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Cyclometalated iridium(III)-guanidinium complexes as mitochondria-targeted anticancer agents.
Ind. J. Pharm. Edu. Res., 2024; 58(1s):s26-s39.
Review Article
https://www.ijper.org
Heterocyclic Compounds and their Derivatives with
Potential Anticancer Activity
Avneet Kaur1,*, Ashok K. Shakya2, Rohit Singh3, Reena Badhwar1, Shalini Kapoor Sawhney4
SGT College of Pharmacy, Shree Guru Gobind Singh Tricentenary University, Gurugram, Haryana, INDIA.
Faculty of Pharmacy and Medical Sciences, Al-Ahliyya Amman University, Amman, JORDAN.
3
Institute of Pharmaceutical Sciences, University of Lucknow New Campus, Jankipuram, Lucknow, Uttar Pradesh, INDIA.
4
ITS College of Pharmacy, Muradnagar, Ghaziabad, Uttar Pradesh, INDIA.
1
2
ABSTRACT
Cancer is the second leading cause of the death worldwide. As per the reports published by
WHO, the cases of cancer in the world will increase to 22 million by 2030. Many resources
are investigated all around the world for developing preventive, diagnostic and therapeutic
strategies for cancer. Malignant cells display metabolic changes because of genetic and
epigenetic alterations as compared to normal cell. Heterocycles are the key structural feature of
many anti-cancer drugs present in the market. Between 2010 to 2015, FDA approved anticancer
drugs also contain heterocyclic rings in their structures. Their presence in anti-cancer drugs can
be credited to their being extremely common in nature, with enormous cellular processes and
mechanisms. This review throws light on several heterocyclic compounds containing nitrogen,
sulphur and oxygen in their rings, possessing anticancer activity on different cell lines. A compiled
data of heterocyclic rings will help in providing a new way towards future development of new
compound for treatment of cancer.
Correspondence:
Dr. Avneet Kaur
SGT College of Pharmacy, SGT University,
Gurugram-122505, Haryana, INDIA.
Email: avneetkaur1986@gmail.com
Received: 24-01-2023;
Revised: 27-05-2023;
Accepted: 29-08-2023.
Keywords: Heterocyclic compounds, Anticancer activity, Cell lines, Cytotoxicity, Natural product,
FDA.
INTRODUCTION
Heterocyclic containing compounds constitutes diverse family
of organic compounds. They are the cyclic compounds which
constitute at least one or more hetero atoms.1 Nitrogen, oxygen
and sulphur are the most communal hetero atoms which are
widely known whereas other heterocyclic rings containing
other heteroatom are also of great importance.2 Heterocyclic
compounds are reviewed as one of the essential classes of organic
compounds that are employed in various biological fields due to
its activity in multiple diseases.3-7 Heterocyclic compounds occur
widely in nature and in diversity of non-naturally occurring
compounds. Large number of heterocyclic compounds are
essential to life.8 Numerous compounds including vitamins, amino
acids, antibiotics, alkaloids, hormones, hemoglobin and huge
quantity of synthetic compounds and dyes contain heterocyclic
ring in their structure.9-13 Many heterocyclic compounds have
wide application in common diseases.14-16 Heterocycles bearing
nitrogen atoms in their ring structure are considered as vital
DOI: 10.5530/ijper.58.1s.3
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S26
class of compounds among physiologically active complexes,
natural products and chemicals that are extensively used in
medicinal chemistry.17-19 Nitrogen bearing compounds like
indole,20 imidazole,21 pyrrole,22 triazole,23 piperazine24 have
acquire importance in many research sectors including synthesis
and medicine.24-29 Whereas, oxygen containing compounds
covers hefty portion of FDA approved drugs and therapeutically
important structures.30 The sulphur containing compounds like
benzthiazole, thiophene have been proven to exert anticancer,31,32
antimicrobial,33 antiviral,34 anti-inflammatory35 and many
other biological activities. In addition to it, sulphur containing
compounds are used to flavour food products.36 Numerous FDA
approved drugs include nitrogen and sulphur heterocycles such as
anastrazole, ademaciclib, anastrazole, tamoxifen, 5-flourouracil,
clopidogrel, raloxifene etc are used to cure breast cancer, diabetes
and many other diseases (Table 1).37
Cancer is a group of diseases characterized by uncontrolled
growth and spread of abnormal cells, which leads to death if
not treated at the right time.38 It is one of the most important
health concern for human being with highest fatality rate.39 Many
substances may be natural, biological, chemical are the causing
agents of cancer.40 Many drugs are used to cure this disease but
they possess their own toxic effects. Therefore, lot of research is
required to synthesize new entities with better selectivity, least side
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
Kaur, et al.: Heterocycles as Anticancer Agent
Table 1: Clinically approved drugs containing heterocyclic compounds.
Drug
Brand name
Abemaciclib
Verzenio
Structure
F
N
H3C
H3C
Trexall,
Xatmep
N
H2N
CH3
N
N
N
F
CH3
Methotrexate
sodium
H
N
N
N
N
N
N
N
N
Clinical indication
Piperazine, Pyrimidine,
Benzimidazole,
Pyridine.
CDK 4/6 inhibitor, use for
treatment of breast cancer.
Pyrazine, Pyrimidine.
Acute lymphoblastic leukaemia,
breast cancer, lung cancer.
Triazole.
Breast cancer in menopausal
women.
Indole, Pyrimidine.
Colorectal cancer, hepatocellular
carcinoma,
stomach adenocarcinoma.
Piperazine, pyridine,
pyrimidine.
Classic Hodgkin lymphoma.
Pyrazole, pyrimidine.
Non-small cell lung cancer,
Medullary thyroid cancer, Thyroid
cancer.
Imidazole, Pyridine.
Actinic keratosis,
Basal cell carcinoma,
Genital warts
Pipetazine, piperidine,
pyrimidine.
Lung carcinoma.
Pyridine.
Use in adults with Phase III
non-small lung cancer that cannot
be remove by surgery.
O
H
N
NH2
Heterocyclic ring
involved
O-Na+
O
HO
Anastrozole
Arimidex
N
N
HN
CN
Ramucirumab
O
CN
Cyramza
N
H
HN
O
N
NH
N
Nivolumab
Opdivo
O
H
N
H
N
N
O
P
N
N
N
N
Selparcatinib
Retevmo
O
HO
N N
N
N
N
N
N
O
Imiquimod
Aldara
Zyclara
NH2
N
N
N
Brigatinib
Alunbrig
O
H
N
N
N
N
H
N
P
O
Cl
N
N
Durvalumab
Imfinzi
Cl
O
O
N
H
NH
N
O
N
NH
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
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Kaur, et al.: Heterocycles as Anticancer Agent
Drug
Brand name
Nelarabine
Arranon
Structure
O
N
N
O
Heterocyclic ring
involved
Clinical indication
Imidazole, pyrimidine.
Use to treat children 1 year or above
with T-cell lymphoblastic leukemia.
N
N
NH2
HO
HO
HO
Acletinib
Alecensa
N
H
N
N
O
Lenalidomide
Morpholino, piperidine, Receptor tyrosine kinase anaplastic
indole.
lymphoma kinase.
O
Revlimid
NH2
O
N
NH
N
Indole, Piperidine.
Follicular lymphoma, multiple
myeloma, marginal zone
lymphoma.
Indole, piperidine.
Use to treat Kaposi sarcoma and
multiple myeloma.
Imidazole, pyrimidine,
piperidine.
Chronic lymphocytic leukemia,
small lymphocytic leukemia.
O
O
Pomalidomide
Pomalyst
O
N
O
NH2
Ibrutinib
O
NH
O
Imbruvica
O
NH2
N
N
N
N
N
O
effects and minimum dosages for the cure of cancer. Discovery
of newer drugs involves use of heterocyclic chemistry.41,42 In this
review an effort has been made to study different heterocyclic
compounds containing nitrogen, sulphur, and oxygen in their
ring, having anti-cancerous activity (Figure 1). The combined
data from all the recent articles will help in providing a new
way for future research in developing new compounds for the
treatment of cancer.
Murty et al., synthesized benzoxazole derivatives coupled with
piperazine ring (2) and evaluated their cytotoxic potential towards
five distinct human cancer cell lines of various origins viz. Hela
(cervical), MCF-7 (Breast), A431 (skin), HepG2 (liver) and A549
(lung). All the synthesized compounds displayed IC50 value lesser
than 100 in MCF-7. cell line. The compounds possessing amide
linkage showed increased cytotoxicity against A431 cell line as
compared to other cell lines.44
Benzoxazole
Altintop et al., reported newer benzoxazole hydrazone
derivatives and reported in vitro cytotoxicity studies on
rat glioma and NIH/3T3 mouse embryonic fibroblast
cell lines using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl
tetrazolium bromide (MTT) assay shadowed by apoptosis
in C6 cell line. From the studies it was reported that
the
compound
N’-(1,1’-Biphenyl-4-yl-methylene)-2[(5-fluorobenzoxazole.-2-yl) thio] acetohydrazide (3) was
found to be more active on C6 cell line with IC50=4.30±0.28 µg/
mL in comparison to mitoxantrone with IC50=4.56±1.24 µg/
mL. Increased in SI value of (3) compound indicates selective
Al-Harthy et al., synthesized benzoxazole derivatives linked
to the piperazine and fluorine group. These benzoxazole
clubbed piperazine hybrids were prepared by nitration and
piperazinylation followed by in situ reductive cyclization. The
prepared compounds were evaluated against human lung cancer
epithelial cells A549. The cytotoxicity study was measured using
CellTitre-Glo luminescent cell proliferation assay and it was
observed that some intermediates (1) showed promising activity
and cell dependent toxicity. Whereas, the initial results obtained
were too low owing to the low solubility of aryl-piperazine.43
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Kaur, et al.: Heterocycles as Anticancer Agent
anti-glioma activity. In comparison to results, it was observed
that this compound causes dose-dependent late apoptosis.45
El-Helby et al., prepared a series of sulphamide linked
benzoxazole derivatives and evaluated them for their ability
to inhibit VEGFR-2 as well as their anti-tumor activity against
MCF-7 (breast cancer), HepG2 (hepatocellular carcinoma) and
HCT-16 cell lines. The compounds prepared contain essential
pharmacophoric groups having substituted and unsubstituted
hydrophobic moieties linked through spacers and linkers
which interact as hydrogen bond donor and -NH linked to
carboxylate of essential amino acid. Among the prepared series,
compound N-(4-(N-(cyclohexylcarbomoyl) sulfamoylphenyl)3-((5-methylbenz-oxazol-2-yl) thio) propenamide (4) was most
potent and had appreciable activity against all three cell lines.
This compound was further examined for VEGFR-2 inhibitory
activity. Results obtained showed that in comparison to sorafenib
(standard) (IC50=0.1±0.02 μM): synthesized compound (4)
strongly inhibited VEGFR‐2 with lower IC50 values.46,47
Wu and Ding et al., synthesized a set of piperazine clubbed
acetamide derivatives. All the prepared compounds were
characterized by 1H NMR,13C NMR, elemental analyses and
further evaluated against different cancer cell lines. Compound
N-(5-benzyl-4-(tert-butyl)
thiazol-2-yl)-2-(piperazin-1-yl)
acetamides (7) showed appreciable cytotoxicity against. HeLa
cancer cells with IC50 value ranging from 1.6±0.8µM. Further Wu.
and co-workers also stated that this compound stopped G1 phase
cell cycle, which causes cell apoptosis.50
Ciprofloxacin is an antibiotic having apoptotic and
antiproliferative activity. Considering the importance of
ciprofloxacin Azema et al., reported set of piperazine compounds
linked to ciprofloxacin derivatives of varying lipophilicities
and tested them against different cancer lines. Among the
synthesized
compound
7-(4-2-chloroacetyl)piperazin-1yl)-1-cyclopropyl-6-fluoro-1,4-dihydr0-4-oxoquinoline-3-car
boxylic acid (8) and 7-(4-decanoylpiperazin-1-yl)-1- cyclopropyl6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (9) was
the most potent with their IC50 values in the range ≤10 µM in
cancer cell lines.51
In an extension. of the work piperazine analogues linked
with benzofuran were prepared by Mao and co-workers and
assessed them against four tumor cell lines (Hela, A549,
MCF-7, SGC7901) using MTT assay. Among the prepared
analogues 2-(2,4-dichlorophenoxy)-1-(4-(4-(6-(diethylamino)
benzofuran-2-carbonyl) piperazin-1-yl) ethenone (10) was most
effective compound against four strains of tumor cell lines and
was also found to be more actives than standard cisplatin, and
exhibited cytotoxicity selectively against HeLa.52
Piperazine
A new series of mono mannich bases containing piperazine
scaffold were prepared and their cytotoxicity and inhibitory
activity against carbonic anhydrase I (hCAI) and carbonic
anhydrase II isozymes (hCAII) were tested in vitro. All
compounds showed good inhibition towards hCAI with Ki value
in range of 29.6-58.4 nM and 38.1-69.7 nM. Among the series,
compound 4-fluorophenyl piperazine (6) had highest tumor
selectivity value (TS: 59.6) by causing cell death.48,49
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
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Kaur, et al.: Heterocycles as Anticancer Agent
Oxazole
Indole
Romagnoli et al., prepared new 2-methyl- 4,5 -disubstituted
oxazole derivative and screened them for anti-cancerous activity
against series of seven human tumor cell lines in comparison to
standard combrestatin-4 with IC50=0.8-3100 nM. Compound 11a
and 11b was found to be most active having IC50 value 0.35-4.6
nM and 0.5-20.2 nM respectively. SAR studies revealed that
compounds having 3,4,5-trimethoxyphenyl moiety at C-4 with
respect to oxazole was beneficial for showing anticancer activity.
Whereas, presence of electron releasing group placed at para
position to phenyl ring showed increase in the activity and when
placed on meta position was found to be detrimental for the
activity.53
For a search of new scaffold for anti-cancer activity Patil. et al.,
prepared series of pyrido[3,4-b] indole derivatives and screened
them for anti-proliferative. activity against panel of human
cancer cell lines, containing HCT116 colon, MIA, HPAC, MCF-7,
PaCa-2, Panc-1 pancreatic and MDA-MB-468 breast, WM164
and A375 melanoma, A549 lung, and LNCaP, DU145 and PC3
prostate cancer lines.1-Napthyl group at first carbon clubbed with
methoxy group at sixth carbon (1-naphthyl-6-methoxy-9H-pyrido
[3,4-b] indole) (14) showed the highest anticancer. and highest
potency.55
Katariya et al., synthesized some biologically active heterocyclic
ring containing propenones (12a-12e) and methadone (13a-13e)
derivatives clubbed with biologically active heterocyclic rings
including oxazole, pyridine and pyrazoline. All the compounds
prepared were further screened for in vitro anticancer activity
against sixty cancer cell lines at NCI, USA. Based on the
bio-activity results, SAR studies revealed that the chalcone
with floro substitution showed poor inhibition in comparison
to other prepared chalcones derivatives. Whereas, compound
12d with bromo substitution showed highest potency among all
the prepared compound with inhibition of 55%, 52% and 50%
against T47D (breast cancer), OVCAR-4(ovarian cancer) and
RPMI-8226 (leukemia) respectively.54
In addition to above research, indole-based imidazo[2,1-b][1,3,4]
thiadiazole compounds (15) were synthesized by Casciofero et
al., and evaluated for anticancer efficacy on series of Pancreatic
Ductal Adenocarcinoma Cells (PDAC) including Panc-1,
Capan-1, and SUIT-2. From the result it was observed that
compound 15 significantly inhibited the release of Capan-1 cells
and SUIT-2 in wound healing assay and showed appreciable in
vitro anti-cancer activity on all three preclinical models with IC50
ranging from 5.11 -10.80 µM.56
A new series of heterocyclic compound was prepared by
Lotify et al., indole derivatives was prepared by condensing
L-proline and dicarbonyl compound isatin, with dipolar groups
containing spiro-oxindole and pyrrolidine rings. Further the
prepared analogues were screened for breast cancer cell lines
(MCF-7) and leukemia (K562). Among the prepared series, (1R,
5’R)-3-(E) -4-bromobenzylidiene)-7’,7a-dihydro-1’H,3’H disp
iro[cyclohexane-1,6’pyrrolo[1,2-c]thiazole-5’3”indoline]-2,2”dione (17) was recognized as the most effective compound with
IC50 values of 15.49 ± 0.04 μM, against breast cancer cell lines
(MCF-7) comparison to standard drug 5-florouracil (IC50=78.28
± 0.2 μM).57
Islam et al., synthesized in high yields a series of functionalized
3-acylindole linked with spiro-oxindole. Chalcones obtained
from 3-acetyl indole was used as a starting material. These
spiro-oxindole hybrids screened in vitro for their anticancer effect
counter to colon cancer (HCT-116), hepatocellular carcinoma
(HepG2) and prostate cancer (PC-3). Compound (17) found to
have high selectivity and cytotoxicity against HCT-116.58
By condensation of nitro indole with diazotized
p-aminoacetophenone and different heteroaromatic amines Kaur
at al., prepared a series of indole linked diazinyl compounds
and screened them for cytotoxicity against breast cancer
(MDAMB231), human lung carcinoma (HCT-116), leukemic
and normal (K562 and HEK293) cell lines using MTT assay kit
and doxorubicin as standard. Two compounds (18, 19) found
to be active against human colon and breast carcinoma having
IC50=19-65 µg/mL.59
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Kaur, et al.: Heterocycles as Anticancer Agent
Imidazole
In a search for a new lead, Chen et al., carried out reaction of
1-benzyl-5-nitroimidazole with carbanion produced tertbutoxide to synthesize benzyl-dichloromethyl-nitroimidazole
derivative (20-22) and screened their anticancer activity. All the
derivative compounds were biologically active compounds and
showed prominent action against cancer cells.60
In addition, Kostakis et al., reported a series of substituted amino
xantheno imidazole derivatives (23-24) and screened their
anticancer activity against human breast MDA-MB-231 cell line.
A series of synthesized test compounds having two side chains
exhibited maximum antiproliferative activity at higher dose while
increase in the size of substituent and increase in basicity of alkyl
substituent causes increase in anticancer activity.61
Whereas, Jones et al., synthesized a set of imidazole linked
pyrimidine amides (25-30) as CDK inhibitors (cyclin-dependent
kinase). All synthesized compounds exhibited better activity
against CDK enzymes as anti-proliferative agents.62
Further series of derivatives was synthesized by Yang et al., they
prepared hybrid between 2-phenylbenzofuran and imidazole
(31-42) and tested for their in vitro anti-tumor activity on
different tumor cell lines. Results revealed that imidazolyl group
placed at third position with bromophenacyl (42) or naphthylacyl
(43) group was essential for modifying anticancer activity.
Among all the twelve synthesized derivatives, compound (43)
showed remarkable activity against four different strains of
human tumor cell lines.63
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Kaur, et al.: Heterocycles as Anticancer Agent
In addition to above research, Makawana et al., synthesized
new Schiff base derivatives of imidazolyl ethanones with benzo
hydrazides (43-49) and tested for inhibition of Epidermal
Growth Factor Receptor (EGFR) as anti-cancer agents. Among
the compounds studied, compounds 46, 49 and 50 inhibited
epidermal growth factor receptor and compounds 44, 45, 47 and
49 exhibited effective antibacterial activity. Compound 50 shows
effective inhibition against EGFR receptor.64
In an effort to identify anticancer agent, Oskuei et al., synthesisized
novel imidazole based chalcone derivatives as polymerization
inhibitors on tubulin protein. Anticancer activity of imidazole
based chalcone derivatives (56-65) was evaluated and tested on
some human cancer cell lines including adenocarcinoma human
alveolar basal epithelial cells (A549), mitoxantrone resistant
human breast cancer cell (MCF-7/MX), Human hepatocellular
carcinoma cells (HEPG2). Compound (63) and (65) exhibited
significant cytotoxicity activity with IC50 against all four human
cancer cells.66
Pyrrole
Vaupel et al., synthesized few new classes of inhibitors based on
tetra substituted imidazole scaffold. They showed considerable
antiproliferative activity on a p53-dependent MDM2 amplified
cell line. All the derivatized compounds showed significant
anti-cancerous activity towards p53 dependent MDM2 amplified
cell line.65
S32
Bavadi et al., in search of new derivative synthesize some novel
pyrrole derivatives incorporating sulphonamides and screened
against different cancer cell lines MCF-7, MOLT-4 and HL-60.
Among the synthesized compounds, the compound (66)
possessing morpholine group clubbed with pyrrole derivative
was found to be more effective against these cell lines. Docking
study reveals seven hydrogen bonds between the active site and
pyrrole derivatives.67
To study mechanism of action of pyrrole derivatives with EGFR
and VEGFR. Kuznietsova and co-workers synthesized pyrrole
derivatives: chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)-amino)-1H-pyrrole-2,5-dione
(67a)
and
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
Kaur, et al.: Heterocycles as Anticancer Agent
5-amino-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2dihydro-3H-pyrrole-3-one (67b) and screened them against
various EGFR and VEGFR like protein kinase. From the results it
was obtained that pyrrole derivative bind with VEGFR and EGFR
and form stable complex by forming electrostatic interaction with
polar group of phospholipids in cell membrane.68
Alsaedi et al., synthesized novel nano sized fluorinated thiazoles
and evaluated their antiproliferative activity. They prepared
trifluoro methylated thiosemicarbazone (73a- 73f) by reacting
with thiosemicarbazone in acidic solution of ethanol. They
found that nanosized thiazole derivative was found more active
than standard cisplatin. And also found two thiazole derivatives
exhibited good activity with IC50 value 13.4 and 14.9 µg/mL.71
Thiazole
Siddiqui et al., synthesized thiazole containing derivatives
2-((1R,2R,4S,5R)-4-(hydroxymethyl)- 3,6-dioxabicyclo [3.1.0]
hexan-2-yl)thiazole-4- carboxamide (68) and screened for its
anti-tumour activity against K562 malignant cells. This synthetic
compound showed potent cytotoxic activity with low IC50 value.69
Ramirez et al., derivatized a series of thiazole derivatives and
screened for anti-tumour activity by US NCI (National cancer
Institute) against sixty different human cancer cell lines which
are derived from nine cancer types: ovary, renal, colon, CNS,
leukaemia, lung, melanoma, breast and prostate cancers.
From the results it was obtained that two compounds (E)-6(benzo[d]
[1,3]
dioxol-5-yl)-8-(2,4-dichlorothiazol-5-yl)8,9-dihydro-7H-pyrimido[5,4-b] [1,4] diazepin-4-amine (69) and
(E)-8-(2,4-dichlorothiazol-5-yl)-6-p-tolyl-8,9-dihydro-7H-pyri
mido[5,4-b] [1,4] diazepin-4-amine (70) have potent cytostatic
activity. The compound (69) possesses cytostatic activity against
K-562 of leukaemia, SND-75 of CNS cancer, MDA-MB-435
of melanoma and A498 of renal cancer, whereas compound
(70) found to be more active against K-562 of leukaemia and
MDA-MB-435 of melanoma. This compound has also shown its
viability against HCT-15 of colon cancer, SNB-75 of CNS cancer,
RXF393 of renal cancer and MDA-MB-468 of breast cancer cell
lines.70
Haribabu et al., in a search of new compound synthesized
heterocyclic azole containing compounds, 3-(2,3-dihydrobenzo
[d]thiazol-2-yl)-4H-chromen-4-one (72) and 5-(1H-indol-3-yl)
-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione(73)
which were synthesized from 2-aminothiophenol and 4-oxo4H-chromene-3-carbaldehyde, and (E)-2-((1H-indol-3- yl) meth
ylene)-N-methylhydrazine-1-carbothioamide in the presence of
anhydrous ferric chloride, respectively. They assessed compounds
72, 73 and cisplatin as standard for their cytotoxic study against
a series of three cancer cells of human such as HepG-2 (hepatic
carcinoma), T24 (bladder) and EAHy 926 (endothelial) cells by
using MTT assay. The results exhibited that compound (75) has
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
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Kaur, et al.: Heterocycles as Anticancer Agent
significant cytotoxicity against HepG-2 and EAHy926 cells with
the IC50 values of 33.8 μM.72
Jiang et al., synthesized some new Schiff base linked
1,2,3-triazole derivatives and screened them for human
cancer cell line A549 using paeonol as a standard.
Compounds
(E)-2-[1-{[1-(3-fluorophenyl)-1H
-1,2,3-triazol-4-yl]methyl}imino)ethyl]-5-methoxyphenol
(74)
and
(E)2-[1-{[1-(3-chloroophenyl)-1H
-1,2,3-triazol-4-yl]methyl}imino)ethyl]-5-methoxyphenol (75)
showed cytotoxicity with IC50 value of 45.1µM and 78.9 µM
respectively in comparison to standard having IC50 of 883.0 µM.73
Narsimha et al., synthesized novel coumarin based 1,2,3-triazole
derivatives (76) and observed potent cytotoxic activity with IC50
3.12 and 2.77 µM against HeLa and MCF-7 cancer cell lines in
parallel to standard Doxorubicin having IC50 0.23 µM in HeLa
and 2.67 µM in MCF-7. SAR studies revealed that introducing
7-hydroxycoumarin, 7-hydroxy-4-methylcoumarin, 8-hydroxy
quinoline and 2-mercaptobenzoxazole derivatives at the fourth
position of 1,2,3-triazole ring affect the cytotoxicity.74
Tubulins play an important role in several cellular life processes.
Tubulin polymerase inhibitors are agents that interfere with the
tubulin system. Du and co-workers synthesized some triazole
derivatives as tubulin polymerase inhibitors. Compound
5-(2-Chlorophenyl)-4-[4-(3,5-dimethoxyphenyl)piperazine-1carbonyl]-2H-1,2,3-triazole (77) which showed strong
cytotoxic effect on A549 and taxol resistant cells which inhibit
polymerization by arresting G2/M phase.75
Furan
In search of new compound as anticancer agent, Islam and
co-workers synthesized furan derivatives by cyclizing 1-(aryl/
alkyl(arylthio)methyl)-naphthalen-2-ol
and
pyridinium
bromides in the presence of 1,8- diazabicyclo[5.4.0] undec-7ene (DBU) in good yield. The compound was evaluated against
triple negative MCF-7 breast cancer cell line, MDA-MB-468 and
non-cancerous lung fibroblast cell line FI-38 cells using MTT
assay. The prepared furan derivatives, (1,2-dihydronaphtho[2,1-b]
furan-2-yl)(p-tolyl) methanone (78) considered to have best
anti-cancer activity from the series of prepared compounds.76
Thiophene
Gomha et al., synthesize 5-(thiophen-2-yl)-1, 3, 4-thiadiazole
derivatives (79) as potential antiproliferative compounds. By
cyclization of N-(4-nitrophenyl) thiophene-2-carbohydrazonoyl
chloride with arylidene thiosemicarbazones, the 1,3,4-thiadiazoles
derivatives was prepared. The compound exhibited potent activity
against human lung cancer A-549 and human hepatocellular
carcinoma (HepG-2) using cisplatin as a standard. From the SAR
(structure activity relationship) analysis, it was observed that
introducing electron donating methoxy group on aryl moiety
showed promising anticancer activity. Whereas, on replacing
methoxy group with chlorine does not show appreciable activity
as that was observed with methoxy group.77
Othmana et al., derivatised a series of thiophene compounds
and screened their anticancer activity against four cancer cell
lines HeLa, HepG2, MCF-7 and HCT-116 and result displayed
that benzyloxy derivatives exhibited good anticancer activity
against MCF-7 with IC50 value=28.36 µM. Structure activity
relationship studies (SAR) showed that presence of lipophilic
group (benzyloxy) increases the antiproliferative activity in
comparison to other synthesized derivatives. In addition,
introduction of substituent’s like fluoro, trifluoromethyl, chloro
group at fourth position of benzene ring causes increase in the
anticancer activity. This compound (80) also showed effective
inhibition against EGFR-TK enzyme having IC50=3.66 µM, which
indicated this inhibition activity of the compounds may be due to
strong interaction with EGFR-TK enzyme.78
S34
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
Kaur, et al.: Heterocycles as Anticancer Agent
Volodina et al., synthesized thiophene-2-carboxamide derivatives
of anthraquinone. This anthraquinones since ages known as
a source of efficacious antitumour drugs. Various chemical
modifications in the side chain of the compound yielded the
compound with various anti-tumour activities. Among the
prepared anthraquinone derivatives, anthra[2,3b] thiophene-2carboxamide (81) was found to be potent against variety of
human tumour cell lines. Sub micromolar or low molecular
concentration of the prepared compound was effective against
chronic myelogenous leukaemia K562.79
Targeted receptor for anti-cancer drug
Protein kinase
They are the enzymes that modify the shape of proteins by
phosphorylating certain amino acids with ATP to control
functions of protein. This mechanism activates intracellular
signaling pathway through gene expression via cell proliferation,
growth and apoptosis.80,81 Protein kinase are often considered
as oncogenic and essential for the survival and spread of the
cancerous cells. Other kinase targets include tyrosine Kinase
(TKs) and cyclin-dependent kinase (CDKs). TKs is crucial for
controlling the survival and cell growth of cancer cells (Figure 2).82
Conversely, CDKs are in charge of cellular transcription and the
advancement of the cell cycle.83 Tyrosine kinase consist of around
thirty different families including VEGFR, EGFR and NGF.
Genome of human consists of 90 tyrosine kinase and 43 tyrosine
like genes. Stimulation of TKs causes activation of number of
signaling pathways. These pathways in turn are responsible for
cell movement and reorganization which causes metastasis of
tumour.82 Hence, protein kinases emerged as an attractive group
of targets for the anti-cancer drug development.
Figure 1: Heterocyclic scaffolds containing anticancer activity.
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Kaur, et al.: Heterocycles as Anticancer Agent
Figure 2: Kinase inhibitors approved for the treatment of cancer.
Apoptosis inducers
Apoptosis also known as “cellular suicide”. It is a form of
programmed cell death in which infected cells or cancerous
cells are removed from the body. Cells generally try to repair the
damaged DNA but when the damaged DNA is beyond repair
then apoptosis takes place and remove this damage cells. When
this damage DNA does not undergo apoptosis then it may lead
to cancer.84
Topoisomerase
DNA topoisomerase I and topoisomerase II are the nuclear
enzymes that play an important role in replication, recombination
S36
as well as repair and transcription of DNA. These enzymes cause
transient breaks in DNA molecule by slicing one strand or both
the strands of DNA, thereby relieving the topological tensions
and relaxing DNA helices. Hence topoisomerase I and II are
considered as important target for the anticancer drug design.85,86
Microtubules
They are cytoskeletal structures that are formed by association of
two subunits i.e., α and β. These microtubules play an important
role in providing shape and rigidity to the cell. They are also
involved in the process of cell division, cell reproduction; cell
signalling and cellular movement.87 Two types of microtubules
such as stabilising and destabilizing agent are the important
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
Kaur, et al.: Heterocycles as Anticancer Agent
target for the anticancer drugs. Microtubule Stabilizing Agent
(MSA) act by binding to tubulin in the polymeric tubular form.
and stop the process of depolymerization. These MSA bind with
one of the two binding site that promote stabilization and prevent
depolymerizations. As a result, cell cycle arrest takes place at
G2/M stage.88
Whereas, microtubule destabilising agent act by binding to
colchicine and vinca domain thereby destabilizing microtubules
and prevent tubulin polymerisation process. Tubulin emerged as
an important target for anticancer drug development.89
Cancer stem cells
These are the cells which are present within the tumor. Cancer
stem Cells (CSC) produces daughter cells and reproduces very
fastly for a short period of time. These types of cells further
segregate and produce cell in the tumor mass that are noncancer stem cells. CSC’s play role in development of tumors
and maintenance of population of cells that proliferate rapidly.90
According to the study, cancer stem cells are present in variety
of tumors91 including those of prostate,92-94 brain,95-98 ovarian,99-100
colon,101 lung102 and in chronic leukemia.103,104 Therefore, it is
believed that different types of cancer contain subset of stem like
tumor cells. So, targeting cancer stem cells are essential for an
effective anticancer drug development.
CONCLUSION
This review is focused on recent development of heterocyclic
ring containing synthesized derivatives having anticancer
properties which mainly focused on development of target based
anticancer drugs. Heterocyclic moieties play an important role
as they are present in majority of drugs which improves both
pharmacokinetic and pharmacodynamics properties of the
anticancer agents. About 30% of FDA approved anticancer drugs
have one or more heterocyclic rings containing oxygen, nitrogen
and sulphur. Heterocyclic moieties play a vital role in metabolism
of all living creatures approximately through many biochemical
processes necessary to sustain life. Their involvement of about
two thirds of anticancer drugs approved by FDA in the first
half of decade to highlight their ongoing importance in cancer
research play a center role to fight against cancer. Moreover,
efforts have been made to provide recent advances in heterocyclic
compounds as anticancer agents and a new way in developing
new compounds for the treatment of cancer.
CONFLICT OF INTEREST
The author declares that there is no conflict of interest.
ABBREVIATIONS
FDA:
Food
drug
administration;
MTT:
(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl
tetrazolium
bromide); CSC: Cancer stem cells; HeLa: Henrietta Lacks SAR:
Structure activity relationship; IC50: Half maximal inhibitory
concentration; TK: Tyrosine kinase; hCAI: Human carbonic
anhydrase I; hCAII: Human carbonic anhydrase II; CDK: Cyclin
dependent kinase; CSC: Cancer stem cells; MSA: Microtubule
stabilising agent VEGFR: Vascular endothelial growth factor;
HPAC: Human pancreatic cancer; Hep: Hepatoblastoma; PDAC:
Pancreatic ductal adenocarcinoma; MCF: Michigan cancer
foundation; MDM2: Murine double minute.
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Cite this article: Kaur A, Shakya AK, Singh R, Badhwar R, Sawhney SK. Heterocyclic Compounds and their Derivatives with Potential Anticancer Activity. Indian
J of Pharmaceutical Education and Research. 2024;58(1s):s26-s39.
Indian Journal of Pharmaceutical Education and Research, Vol 58, Issue 1 (Suppl), Jan-Mar, 2024
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