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doi: 10.18282/amor.v1.i1.12
REVIEW ARTICLE
Indoles as anti-cancer agents
Mardia T. El Sayed1*, Nehal A. Hamdy1, Dalia A. Osman1, Khadiga M. Ahmed2
1
2
Applied Organic Chemistry Department, Chemical Industries Division, National Research Centre, Egypt
Natural Products Department, Pharmaceutical Industries Division, National Research Centre, Cairo, Egypt
Abstract: Indoles are natural products which are well known for its anti-cancer activity due to its ability to induce cell
death for many cancer cell lines. This review addresses indoles as natural products, mechanism of indoles, facilitated
induction and recent studies with indoles and related compounds that were investigated via anti-cancer screening and
that led to drug approval.
Keywords: indoles; natural biosynthesis; cell death induction; screening; anti-cancer agents
Citation: El Sayed MT, Hamdy NA, Osman DA, et al. Indoles as anti-cancer agents. Adv Mod Oncol Res 2015; 1(1):
20–35; http://dx.doi.org/10.18282/amor.v1.i1.12.
*Correspondence to: Mardia T. El Sayed, Applied Organic Chemistry Department, Chemical Industries Division, National Research Centre, Egypt, [email protected].
Received: 30th July 2015; Accepted: 4th September 2015; Published Online: 6th October 2015
A
n indole is an aromatic heterocyclic composite
which has its heterobicyclic configuration as a
six-membered ring fused to a five-membered
pyrrole ring. ‘Indole’ is the name given to all indole derivatives which have an indole ring system[1,2]. Indoles
are obtained from coal pitch or a variety of plants and
produced by the bacterial decay of tryptophan in the intestine. It has been synthesized by one of the oldest
method that known as Fischer indole synthesis[2]. Indoles
function as signal molecules in plants and animals. They
also serve as a raw material, nucleus building blocks and
an efficient group of numerous imperative biochemical
molecules and compounds, such as alkaloids, indigoids,
etc. Most of these important molecules and compounds
originate, either fully or partly, from bio-oxidation of
indoles.
Naturally biosynthesized indole
products
Indoles are natural compounds can be found in numerous
types of plant. They are, however more predominantly
found in cruciferous vegetables[2]. Cruciferous vegeta-
bles comprise of cauliflower, cabbage, turnip, broccoli
and brussels sprouts (Figure 1). Indoles fit in a class of
phytonutrient compounds (plant compounds with healthprotecting qualities) which have been systematically
proven to profit the body in a number of imperative ways.
Consuming of cruciferous vegetables has been associated
with reduced of the risk of colon, breast and prostate cancers. Cruciferous vegetables are a rich source of
many phytochemicals, including indole derivatives,
dithiolethiones and isothiocyanates. Cruciferous vegetables are full of glucobrassicin (GB) which throughout
metabolism, produce indole-3-carbinol (I3C), 3,3′diindolylmethane (DIM) and ascorbigen (ASC) (Figure
2). The anti-carcinogenic property of I3C and DIM was
exhibited in human cancer cells. It appears that these
indolic compounds may be efficient anti-cancer agents
for several cancer cell lines[3-6].
Natural compounds found in fruits and vegetables are
recognized to have anti-mutagenic and anti-carcinogenic
properties. A high dietary intake of fruits and vegetables
has proved to be beneficial against carcinogenesis. An
inhibitory effect of indoles and cruciferous vegetables
against tumorgenesis and cancer hazard has also been veri-
Copyright © 2015 El Sayed MT, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and
reproduction in any medium, provided the original work is properly cited.
20
El Sayed MT, et al.
fied[7]. Epidemiological statistics reveal that populations
that consume higher amounts of cruciferous vegetables
have lower incidences of cancer or improved biochemical parameters, such as decreased oxidative pressure compared to controls. Cruciferous vegetables protect against
cancer more successfully than fruits and other vegetables.
The National Research Council, USA, has recommended consumption of cruciferous vegetables as a measure
to diminish the commonness of cancer[8-11].
Bio-oxidation of indoles and respective enzymes in
microorganisms and in plants has been well documented
in the recent review by Yuan et al.[3] In this review, the
pathways of indole bio-oxidation which lead to configuration of indigo and indirubin in plant and the perspectives of the study in indole bio-oxidation have been
discussed (Scheme 1). Where E1 is indole oxygenase, E2
is indole oxidase, E3 is indole 2,3-dioxygenase, E4 is
indican synthase, E5 is indoxyl-UDPG-glucosyltransferase, E6 is formylase, E7 is aldehyde oxidase, S is
Brussel Sprout
Kohlrabi
Broccoli
spontaneous reaction, P is plant tissues and organs, GT?
is glucosyltransferase (unidentified) and GLU? is glucosidase (unidentified)[3].
The amino acid tryptophan is a biogenetic precursor
of all indole alkaloids. The first step of synthesis is decarboxylation of tryptophan to form tryptamine. Dimethyltryptamine (DMT) is formed from tryptamine by
methylation with the contribution of coenzyme of Sadenosyl methionine (SAM). Psilocin is produced from
dimethyltryptamine by oxidation and is then phosphorylated into psilocybin. In the biosynthesis of serotonin, the
intermediary product is not tryptamine but 5-hydroxytryptophan, which is sequentially decarboxylated to
shape 5-hydroxytryptamine (serotonin) (Figure 3)[12-14].
Biosynthesis of β-carboline alkaloids takes place via
formation of Schiff base from tryptamine and aldehyde
(or keto acid) and consequent intramolecular Mannich
reaction, where the carbon in position two of indole acts
as a nucleophile (Figure 4). This is followed by the
Radish
Cauliflower
Figure 1 Cruciferous vegetables. [Source available from: http://www.fotosearch.com/photos-images/cruciferous-vegetables.html]
OH
S
GB
O
OH
OH
OH
OH
N O SO
3
N
H
H
Myrosonase
H2O
D-glucose
HSO4
N
-
I3C
SCN
S
H2O
N
H
H
NN
HH
L-ascorbic
acid
H
OH
O
HO
N
H
H
DIM
N
N
H
H
H2 O
O
O
OH
N
H
ASC H
Figure 2 Biosynthesis of indoles: 13C, DIM and ASC from GB
doi: 10.18282/amor.v1.i1.12
21
Indoles as anti-cancer agents
aromaticity being restored via the elimination of a proton
at the C two atom. The consequential tetrahydro-β-carIndigo
plant
Indigoproducing
produc ing
plant
Non-indigoproducing
producing
plant
Non-indigo
plant
O
HO
N
H
N
H
HO
Hydroxy indo
le
OH
O
E4 /E5
N
H
6-Hydroxyindole
6-Hydroxyindole
55-Hydroxyindole
boline frame steadily oxidizes to dihydro-β-carboline and
β-carboline afterwards[16,20].
OH
HO
3-Oxindole
3-O xindole
NH
Indican
Indican
P
P
O
OH
OH
O2
P
N
N
H
H
N
H
H
Indole hydroxylase
hydrunulase ?
Indole
HO
G T?
GT?
N
N
H
H
Indole
O2
O
O
Glycosylation
Gly cosy lation
Indole
O
G T?
OO22
OH
Hydrolysis
Hydrolysis
N
H
GLU ?
GLU?
N
H
O
GT?
Indoxy l
Indoxyl
HO
IsatanBB
Isatan
O
E6 ?
Isatine
Isatine
CHO
OH
N
H
N
H
Dioindole
Dioindole
O
O-aminobenzaldehyde
O- aminobe nzaldehyde
N
H
CO2H
O2
H
N
O
Indigo
Indigo
NH
O
C 11H7O2
GT?
O
NH
IsatanCC
Isatan
O2 S
NH 2
O
OH
O
O2 S
OH
O
NHCHO
N-form yla minobenzaldehyde
benzaldehy de
N-formylamino
NH
Isatan
AA
Isatan
IsatanA
OH
3 -Oxindole
3-Oxindole
OH
HO
O
O
HO
Indoxyl
Indoxyl
E1
E2
E3
CHO
H
C
O
HO
Precursors
inInVivo
P re cursors
Vivo
S
O
?
N
H
Indirubin
Indirubin
NH
O
O
N
Anthranil
Anthranil
(E2/E3)
NH 2
Anthranilic
a cid
Anthranilic acid
(E1/E3)
(E1/E3)
Scheme (1): Bio oxidation of indole in higher plants.
Scheme 1 Bio-oxidation of indole in higher plants
Figure 3 Tryptophan as a biogenetic precursor of all indole alkaloids
22
doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
NH2
N
RCHO
RCHO
N
H
N
H Schiff
schiff base
base formation
formation
NH
NH
R
tryptamine
tryptamine
R
N
H
terahydro-β-carboline
terahydro-B-carboline
R
N
H
Mannich
Mannichreaction
reaction
oxidation
oxidation
oxidation
R
N
H
dihydro-β-carboline
dihydro-B-carboline
R
N
H
Beta-carboline
beta-carboline
Fig. (4): Biosynthesis of beta-carboline alkaloids.
N
oxidation
oxidation
N
Figure 4 Biosynthesis of beta-carboline alkaloids
The biosynthesis of ergot alkaloids starts with the alkylation of tryptophan via dimethylallyl pyrophosphate
(DMAPP), in which the carbon atom in position 4 of the
indole ring acts an important facilitator of the nucleophile (Figure 5). The consequential 4-dimetilallil-Ltryptophan is followed by N-methylation. Additional
products that result from the biosynthesis are chanoclavine-I and agroclavine—the latter is hydroxylated to
elymoclavine, that in turn oxidizes into paspalic acid
OH
O
O
O P O PO
O
O
COOH
NH2
HN
COOH
DMAPP
H
N
H
N
HO
NH2
NN
HH
N
H
H
L-tryptophan
which is converted to lysergic acid through the process
of allyl rearrangement[16,21].
Biosynthesis of monoterpenoid indole alkaloids starts
with the Mannich reaction of tryptamine and secologanin;
this produces strictosidine, which is renewed to 4,
21-dehydrogeissoschizine (Figure 6). After that, the biosynthesis of alkaloids containing the composed
monoterpenoid fraction (Corynanthe type) was shaped
throughout cyclization with the configuration of
N
N
H
H
chanoclavine-1
4-dimetilallil-L-tryptophan
HOOC
H
oxidation
N
N
H
H
agroclavine
N
HOOC
H
N
H
oxidation
N
N
H
H
elymoclavine
N
H
H
paspalic
N
N
H
H
D-(+)-lysergic acid
Figure 5 Ergot alkaloids biosynthesis.
Mannich reaction
Mannich
NH2
N
N
H
H
OHC
NH
OGlc
O
N
N
H
H
secologanin
N
N
N
H
H
N
H
H
H3 COOC
strictosidine
OAc
OH
COOCH3
N
N
O
CH3
vindoline
Aspidospirma type
OGlc
N
N
N
H
OH
H3 COOC
dehydrogeissoschizine
N
N
H
H
O
H3 COOC
cathenamine
CH3
COOCH3
tabersonine
Aspidospirma type
Figure 6 Biosynthesis of monoterpenoid indole alkaloids
doi: 10.18282/amor.v1.i1.12
23
Indoles as anti-cancer agents
scores of important modules of therapeutic agents in medicinal chemistry such as anti-cancer[22], anti-oxidant[23],
anti-rheumatoidal[24], anti-HIV[25,26], anti-microbial[27-29],
anti-inflamatory[30] , analgesic [31] , antipyretic [32] , anti-convulsant[33,34], anthelmintic cardiovascular[35], selective COX-2(cyclooxygenase-2) inhibitory activities[36-39]
(which is an enzyme accountable for inflammation and
pain) and DNA binding ability[40]. Furthermore, countless
essential indole derivatives are used in disease management, for example, the non-steroidal anti-inflammatory
drug indomethacin (Indocin®), the beta blocker pindolol
(Viskin®) for management of high blood pressure (hypertension), the psychedelic, dimethyltryptamine (DMT)[41] and
BioResponse DIM® for estrogens for men and women
(http://www.bioresponse.com/Home.asp) (Figure 7)[12,13].
cathenamine, and following reduction reaction into
ajmalicine in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). With the biosynthesis of
previous alkaloids, 4,21-dehydrogeissoschizine changed
into preaquamycin (an alkaloid of subtype Strychnos,
type Corynanthe) which ascends to other alkaloids of
subtype Strychnos and of the types Iboga and Aspidosperma[21].
Indoles in medicinal chemistry
Indole derivatives are imperative heterocycles in the
drug-discovery studies. They are a very important category of compounds that play a key role in cell physiology and are probable intermediates for numerous
biological reactions. Indole derivatives correspond to
Me
HN
OH
Me
Me
MeO
O
HO
N
Me
Me
N
O
N
N
H
H
N
N
H
H
Pindolol
DMT
Cl
NN
HH
N
H
H
DIM
Indomethacin
Figure 7 Marketed indole drugs
Cell death induction by indoles
Anti-cancer agents have been usually evaluated for their
ability to induce apoptosis. Indoles have been verified to
inhibit proliferation, expansion and invasion of human cancer cells[1,2,42-44]. Many mechanisms of apoptosis
stimulation of indole derivatives, I3C and DIM, were
reported for, (a): down-regulation of anti-apoptotic gene
products such as Bcl-2 (B-cell lymphoma 2) and Bcl-XL
(B-cell leukemia-extra large), (b): down-regulation of the
inhibitor of apoptosis proteins, e.g. CIAPs, X-chromosome linked inhibitor of apoptose protein (XIAP) and survival, (c): up-regulation of pro-apoptotic factors such as
Bax gene, (d): liberation of mitochondrial cytochrome C
in addition to stimulating of caspase-9 and caspase-3[45],
and (e): inhibition of the NF-kB signaling pathway[46-51].
A vast number of diverse mechanisms of apoptosis induction by indoles have also been reported[52-56]. Figure 8
demonstrates the extrinsic and the intrinsic pathways of
apoptosis (programmed cell death). The Extrinsic Route:
In the extrinsic pathway, signal molecules identified as
24
ligands, which are released by the immune system’s natural killer cells possess the Fas ligand (FasL) on their
exterior to connect to transmembrane death receptors on
the target cell. After the binding of the death ligand to the
death receptor the target cell triggers multiple receptors
to aggregate together on the surface of the target cell.
The aggregation of these receptors recruits an adaptor
protein known as Fas-associated death domain protein
(FADD) on the cytoplasmic side of the receptors. FADD,
in turn, recruits Caspase-8. Caspase-8 will then be activated and will be now able to directly activate caspase-3
and caspase-7. The activation of caspase-3 will initiate
the degradation of the cells[57]. The Intrinsic Route: The
intrinsic pathway is triggered by cellular strain, particularly mitochondrial stress caused by factors such as DNA
damage from chemotherapy or UV exposure. Upon delivery of the stress signal, the pro-apoptotic proteins in
the cytoplasm (Bcl-2-like protein 4 (BAX) and BAX-like
Bcl-2 homology domain 3 protein (BID)) bind to the
outer membrane of the mitochondria to signal the release
of the internal content.
doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
The interaction between the pro-apoptotic (BAX and
BID) and the antiapoptotic proteins (Bcl-2) on the surface of the mitochondria is thought to be important in the
formation of the PT pores in the mitochondria, and hence,
the release of cytochrome c and the intramembrane content from the mitochondria. Following the release, cytochrome c forms a multi protein complex known as apoptosome which consists of cytochrome c, Apaf-1, procaspase-9 and ATP. Following its formation, the complex
will activate caspase-9. The activated caspase-9 will then
turn the procaspase-3 and procaspase-7 into active cas-
pase-3 and active caspase-7. These activated proteins
initiate cell degradation or cell death. Besides the release
of cytochrome c from the intramembrane space, the
intramembrane also releases Smac/Diablo proteins to
inhibit the inhibitor of apoptosis (IAP). IAP is a protein
family which consists of 8-human derivatives. Their
function is to stop apoptotic cell death by binding
to caspase-3, caspase-7 and caspase-9 and inhibit them,
the schematic representation of these pathways are
shown in Figure 8[12,13,58].
Figure 8 Intrinsic and extrinsic pathways leading to apoptosis. [Available from https://innspubnet.files.wordpress.com/2015/04/
mitochondrial-pathway.jpg]
doi: 10.18282/amor.v1.i1.12
25
Indoles as anti-cancer agents
Indoles for inhibition of invasion and metastasis
Cancer cells are able to travel through the lymphatic
and blood vessels, pass through the bloodstream, and
then occupy and produce in healthy tissues elsewhere.
This ability to spread to other tissues and organs leads to
malignancy and makes cancer a potentially life threatening disease. Tumor angiogenesis is the propagation of
a complex of blood vessels that penetrate into cancerous
growths, supply blood and oxygen and eliminate waste
products[59]. In reality, tumor angiogenesis starts with
cancerous tumor cells releasing molecules that post signals to the neighboring host tissues. This signaling activates definite genes in the host tissue that, in turn, build
proteins to support growth of new blood vessels. Indole
derivatives, I3C and DIMs have been reported to restrain
the invasion of cancer cells[57-60] and the expansion of
new blood vessels (angiogenesis)[59,60].
Indole compounds for chemosensitization
Chemosensitization is the progression by which compounds for example, indole compounds, I3C and DIM
adapt the cellular signaling pathways leading to apoptosis and thus conquer the chemo- plus immune-resistance
of well-known chemotherapeutic drugs[1,61]. I3C has been
reported to sensitize multidrug resistant tumors to chemotherapeutic drugs without any related toxicity[1,62-64].
Mechanisms of anti-cancer and chemosensitizing effects
of indole compounds were summarized in Figure 9.
Indole compounds, such as I3C and its dimmer DIM, induce apoptosis through inhibition of several prosurvival
pathways. Emerging evidence also documents the ability
of indoles to reverse the process of EMT via regulation
of key miRNAs. An efficient induction of apoptosis and
reversal of EMT not only ensures increased sensitivity
to conventional drugs (chemosensitization) but also results in significantly reduced invasion and metastasis[1,62-64].
Reported indoles as anti-cancer active agents
Nowadays, clinical association of human reproductive
organ cancers requests new chemotherapeutics. In recent
times, a lot of hard works have been done to organize
antiproliferative signaling pathway of indole-3-carbinol
and its foremost indole metabolite 3,3′-diindolylmethane
(DIM)[65-71]. While DIM significantly reduces the occurrence of impulsive and carcinogen induced mammary
tumor establishment (Figure 10)[72-74]. It also exhibits
unpleasant promoting action in convinced investigation
procedure[75,76]. As a result, the decision was to look for
novel effective chemotherapeutics amongst 3,3′-diindolylmethane derivatives. Moreover, the X-ray studies
of 5,5′-dimethoxy-3,3′-methanediyl-bis-indole[77] revealed its ‘butterfly’ conformation, which is analogous to the
one proposed earlier for inhibitors of HIV-1 reverse
transcriptase, sharing the mode of action of nevirapine[78].
Other diindolylmethane derivatives and their corresponding tetrahydroindolocarbazoles have been synthesized and screened for anti-cancer activity in which
two compounds indicated were significantly more sensitive for several cancer cell lines corresponding to their
GI50 values. The highest antipoliferative activity recorded for the carbazole derivatives in a nanomolar scale
towards the three certain cancers cell lines: non-small
lung cell NCIeH460 with GI = 616 nmol/L, ovarian cancer cell line OVCAR-4 with GI = 562 nmol/L and breast cancer cell line 50 nmol/L scale MCF7 with GI = 930
nmol/L (Figure 10)[16].
X
X
H
N
H
H
H
N
N
H
H
N
N
H
H
X== F, X
X=CN
X
= CN
Figure 9 Summary of mechanisms of anti-cancer and chemosensitizing effects of indole compounds. [Original source from
http://www.mdpi.com/cancers/cancers-03-02955/article_deploy
/html/images/cancers-03-02955f 1-1024.png]
26
N
N
H
H
Carbazole
Carbazole derivative
derivative
Figure 10 3,3′-diindolylmethane derivatives and tetrahydroindolocarbazoles
Dorota et al.[79,80] in 2005 synthesized the disubstituted
diindolylmethanes flouro and cyano derivatives which
decrease the expansion of MCF7 (breast), NCI–H460
doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
(lung) and SF-268(NCS) cells, considerably 5,5′difluoro-3,3′-methanediyl-bis-indole and 5,5′-dicyano-3,
3′-methanediyl-bis-indole were tested against the MCF7
(breast), NCI-H460 (lung) and SF-268 (CNS) tumor cell
lines. The results are reported as the proportion of growth
of the tested cells to untested control cells (Figure 10).
F-derivative at concentration 1.10–4.00 mol/L reduces
the growth of MCF7, NCI-H460, and SF-268 cell lines to
1%, 0% and 2%, whereas the CN derivative at concentration 5.10–5.00 mol/L to 4%, 1% and 9%, respectively.
Both compounds are extremely cytotoxic in vitro towards those tumor lines. Their cytotoxicity indicates that
they could be motivating as prospective antitumoral chemotherapeutics[79,80].
Indoles (I3C and DIM or its derivatives) have been
revealed to induce apoptosis in breast [81-87] , squamous cell carcinoma[88], cholangiocarcinoma[89], colon[90-93],
Me2N
N
NMe2
N
R2
N
N
O
I
Indole-PMM
Me
Z
R1
Me
N
H
N
HN
C2H3
MeO
O
cervical[94], ovarian[95], pancreatic[96,97] and prostate[98-101]
cancer cells. Many other indole derivatives that were
reported as active anti-cancer agents as follow: the potential prodrug (1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N-trideuteronmethylaminome
thyl)-5-methoxyindole-4,7-dione), pentamethylmelamine
(PMM) in which the labeled pentamethylmelamine is
attached to an indole-4,7-dione moiety has attracted
much interest as an anti-tumor agent for over 35 years
(Figure 11). It entered clinics in the 1970s for the treatment of ovarian carcinoma but difficulties were encountered, as it was insoluble in water and thus is difficult to
formulate. However, it has recently been recognised as a
second-line treatment for ovarian carcinoma [12-19,102-104].
Schoentjes et al.[105] reported a patent of indole derivatives with general formula (I) in 2011 and reported its
use for the treatment of cancers (Figure 11).
N
H
Figure 11 Structure of prodrug indole-PMM derivative and tryptamine derivative
Numerous aroylamide indole derivatives have been
synthesized and preliminarily screened for their in vitro
anti-cancer activity in A431 and H460 cell lines (Figure
12). All the compounds examined exhibited strange effectiveness in a tumor cell cytotoxicity evaluation. The
findings indicated that the indole derivatives would be
talented candidates for the improvement of new anticancer agents. 3-aroylindole is a probable anti-cancer
drug candidate designed and projected from in vitro human microsome studies with better pharmacokinetics and
enhanced influence in the tumor xenograft represenH3CO
R1
OCH3
H3 CO
N
N
R2
NH2
O
O
R3
Aroylamide indoles
H3CO
NN
H
H
Aroylindole
Figure 12 Molecular structure of aroyl- and aroylamide-indoles
doi: 10.18282/amor.v1.i1.12
tation [106,107].
Dragmacidin is an inaccessible bis-indole alkaloid
(Figure 13) isolated from a deep water marine sponge[108,109] collected from the southern Australian
coast[110]. Dragmacidin was set up to hold two indole
groups fixed by a piperazine ring system. Dragmacidin
exhibited in vitro cytotoxicity with IC50 values of 15
µg/mL against P-388 cell lines and 1–10 µg/mL against
A-549 (human lung), HCT-8 (human colon) and
MDAMB (human mammary) cancer cell lines. In 1995,
Murray et al.[110] reported the isolation of dragmacidin D
(Figure 13). Dragmacidin D was found to be active
against human lung tumour cell lines and inhibited in
vitro growth of the P-388 murine and A-549 with IC50
values of 1.4 and 4.5 μg/mL, respectively[108,109].
Four new bis-indole alkaloids nortopsentins A–D
(Figure 13) were extracted from the Caribbean deep sea
sponge Spongosorites ruetzleri[110]. These derivatives of
nortopsentins A–C exhibited anti-cancer activity against
P-388 cells with IC50 values of 7.6, 7.8 and 1.7 respectively, and for Trimethylnortopeentin B derivative is 0.9
µg/mL.
27
Indoles as anti-cancer agents
R2
R3
R1
NH
N
Br
R5
N
R1
HN
R2
R1
HN
HN
N
H
H
OH
R2
HN
NH
R1=R2 = Br
R1=Br, R2= H
R1=H, R2=Br
R1=R2 = H
HO
HO
N
NH
Topsentin R1=H, R2=OH
Bromotopsentin R1 =Br, R2 =OH
Deoxytopsentin R1 =R2=H
Nortopsentins A,
Nortopsentins B,
Nortopsentins C,
Nortopsentins D,
NH
NH2
Dragmacidin D
O
N
HN
HN
N
Dragmacidin
H
H
N
OH
N
R2
HN
O
H
N
O
O
OH
NH
N
Hyrtinadine A
N
N
H
H
N
N
H
H
Hyrtiosins B
Figure 13 Marine natural bisindole alkaloids as anti-cancer agents
Topsentin showed self-conscious proliferation of cultivated human and murine tumor cells. It exhibited in
vitro anti-cancer activity against P-388 with IC50 value of
3 μg/mL, human tumor cell (HCT-8, A-549, T47D) with
IC50 value of 20 μg/mL and in vivo activity against P-388
(test/control (TC) 137%, 150 mg/kg) and B16 melanoma
(T/C 144%, 37.5 mg/kg). Bromotopsentin showed
antiproliferative activity against human bronocopuemonary cancer cells (NSCLC-N6) with an IC50 = 6.3
μg/mL. Deoxytopsentin showed antiproliferative activity
against human bronocopulmanary cancer cells (NSCLCN6) with an IC50 value of 6.3 μg/mL. It also displayed
moderate activity against breast cancer and hepatoma
(HepG2) with an IC50 of 10.7 and 3.3 μg/mL, respectively[111-113].
Recently, Kobayashi et al. reported a new cytotoxic
bisindole alkaloid hyrtinadine A (Figure 13) from an
Okinawan marine sponge Hyrtios sp[114-116]. Hyrtinadine
reported to exhibit in vitro cytotoxicity against murine
leukemia L-1210 and human epidermis carcinoma
KB cells.
Schupp et al. isolated a couple of new indolocarbazole
alkaloids, staurosporines (Figure 14) from the marine
ascidians Eudistoma toealensis and its predator[116,117].
Schupp et al. reported the prospects of these staurosporine derivatives as inhibitors of cell explosion and
macromolecule synthesis[117]. Staurosporine D was found
to be the main vigorous staurosporine candidate as a
MONO-MAC-6 (human monocytic cell lines) inhibitor
and inhibit the RNA and DNA synthesis. The IC50 values
of staurosporine A, D and E for inhibiting MONOMAC-6 cells were 24.4, 13.3 and 33.9 mg/mL, respectively while those of staurosporine B and C were >100
28
µg/mL. The percentage of inhibition of RNA and DNA
synthesis of compounds staurosporine A and D were 93
and >98, 98 and >98, respectively. Analysis of structure
activity relationship verified that hydroxylation of
staurosporine at position 3 of the indolocarbazole moiety causes an increase in antiproliferative activity. The
position of the–OH group is critical to determine the
antiproliferative property of a range of staurosporine
analogues. A novel carbazole alkaloid, coproverdine
(Figure 14) was isolated from a nameless ascidians,
Anchorina sp. collected from the North Island of New
Zealand[118]. Coproverdine was screened against a diversity of murine and human tumor cell lines such as P-388,
A-549, HT-29, MEL-28 and DU-145 exhibiting IC50
values of 1.6, 0.3, 0.3, 0.3 and 0.3 µmol/L, respectively.
The hyrtioerectine alkaloid A (Figure 15) was inaccessible from a red coloured marine sponge Hyrtios
erectus[119,120]. Hyrtioerectine A was tested for its cytotoxic activity towards HeLa cells and showed sensible cytotoxicity with IC50 assessment of 10 µg/mL.
Foderaro et al. published the isolation of a new tetrahydro-β-carboline alkaloid (Figure 15) bengacarboline
from the Fijian ascidians Didemnum sp[121]. Bengacarboline was found to be cytotoxic against a 26 human
tumor cell line panel in vitro with a mean IC50 value
around 0.9 µg/mL and also inhibited the catalytic activity
of topoisomerase II at 32 µmol/L.
In 1994, Bifulco et al. reported the isolation of two
tris-indole alkaloids, gelliusines A and B (Figure 15)
from a deep water new caledonian sponge Gellius or
Orina sp[122]. Gelliusin A and B were found to be
diastereomeric alternatives prepared by the coupling of
three indole units in which two 6-bromo tryptamine units
doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
tive configuration at C-8 and C-8 named (±) gelliusines
A and B. Gelliusines A and B showed anti-cancer activity
with an IC50 value of between 10 and 20 μg/mL against
KB, P-388, P-388/dox, HT-29 and NSCLCN-6 cell lines.
are linked through their aliphatic chains to the C-2 and
C-6 position of a middle serotonin moiety. The coupling
of the indole unit appears to be non-stereoselective giving two enantiomeric pairs, having dissimilar comparaH
N
O
O
H
N
O
R1
CHO
N
H
H
H
H
N
OH
N
Me
R3
O
HH
R2
N
OH
O
O
Coproverdine
O
Staurosporine A: R1=H, R2 =CH3, R3=OCH3, R4 =H
Staurosporine B: R1=OH, R2 =CH3, R3=OH, R4 =H
Staurosporine C: R1=H, R2 =H, R3=OCH3, R4 =OH
Staurosporine D: R1=OH, R2 =CH3, R3=OCH3, R4=H
Staurosporine E: R 1=H, R2 =CH3, R3=OH, R4 =H
N
N
H
Me
Staurosporine G
Figure 14 Chemical structures of marine natural products, staurosporines and coproverdine
H2N
HO
HO
O
O
H
N
N
NH2
OH
HO
NH
N
H
N
H
NH
N
H
Hyrtioerectine A
NH2
HN
N
H
Br
H2N
(±) Gelliusines
N
H
Br
Bengacarboline
Figure 15 Molecular structures of Hyrtioerectine A, Bengacarboline and (±) Gelliusines
Dendridine A (Figure 16), a distinctive C2-symmetrical 4,4′-bis(7-hydroxy) indole alkaloid was isolated
from an Okinawan marine sponge Hyrtios sp[123]. It exhibited reasonable cytotoxicity towards murine leukemia
L-1210 cells with IC50 value of 32.5 µg/mL. Chetomin
was acknowledged as a natural product anti-tumor candidate which prevents the configuration of the HIF-1,
N
H
Dendridine A
N
H Chetomin
Figure 16 Chemical structure of Dendridine A and Chetomin
doi: 10.18282/amor.v1.i1.12
P300 complex (Figure 16). Universal management of
chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth[124].
It has been established by Lee et al. that 1,1,3-tri
(3-indolyl)cyclohexane (Figure 17) inhibits cancer cell
expansion in lung cancer cells of xenograft models[125].
Consequently, it is a potential anti-cancer product derived from its strong tumor growth inhibition and positive pharmacologic properties. It also increases the manufacture of reactive oxygen species (ROS) and triggers
DNA damage[126-128]. Cyclohepta [b] indole and benzo[6,7]
cyclohepta [1,2-b] indole (Figure 17) were subsequently
screened for cytotoxic activity against human nasopharyngeal carcinoma (HOME-1) and gastric adenocarcinoma (NUGC-3) cell lines, where the product showed
imperative cytotoxicity at a concentration of 4 µg[126]. In
2014, it has been proved that an indole and its derivatives
NC001-8 could be novel therapeutic agents for spinocerebellar ataxias (SCA17). The development of indole-
29
Indoles as anti-cancer agents
O
HN
NH
N
H
N
N
H
N
H
cyclohepta[b]indole
NH
benzo[6,7]cyclohepta[1,2-b]indole
3,3',3''-(cyclohexane-1,1,3-triyl)tris(1H-indole)
NC001-8
Figure 17 Chemical structure of some cycloalkano indoles have anti-cancer activity
the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing
energy are discussed with developing a new strategy to
achieve chemosensitization of cancer cells[129].
based compounds offers a promising strategy for the
treatment of polyglutamine (polyQ) diseases via activation of haperone expression to reduce polyQ aggregation
in SCA17 neuronal cell and slice culture models[127].
Sandra et al.[129], reported the relevance of goldcontaining indoles as anti-cancer agents. It displayed
cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles showed
unique behavior by increasing the cytotoxic property
of clinically relevant levels of ionizing emission (Figure
18). Quantification of the amount of DNA demonstrates
that each gold-indole enhances apoptosis by restraining
DNA fixation. Both Au(I)-indoles were screened for inhibitory property towards a mixture of cellular targets counting thioredoxin reductase, an identified target
of numerous gold compounds and a variety of
ATP-dependent kinases. Both compounds showed inhibitory property against numerous kinases connected with
the beginning of cancer and its progression. The inhibition of these kinases provides a probable mechanism for
the capability of these Au(I)-indoles to potentiate
P
Au
P
N
O
Au
N
O
O
O
Figure 18 Gold-containing indoles compounds
A progression series of novel 5-(2-Carboxyethenyl)
indole derivatives were designed and synthesized (Figure
19). Two of the seven recently prepared compounds were
screened for their anti-cancer activities towards K562 and
HT-29 cell lines resulting in 5-(2-Carboxyethenyl)indole
derivatives being verified for major anti-cancer activity
against HT-29 cell, their effectiveness was around 4.67,
8.24 and 6.73 μmol/L[130].
R4
H3 COOC
R1
N
R1= H, CH3 , CF3
R1
5-(2-Carboxyethenyl) indole derivatives
CH3
N
N
H
R1
CH3
R1= H, F
2,3-Dimethylindole
R2
R3
N
H
R1= H, F, CH3, OCH3
R2 = H, F, R3 = H,F
R4 = H, CH3, Ph, PhCN
Tetrahydrocarbazole
Tetrahydrocarbazole
Figure 19 Simple indoles recently evaluated for anti-cancer activity
Kumar et al.[131] have synthesized 2,3-dimethylindoles and tetrahydrocarbazoles using Phenylhydrazine
hydrochlorides and different cyclic and acyclic ketones
in presence of antimony phosphate as catalyst (Figure
19). The products were tested for anti-cancer activity
against five different cell lines such as kidney adenocarcinoma (ACHN), pancreas carcinoma (Panc1), lung car-
30
cinoma (GIII) (Calu1), non-small cell lung carcinoma
(H460), colon cancer cell (HCT116) and normal breast
epithelium (MCF10A) cell lines. The results showed that
2,3-dimethylindole (R1 = H, F) exhibited promising activity against both lung carcinoma and pancreas carcinoma cell line with IC50 value 2.7, 3.1, 2.8 and 3.2
nmol/L. Tetrahydrocarbazole (R1 = OCH3, R2 = F, R3 =
doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
F, R4=PhCN) showed high activity against lung carcinoma cell line only, with IC50 2.5 nmol/L.
Conclusion
The current review covered three important topics about
indoles: Firstly, indoles as natural products and its biosynthesis. Secondly, the mechanisms of induction of cell
death for numerous cancers cell lines by indoles. Thirdly,
recent studies with indoles and associated compounds that
are investigated for anti-cancer screening and that are
directly forwarded for drug approval.
Conflict of interest
The authors declared no potential conflict of interest with
respect to the research, authorship, and/or publication of
this article.
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