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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5596_Библиотеки_им_академика_М_И_Перельмана
.pdf
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Contributors
Dinesh K. Agarwal
Department of Pharmacy
Pacic Institute of Pharmacy
Pacic University
Udaipur, Rajasthan, India, 313001.
Shikha Agarwal
Department of Chemistry
Synthetic Organic Chemistry
Laboratory, MLSU
Udaipur, 313001, India.
Vnira R. Akhmetova
Laboratory of Heteroatomic Compounds
Institute of Petrochemistry and
Catalysis
Russian Academy of Science
141 Prospekt Octyabrya, Ufa 450075,
Russian Federation
Nail S. Akhmadiev
Laboratory of Molecular Design and
Biological Screening of Candidate
Substances for the Pharmaceutical
Industry
Institute of Petrochemistry and
Catalysis, Russian Academy of
Science, 141 Prospekt Octyabrya, Ufa
450075, Russian Federation
Chetna Ameta
Department of Chemistry
University College of Science,
M. L. Sukhadia University
Udaipur (Raj.)
Saroj R. Bembalkar
Department of Chemistry
B. U. Patil Arts and Science College
Sultanpur 431101 MS, India.
Devidass S. Bhagat
Department of Forensic Chemistry
Government Institute of Forensic
Science
Aurangabad 431004 MS, India.
Keyur Bhatt
Department of Chemistry
Faculty of Science, Ganpat University,
Kherva- 384012
Mehsana, Gujarat, India
Ravikumar M. Borade
Department of Forensic Chemistry
Government Institute of Forensic
Science
Aurangabad 431004 MS, India.
Dharmendra
Department of Chemistry
University College of Science, M. L.
Sukhadia University
Udaipur (Raj.)
Surabhi Dhadda
Department of Chemistry
Faculty of Basic and Applied Sciences
Vivekananda Global University,
Jagatpura, Jaipur, Rajasthan
303012, India.
Surendra Kumar Bagaria
Department of Chemistry
Govt. Science College
Sikar, Rajasthan 332001, India.
Santosh B. Gaikwad
Department of Chemistry
L P G Arts and Science College,
Shirpur (Jain)
Washim- 444 504 (Maharashtra), India.
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xvi
Jagannath S. Godse
Department of Chemistry
Deogiri College
Aurangabad – 431 005
(Maharashtra), India.
Rajita Ingle
Department of Chemistry
Deogiri College, Station Road
Aurangabad 431 005, MS, India.
Dinesh Kumar Jangid
Department of Chemistry
University of Rajasthan, Jaipur
India- 302004.
Nidhi Jangir
Department of Chemistry
University of Rajasthan, Jaipur
India- 302004.
Kuldeep V Joshi
Department of Applied Chemistry
School of Applied material
Sciences, Central University
of Gujarat,
Gandhinagar- 382030,
Gujarat, India
Contributors
Mukesh Kumar
Department of Chemistry
Sahu Jain Degree College
Najibabad, Bijnor- 246763, UP, India.
Danil V. Leont’ev
Laboratory of Heteroatomic Compounds
Institute of Petrochemistry and
Catalysis
Russian Academy of Science
141 Prospekt Octyabrya, Ufa 450075,
Russian Federation
Dattatraya Pansare
Department of Chemistry
Deogiri College, Station Road
Aurangabad 431 005, MS, India.
Jaymin Parikh
Department of Chemistry
Faculty of Science, Ganpat University
Kherva- 384012, Mehsana,
Gujarat, India
Rajendra P. Pawar
Department of Chemistry
Shiv Chhatrapati College
Aurangabad, 431 001, MS, India.
Swati B. Kale
Department of Applied Science
Government Polytechnic
Aurangabad 431004 MS, India.
Dhanraj P. Kamble
Department of Chemistry
S. B. E. S. College of Science
Aurangabad 431001 MS, India.
Monika Kumawat
Department of Chemistry
University College of Science
M. L. Sukhadia University,
Udaipur (Raj.)
Aniket Sarkate
Department of Chemical Technology
Dr. B.A.M. University Aurangabad
414004, MS, India.
Shivangi Sharma
Department of Applied Chemistry
Amity School of Applied Sciences,
Amity University Madhya Pradesh
Gwalior, Madhya Pradesh- 474 005,
India
Mubarak Shaikh
Department of Chemistry
Radhabai Kale Mahila Mahavidyalaya
Ahmednagar, 414001, MS, India.
newgenprepdf
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Contributors
Rohini Shelke
Department of Chemistry
Radhabai Kale Mahila Mahavidyalaya
Ahmednagar, 414001, MS, India.
Shivani Soni
Synthetic Organic Chemistry Laboratory
Department of Chemistry,
UCOS, MLSU
Udaipur, India 313001
Shivendra Singh
Department of Applied Chemistry
Amity School of Applied Sciences,
Amity University Madhya Pradesh
Gwalior, Madhya Pradesh- 474
005, India
Pankaj Teli
Synthetic Organic Chemistry Laboratory
Department of Chemistry,
UCOS, MLSU
Udaipur, India 313001
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Shankar Thopate
Department of Chemistry
Radhabai Kale Mahila Mahavidyalaya
Ahmednagar, 414001, MS, India.
Sunil U. Tekale
Department of Chemistry
Deogiri College
Aurangabad – 431 005
(Maharashtra), India.
Sunita Teli
Synthetic Organic Chemistry Laboratory
Department of Chemistry,
UCOS, MLSU
Udaipur, India 313001
Sanjay B. Ubale
Department of Chemistry
Deogiri College
Aurangabad – 431 005
(Maharashtra), India.
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β-Carbolines
1
as Anti-Cancer Agents
Synthesis and
Biological Study
Ravikumar M. Borade, Devidas S. Bhagat,
Swati B. Kale, Dhanraj P. Kamble,
Saroj R. Bembalkar, and Rajendra P. Pawar
1.1 INTRODUCTION
A broad class of indole alkaloids, including natural and produced, referred to as
“carboline derivatives,” have a common tricyclic pyrido-[3, 4-b] indoles ring unit
in their structural component. The β-carboline alkaloids were rst discovered in the
seeds of Peganumharmala, which can be found in Northwest China, North Africa,
and the Middle East. This plant has been used for hundreds of years in traditional
medicine to treat conditions such as malaria and esophageal cancer (Wesson et al.
1996), which suggests that these compounds have become important scientic development triggers for the synthesis of numerous anticancer agents (Pfau and Skog 2004;
Cao et al. 2004). β-Carbolines are used as an emmenagogue and an abortifacient in
various parts of South America (Grella et al. 1998).
β-carbolines is a group of indole alkaloids that can be either natural or synthetic.
It is most commonly dened by nitrogen-containing six-membered rings. Fully aromatic carbolines (Cs) are unsaturated carbolines, whereas dihydrocarbolines (DHCs)
are partially saturated alkaloids and tetrahydrocarbolines (THCs) are fully saturated
alkaloids (Cain et al. 1982; Gooyit et al. 2015; Jiang et al. 2002; Laine et al. 2014;
Stohler et al. 1995). The pyrido ring or indole ring of tricyclic compounds are
substituted in a variety of reported derivatives of carbolines (Cao et al. 2007). Several
carboline saturated or unsaturated tricyclic ring alkaloids systems from a number
of terrestrial plants have been used to extract and characterize their main bioactive
components (Wang et al. 2017). Several other types of carboline alkaloids have also
been isolated and identied from marine invertebrates, such as soft corals (Lignopsis),
bryozoans (Cribellina, Catenicella), tunicates (Ritterella, Pseudodistoma, Eudistoma,
Didemnum, Lissoclinum), and hydroids (Aglaophenia) (Aiello et al. 1987; Blunt
et al. 2009; Cheng et al. 2012; Suarez-Jimenez et al. 2012). Carbolines are classied
as α-, β-, γ-, or δ-carbolines based on the position of the nitrogen in the ring structure.
Similar to natural or synthetic cases, monomers display a linkage primarily
1
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2
2
β- Carbolines
FIGURE 1.1 Structural diversity of carbolines.
through the 1- 1, 2- 2, 3- 3, or 9- 9 positions depicted in Figure 1.1, and monomeric and
dimeric congurations seem to have a single β- carboline core (Dai et al. 2018; Devi
et al. 2018).
A β- carboline alkaloid was rst obtained in 1841 and since then several β-
carbolines have been isolated from numerous sources generally comprising plants
from families like Rutaceae (Smirnova O B, 2011), Simaroubaceae (Ohishi
et al. 2015), Amaranthaceae (Porta et al. 2017), Caryophyllaceae (Chen et al. 2010),
Rubiaceae (deOliveira Figueiredo et al. 2014), and Zygophyllaceae (Wang et al.
2014); marine creatures such ashydroids (Skropeta and Wei 2014), bryozoans (Till
and Prinsep 2009), soft corals (Gao et al. 2013), and sponges (Tanaka et al. 2014);
along with various microorganisms (Savi et al. 2015), insects (Marques et al. 2005),
food products (Kim et al. 2016), alcoholic beverages (Tsuchiya 2016), tobacco smoke
(Herraiz and Chaparro 2005), and human tissue and body uids (Lamounier et al.
2015). β- carbolines also posses wide- ranging biological activities including sedative
(Smith et al. 2013), anxiolytic (Petersen et al. 1982), hypnotic (Kaijima et al. 1984),
anticonvulsant (Pogosyan et al. 2007), antitumor (Zheng et al. 2014), antiviral (Nazari
Formagio et al. 2009), antiparasitic (Gooyit et al. 2015), and antimicrobial properties
(Lee et al. 2015; Montorsi et al. 2014; Park and Nam 2015; Rundfeldt and LÖscher
2014). Recent investigations have shown β- carbolinedimers to be signicantly more
active than their corresponding monomers (Lu et al. 2017).
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β- Carbolines as Anti-Cancer Agents
1.2 ANTICANCER ACTIVITY OF β- CARBOLINES
3
Cancer is a leading cause of mortality and morbidity. Globally, roughly 20 million
individuals are diagnosed with cancer each year, and 9.5 million people die from the
disease (Www.Who.Int/ News- Room/ Fact- Sheets/ Detail/ Cancer, n.d.). Depending on
the type and severity of the cancer, various treatment methods, including chemotherapy, radiation, and occasionally surgery, are used to control it in the present. Even
though this discipline has seen a lot of research, there are still a lot of topics that need
to be studied. The main issue that has hindered this research from expanding on its
early breakthroughs is “drug resistance.”
The majority of research on drug resistance in cancer focuses on cellular resistance, which is primarily explained by the genetic makeup of the cancerous cells.
Toxic chemotherapy may cause mutations in sensitive tumors, and adaptive responses
such as increased expression of the therapeutic target and activation of alternative
compensatory signaling pathways can also result in mutations. The main method for
determining mechanisms of medication resistance is to expose the residual cancer
cells to fatal agents, and then use various cellular and molecular biology tools to
detect the altered genes. This led to the discovery of three primary mechanisms of
drug resistance: rst, an increase in the energy- dependent efux of hydrophobic
drugs out of the cells; secondly, there is a reduction in the absorption of hydrophilic
anticancer medications such as cisplatin, nucleoside analogs, and folate antagonists;
thirdly, there are alterations to cellular processes such as alterations in the cell cycle,
a decline in apoptosis, increased expression of DNA damage repair, and modied
metabolism. Resistance causes cancer to go into remission, which increases the cost
on society and negatively impacts the patient’s mental health. (Housman et al. 2014;
Szakacs et al. 2006).
Combination therapy is now used in cancer therapeutics because it avoids the issue
of resistance and is more efcient than a single agent. Research should next focus
on the removal of cancer progenitor cells because they are frequently medication
resistant and may cause remission in cancer patients (Housman et al. 2014). Several
studies on the use of β- carboline derivatives as potential cancer treatments are currently being published. The present chapter describes the synthesis and biological
assessment of numerous β- carboline- based compounds, classifying them according
to their intended actions.
1.3 SYNTHESIS OF β- CARBOLINE DERIVATIVES AS ANTICANCER
AGENTS
1.3.1 DNA TArgeTiNg AgeNTs
1.3.1.1 Intercalating Agents
In prokaryotic and eukaryotic cells, β- carbolines have been found to have biological
and pharmacological effects that are supported by their ability to intercalate DNA,
which alters the enzymatic mechanisms involved in DNA repair or DNA replication.
Sulfur was used in the dehydrogenation of compound 1 to produce completely
unsaturated methyl- β- carboline- 3- carboxylates. After reduction with LiAlH4 in dry
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4
β- Carbolines
SCHEME 1.1 Synthesis of β- carboline- benzimidazole conjugates.
SCHEME 1.2 Synthesis of 3- substituted β- carbolines.
tetrahydrofuran (THF), a variety of β- carboline- benzimidazole conjugate compounds
containing substituted benzimidazole moieties and aryl rings at the C3 and C1
positions were produced via Dess Martin periodinate- mediated oxidation. The required
substituted benzimidazole linked β- carboline conjugates product 3 is produced by
condensations of the synthesized chemical 2 with various o- phenylenediamines (Devi
et al. 2018; Digwal et al. 2016; Kamal et al. 2014), as shown in Scheme 1.1.
In tests for cytotoxic action against a panel of human cancer cell lines, all the synthetically produced derivatives of compound 3 showed IC50 values ranging from 0.36
to 6.3 M. The pBR322 plasmid DNA was seen to be cleaved by these chemicals when
they were subjected to UV radiation, according to a biophysical experimental research
and molecular modeling (Funayama et al. 1996). The conjugates of β- carboline and
benzimidazole have subsequently demonstrated potential anticancer action (Kamal
et al. 2014; Sobhani et al.2002).
From β- carboline- 3- carboxylic acid 4, Xiao et al. reported produce molecules of
β- carboline that are 3- substituted. To treat β- carboline- 3- carboxylic acid 4, thionyl
chloride was used to produce the appropriate acid chloride, which was then combined
with the necessary component to generate acid chloride (Scheme 1.2). An alkylamine
side chain added to the β- carbolines C- 3 position made the molecule more exible
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β- Carbolines as Anti-Cancer Agents
5
SCHEME 1.3 Synthesis of C3- linked β- carboline- pyridine derivatives.
and increased the intercalating activity 5 of the produced compounds. Using biochemical experimental techniques, examinations of thermal denaturation, binding
mode, and binding strength were combined with molecular modeling to investigate
the compound 5 afnity for binding DNA. According to experimental results, compound 5 had the highest intrinsic binding constant (K = 4.503 X 104 M
binding energy for docking, and the highest rate of inhibition for HL- 60 and BGC
cells. It also demonstrated the strongest CT- DNA stability (Xiao et al. 2001).
- 1
), the lowest
Through a modied Khronke reaction, Nagula et al. reported the synthesis of
C3- linked β- carboline pyridine derivatives. Using barium hydroxides, compound 6
is condensed with acetophenones to produce (E)- 1- (3,4,5- substituted phenyl)- 3- (1(3,4,5- substituted phenyl)9H- pyrido[[3] ,[4- b]]indol- 3- yl]propen- 1- ones 7, which
on addition reacted with acetyl pyridinium salts in anhydrous methanol and ammonium acetate to give derivatives of C- 3- linked β- carbolines 8 (Scheme 1.3). Testing
the DNA binding afnities of the prepared compounds 7 and 8 revealed that compound 7a greatly improved the afnity as compared to doxorubicin. Molecular modeling studies demonstrated the DNA intercalation of these compounds through their
interaction with planar β- carboline rings and DNA base pairs (Nagula et al. 2018;
Srivastava et al. 1999).
1- amino β- carboline motifs were tested for their ability to inhibit the growth of
K- 562, HOP- 92, HT29, M14, UACC- 62, OVCAR- 3, and MDA- MB- 231/ ATCC.
Compound 10 (GI50 value ranging from 0.38 to 5.2 μM) was obtained by direct
amination of 1- chloro- β- carboline 9 by heating the chloride with an excess of the
amine for several hours at 170 °C, either without a solvent or with a few drops of
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6
6
β- Carbolines
SCHEME 1.4 Synthesis of 1- amino- β- carbolines.
SCHEME 1.5 Synthesis of β- carboline amino acid ester conjugates.
N- methyl pyrrolidin- 2- one (Scheme 1.4). Compound 10a exhibited DNA intercalating characteristics because it possessed a planar aromatic structure that could easily
stack in base pairs (Boursereau and Coldham 2006).
The cytotoxic effect and synthesis of β- carboline amino acid ester conjugates were
studied by Zhao et al. Compound 12 (Scheme 1.5) was synthesized by hydrolysis of
methyl 1- methyl- β- carboline- 3- carboxylate 11 in base medium, followed by coupling with a suitable amine in the presence of (dimethylamino)pyridine (DMAP) and
dicyclohexylcarbodiimide (DCC). Compound 12 showed that cytotoxic activities are
signicantly enhanced when cationic amino acids, such as arginine and lysine, are
added to produce the new series of compounds 13, 13a, and 13b, respectively; this
is in contrast to uncharged amino acids. When all of the synthesized compounds 13
were tested in vitro using the human cancer cell lines HeLa, MCF- 7, and HepG2, it
was discovered that compounds 13a and 13b interacted with DNA and had the lowest
IC50 values (Zhao et al. 2006), in the range of 1 to 7 μM, when compared to other
compounds.
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β- Carbolines as Anti-Cancer Agents
7
SCHEME 1.6 Synthesis of bivalent β- carbolines.
The synthesis of many bivalent β- carboline derivatives with spacer lengths ranging
from three to ten carbon units between two indole ring nitrogens was reported by Shi
et al., who also assessed the derivatives’ cytotoxic potential against a range of cancer
cell lines. Symmetric β- carbolines 15 were synthesized by reacting monovalent
β- carbolines 14 with the appropriate dibromo alkane in anhydrous DMF (Scheme
1.6). All the prepared bivalent β- carbolines were evaluated for their antitumor potential using different cancer cell lines. Structure- Activity Relationship (SAR) studies
reveal that the C1 position is essential to the activity; appropriate substitution boosted
the efcacy against the tumor. A linker with a chain length of four to six methylene
units had an effect on the antitumor activity. With IC50 values less than 20 μM,
these drugs demonstrated excellent efcacy against the BGC, A- 375, KB, and SKOV-
3 cell lines. A few of the 15 symmetrical β- carbolines with outstanding activity
were also selected for in vivo testing in mice harboring the malignancies B16 melanoma, Lewis’ lung cancer sarcoma 180, H22 liver cancer, and CT- 26 colon cancer.
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