (Seifert, Allan, and Clarke 2008).
Further investigation into the mechanism of action revealed that ATP- competitive
inhibition against DYRK1A is demonstrated by harmine binding to residues inside
the binding pocket for ATP and displacing ATP. The substitution of valine with alanine
at position 306 (V306A) results in a signicant reduction in harmine potency against
DYRK1A, as it selectively modies the afnity of the protein for both harmine and
ATP. However, the V306A mutation does not seem to affect DYRK1A activity, with
the exception of reducing its ATP binding strength. This decrease can be entirely
offset by providing ATP within the range considered physiological. Consequently,
harmine continues to be a prospective primary compound for crafting selective ATPcompetitive restraints on DYRK1A, exploring the ATP- binding site of DYRK1A
(Adayev, Wegiel, and Hwang 2011).
Diabetes, a health condition resulting from an inadequate number of functional
insulin- producing β- cells within the pancreas, affects an estimated 380 million people
worldwide. In humans, beta cell proliferation occurs during a limited time period
around birth. However, after early childhood and during embryonic life, the replication of beta cells is barely detectable. Efforts to expand beta cells in adult humans
have been unsuccessful so far, emphasizing the signicance of creating therapeutic
compounds capable of stimulating the regeneration and expansion of these cells in
mature individuals. Through a large- scale screening of small molecules, researchers
discovered that derivatives of harmine can serve in the role of a new class of mitogenic compounds for human beta cells. They also pinpointed DYRK1A as the probable target of harmine, while nuclear factors of activated T cells (NFAT) likely act as
mediators of human β- cell proliferation and differentiation. Their study showcased
harmine’s capacity to stimulate beta cell growth, increase islet mass, and enhance
glycaemic control across three distinct human islet and mouse in vivo models. These
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discoveries imply that harmine analogs hold distinctive promise as therapeutic agents
for managing diabetes in humans. The researchers intend to further amplify the
effectiveness and specicity of these compounds in upcoming investigations (Wang,
Alvarez- Perez, et al. 2015).
A study has demonstrated that epigallocatechin gallate (EGCG) (31), a avonoid
found in green tea, can modulate the activity of FoxO transcription parameters in
human skin broblasts cultured in vitro. EGCG is a polyphenol compound found
in green tea, which has been shown to have various health benets. One of the
reported effects of EGCG is its ability to stimulate the nuclear accumulation and
DNA- binding activity of FoxO transcription factors at a low concentration of 1 μM.
At greater concentrations (100 μM) of EGCG, the compound can generate hydrogen
peroxide, which then stimulates the activity of phosphoinositide- 3- kinase (PI3K)/ Akt
signaling. The activation of PI3K/ Akt signaling results in the suppression of FoxO
activity. FoxO phosphorylation prompts its removal from the nucleus and diminishes
its ability to bind to DNA. At lower concentrations, harmine not only inhibits FoxO
but also induces its nuclear aggregation and enhances DNA binding activity. When
Caenorhabditis elegans worms are exposed to EGCG, it elevates the expression of the
DAF- 16 target gene, sod- 3, and triggers nuclear accumulation of the FoxO ortholog,
DAF- 16. Additionally, the mean and maximal lifespan of C. elegans was found to be
increased by 20% and 13%, respectively, upon exposure to EGCG, indicating that the
effects of EGCG may have signicant physiological implications. The results demonstrate that EGCG has insulin- mimetic and insulin- antagonistic effects, depending
on its concentration. EGCG enhances FoxO nuclear localization and DNA- binding
activity at low concentrations, but at higher concentrations, it triggers a signaling
cascade that involves the generation of hydrogen peroxide, leading to the stimulation
of PI3K/ Akt signaling and inhibition within FoxO activity. In conclusion, the study
suggests that EGCG holds potential as a therapeutic remedy for age- related diseases
(Bartholome et al. 2010).
Researchers have investigated the potential of Picrasma quassioides, a Chinese
traditional medicine, to treat Alzheimer’s disease. They found that the extract from
its stems showed neuroprotective properties in cell models and enhanced cognitive
abilities and memory in AD mice. Suppressing neuro- inammation and reducing
Aβ1- 42 deposition were linked to the anti- AD mechanism. Seven canthin- 6- one
alkaloids, six β- C alkaloids, and ve quassinoids were identied from the extract.
The in vitro studies have shown that four β- Cs and six canthin- 6- ones have potential
neuroprotective activities. Moreover, two of these compounds (32 and 33) were found
to have high afnity for both DYRK1A and butyrylcholinesterase (BuChE) according
to molecular docking experiments (Guo et al. 2019).
These studies highlight the diverse range of potential therapeutic applications
of β- Cs and their derivatives, particularly harmine, including the treatment of
neurodegenerative disorders, bone disorders, and cancer, as well as their potential
use in stem cell research and regenerative medicine. However, to fully optimize the
efcacy and safety of β- Cs, and to understand their mechanisms of action, further
research is required.
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β-Carbolines as Kinase Inhibitors
4.2.3 β- cArboliNes AcTiNg As iNhibiTors of MiTogeN- AcTivATeD proTeiN
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KiNAse- AcTivATeD proTeiN KiNAse 2 (MApKApK2)
MAPKAPK2 is a type of kinase that phosphorylates serine and threonine residues.
It is activated as a downstream effector within the MAPK (mitogen- activated protein kinase) signaling pathway (Pearson et al. 2001). The MAPKs are a family of
enzymes that are highly conserved across different species, and they perform an
essential role in regulating diverse physiological processes within mammalian cells.
These processes include cell differentiation, development, proliferation, immune
function, cell death, and stress responses (Coulombe and Meloche 2007). Inhibiting
MAPKAPK- 2 has surfaced as a promising target for drug development aimed at
alleviating a variety of conditions, which includes various autoimmune diseases and
inammatory diseases, neurodegenerative disorders, and cancer (Soni, Anand, and
Padwad 2019). Several drugs have been developed to target MAPKAPK- 2 including
monoclonal antibodies, small molecule inhibitors, and siRNAs. Various β- C analogs
with potential MAPKAPK2 activity are presented in Figure 4.7.
A group of novel tetrahydro- β- C- 1- carboxylic acid analogs has been discovered,
and their potential to inhibit MAPKAPK- 2 has been investigated. The researchers
have also explored the structure- activity relationship (SAR) of these analogs. These
observations encompass the importance of an ether functionality at the 6- position of
the A- ring, the pivotal role of the carboxylic acid, and the improvement in binding
afnity achieved by connecting the C- ring nitrogen with the 4- position. Compound 34
has been found to demonstrate signicant selectivity for MAPKAPK- 2 as compared
to other closely related kinases, such as PRAK and MAPKAPK- 3. In U937 cells, the
researchers observed that the carboxylic acids were inactive. However, they discovered
that compound 35, an ester prodrug derived from compound 34, effectively regulated
FIGURE 4.7 β- carbolines having signicant MAPKAPK- 2 inhibitory activities.
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the production of TNFα in both U937 cellular assays and a rat LPS model (Trujillo
β- Carbolines
et al. 2007).
A collection of highly effective inhibitors of MAPKAPK- 2 based on β- C scaffolds
has been synthesized and the DELFIA assay revealed that these compounds exhibited
remarkable inhibition of MAPKAPK- 2, with low IC50 values of 10 nM. Based on
structural studies using X- ray crystallography, it has been found that these inhibitors
bound to a region that is located in close proximity with the hinge region and p- loop
of MAPKAPK- 2a. These derivatives exhibited moderate selectivity against ERK2
and MAPKAPK- 1 (Wu et al. 2007).
A study was performed over carboline derivatives using pharmacophore modelling
and docking studies to identify potential anti- inammatory agents that can bind to the
MAPKAPK- 2 receptor. The study concluded that receptor binding necessitates two
hydrogen bond donors, two H- bond acceptors, and one hydrophobic characteristic.
The 3D QSAR models generated by the study showed good consistency and correlation with experimental IC50 values. CoMSIA and CoMFA contour maps were also
developed, which can guide the structural modication of compounds to improve
their biological activity. The study’s ndings can help in understanding the structural
features necessary for biological interaction and improving the potency of molecules
that inhibit MAPKAPK- 2 (Nayana et al. 2009).
The production of melanin is controlled by specic enzymes and transcription
factors in melanocytes. Harmaline (3) and harmalol (4), β- C alkaloids found in various
plants and alcoholic drinks were tested for their effects on melanoma cells. The study
results indicated that both harmalol and harmaline increased tyrosinase activity and
melanin content in a manner dependent on concentration and time. Furthermore, it
was observed that expression of proteins that are associated in melanin production
(tyrosinase, TRP- 1, and TRP- 2) also increased. The treatment with both harmaline
and harmalol was observed to activate pathways involving microphthalmia- associated
transcription factor, the cAMP response element- binding protein, and the p38 MAPK
pathway. This activation ultimately led to an increase in melanogenesis, a process of
melanin production (Park et al. 2010).
A group of new hydroxamate derivatives based on β- C were generated and tested
for their effects in various in vitro assays. They were found to exhibit potent inhibition of HDAC1/ 3/ 6 and also showed signicant antitumor activity against ve
different human cancer cell lines. Among the tested β- C derivatives, compound 36
emerged as the most potent, exhibiting the highest anticancer activity with 0.53~1.56
µM IC50 values, signicantly greater than the harmine (1) (IC50 value of 46.7~55.3
µM) and was also observed to be 3 to 10 times lower to SAHA (IC50 = 4.48~6.26 µM).
The HDAC inhibitory effects of the compound 36 were conrmed by immunoblot
analysis, which showed a concentration- dependent inhibition of histone H3 and α-
tubulin acetylation. Additionally, compound 36 caused concentration- dependent cell
cycle arrest in HepG2 cells at the G2/ M phase via the inhibition of cell cycle- related
proteins cyclin- B and CDK1. Notably, it also exhibited strong antimetastasis activity
by inhibiting the MAPK signaling pathway and decreasing the protein level of MMP2
and MMP9 (Ling et al. 2018).
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The researchers synthesized a couple of β- C scaffolds using Pictet- Spengler reaction and evaluated their anti- inammatory activity for human neutrophils. Compound
37 and 38, two compounds synthesized in the study, were found to have notable
inhibitory effects on generating superoxide anion induced by N- formyl- Met- LeuPhe in human neutrophils, without causing cytotoxicity. Specically, compound 38
selectively hindered fMLF- induced phosphorylation of p38 and intracellular calcium levels, while compound 37 was noted for its inhibition of p38 MAPK phosphorylation and reduction of intracellular calcium levels in fMLF- activated human
neutrophils. Molecular docking analysis demonstrated the favorable binding afnity
of compound 38 towards p38 MAP. The suggested synthetic strategy could lead to the
advancement of novel anti- inammatory drugs targeting neutrophilic inammation
(Kumar et al. 2021).
Overall, recent literature highlights the signicant potential of β- Cs and their
derivatives as inhibitors of MAPKAPK- 2, with applications in treating diverse
diseases such as cancer, neurological disorders, and inammatory conditions. Further
research is required to optimize the therapeutic efcacy of these compounds and to
evaluate their safety and efcacy in clinical trials.
4.2.4 β- cArboliNes As iNhibiTors of iκb KiNAse (iKK)
IκB kinase (IKK) is a serine- threonine protein kinase pivotal in the activation of the
transcription factor NF- κB (Hacker and Karin 2006). The IKK enzyme complex
comprises three subunits, IKKγ, IKKα, and IKKβ, collectively known as NEMO
(Regnier et al. 1997). IKKβ specically phosphorylates the inhibitor of NF- κB (IκB),
triggering its degradation and subsequently activating NF- κB (Karin 1999). Targeting
IKK for inhibition has emerged as a promising strategy for treating various cancers
and inammatory conditions. Numerous drugs aimed at IKK inhibition are under
development, including small molecule inhibitors and antisense oligonucleotides
(Llona- Minguez, Baiget, and Mackay 2013). In preclinical studies, IKK inhibition
has demonstrated promising outcomes in the treatment of chronic inammatory
conditions such as rheumatoid arthritis, inammatory bowel diseases, and certain
cancers (Yi et al. 2022). Several β- C derivatives with excellent IKK activity are
shown in Figure 4.8.
FIGURE 4.8 β- carbolines with potential IKK inhibitory activity.
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