doi: 10.18282/amor.v1.i1.12
REVIEW ARTICLE
Indoles as anticancer 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 well known for their anticancer activity, which is related to their 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 anticancer screening and that led to drug approval. Keywords: indoles; natural biosynthesis; cell death induction; screening; anticancer agents Citation: El Sayed MT, Hamdy NA, Osman DA, et al. Indoles as anticancer agents. Adv Mod Oncol Res 2015; 1(1); 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 health-protecting 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 anticarcinogenic 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
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.
1
Indoles as anticancer agents
verified[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
Brussel Sprout
Kohlrabi
Broccoli
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].
Radish
Cauliflower
Figure 1 Cruciferous vegetables. [Source available from: http://www.fotosearch.com/photos-images/cruciferous-vegetables.html] OH O
OH OH
S GB
OH
OH
N O SO 3 N N H H
Myrosonase H2O
I3C
D-glucose SCN
HSO4 N
NN HH
L-ascorbic acid
S
OH H2O
N N H H
H O HO
NN HH
N H H
DIM H2 O O
O OH
N N H ASC H
Fig. (2): Biosynthesisof of indoles: indoles: 13C, 13C, DIM from GB. Figure 2 Biosynthesis DIMand andASC ASC from GB
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 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 S-adenosyl 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
2 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
reaction, where the carbon in position two of indole acts as a nucleophile (Figure 4). This is followed by the aromaticity being restored via the elimination of a proton at Non-indigo producing plant
Indigo produc ing plant O
HO
N H
N H
HO
OH O
E4 /E5 N H
6-Hydroxyindole 5Hydroxy indo le
the C two atom. The consequential tetrahydro-β-carboline frame steadily oxidizes to dihydro-β-carboline and β-carboline afterwards[16,20].
O
HO OH
HO
3-O xindole
NH Indican
P
P
O
OH
OH
O
HO
O
O2
P
Indole hydrunulase ?
N H
N H
Gly cosy lation G T?
O
HO OH
HO
Indole O2
O
G T?
N H
NH
Indoxyl
E1 E2 E3
Isatan A
O
OH O2
CHO
OH
Hydrolysis GLU ?
N H
O
N H
3 -Oxindole
GT?
Indoxy l
OH
O
NHCHO
NH
Isatan B
N-form yla mino benzaldehy de
O
E6 ?
OH O
O2 S
OH
N H
GT? Isatan C
O2 S
P re cursors In Vivo
O2
O
O- aminobe nzaldehyde
O H N
?
N H
NH
N H O Indigo
CO2H
NH
O
S
NH 2
O
C 11H7O2
N H Dioindole
Isatine
CHO
H C
O
HO
O Indirubin
O N
NH 2 Anthranilic a cid (E1/E3)
Anthranil (E2/E3)
Scheme (1): Bio oxidation of indole in higher plants.
Scheme 1 Bio-oxidation of indole in higher plants HO P
COOH NH2 N H
N H
L-tryptophan
N H
methylation
HO oxidation
NH2 N H
phosphorylation
Psilocin
HO
decarboxylation
5-hydroxy-L-tryptophan
L-tryptophan
N N H psilocybin
COOH
COOH NH2
N H
oxidation
DMT
Tryptamine
O
N
N
NH2
decarboxylation
N H
O
OH
O
NH2 N H 5-hydroxytryptamine (serotonin)
Fig. (3): Tryptophan biogenetic ofprecursor all indoleof alkaloids. Figure 3 as Tryptophan as precursor a biogenetic all indole alkaloids
3 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
NH2
N
N H
N H schiff base formation
NH
NH
R
RCHO
R N H terahydro-B-carboline
R
N H
Mannich reaction
tryptamine oxidation
N oxidation
N
Fig. (4): Biosynthesis of beta-carboline alkaloids.
R
N H
R
N H
dihydro-B-carboline
beta-carboline
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
HOOC H
HO
N
NH2
N H
H
oxidation
N H
L-tryptophan
which is converted to lysergic acid through the process of allyl re-arrangement[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 H
4-dimetilallil-L-tryptophan
N H
chanoclavine-1
HOOC H
N
H
oxidation
N H elymoclavine
agroclavine
Fig. (5): Ergot alkaloids biosynthesis.
N
N H paspalic
N H D-(+)-lysergic acid
Figure 5 Ergot alkaloids biosynthesis.
Mannich reaction NH2 N H
OHC
NH
OGlc O
OGlc O
N H
N
H3 COOC dehydrogeissoschizine
CH3 N OAc OH COOCH3
N H vindoline Aspidospirma type
OH
N H
H3 COOC strictosidine
secologanin
N
N
O
N H H3 COOC cathenamine
CH3
COOCH3 N H tabersonine Aspidospirma type
Fig. (6): Biosynthesis monoterpenoid indole alkaloids. Figure 6ofBiosynthesis of monoterpenoid indole alkaloids
4 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
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].
to 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 Bio Response DIM for estrogens for men and women (http://www.bioresponse.com/Home.asp) (Figure 7)[12,13].
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 prob able inter mediates for nume rous biological reactions. Indole derivatives correspond Me
OH Me
HN
Me MeO
Me
O
HO
N
Me N O N H N H
DMT
Cl
N H
N H DIM
Indomethacin
Pindolol
Figure (7): Marketed indole drugs.
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 leukaemia XL), (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
ligands, which are released by the immune system’s natural killer cells possess the Fas ligand (FasL) on their exterior to connect to trans membrane 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 proapoptotic proteins in the cytoplasm (BAX and BID) bind to the outer membrane of the mitochondria to signal the release of the internal content. The interaction between the proapoptotic (BAX and
5 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
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 pro-caspase-3 and pro-caspase-7 into
active caspase-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]
6 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
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 anticancer 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 pro-survival 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 anticancer 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 anticancer 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
H N H
N H X= F, X=CN
N H
N H
Carbazole derivative
Fig. 10: 3,3'-diindolylmethane derivatives and tetrahydroindolocarbazoles. Figure 10 3,3′-diindolylmethane derivatives and tetrahydro-
indolocarbazoles http://www.mdpi.com/cancers/cancers-03-02955/article_deploy/html/images/cancers-03-02955f 1-1024.png
Fig. (9): Summary of Mechanisms of anticancer and chemosensitizing effects of Indole compounds
Figure 9 Summary of mechanisms of anticancer 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]
Dorota et al.[79,80] in 2005 synthesized the disubstituted di-indolylmethanes flouro and cyano derivatives which decrease the expansion of MCF7 (breast), NCI–H460 (lung) and SF-268(NCS) cells, considerably 5,5′difluoro-3,3′-methanediyl-bis-indole and 5,5′-dicyano-3,
7 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
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 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 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], cervical[94], ovarian[95], pancreatic[96,97] and prostate[98-101] Me2N
N
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).
NMe2
N
R2
N
R1
C2H3
MeO
I Me N O
N H
Indole-PMM
Me
Figure (11): Structure of prodrug indole-PMM derivative derivative and tryptamine I. Figure 11 Structure of prodrug indole-PMM and derivative tryptamine
Numerous aroylamide indole derivatives have been synthesized and preliminarily screened for their in vitro anticancer 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 anticancer 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
NH2 O
N R2
O R3
Aroylamide indoles
Z
HN
N
O
H N
H3CO
N H Aroylindole
Figure 12 Molecular Molecular structure of and aroyland aroylamide-indoles Figure (12): structure of aroylaroylamide-indoles.
derivative
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.
8 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
R2
R3 R1
H N
NH
O
R2
R1 HN
H N
Br
N HN
N
N
HN
N
R2 HN
OH
HN
Nortopsentins A, Nortopsentins B, Nortopsentins C, Nortopsentins D,
NH
R5 NH2
Dragmacidin D
NH R1=R2 = Br R1=Br, R2= H R1=H, R2=Br R1=R2 = H
Dragmacidin N R1
O
N H HN
OH
R2
O HO
N
NH HN
Topsentin R1=H, R2=OH Bromotopsentin R1 =Br, R2 =OH Deoxytopsentin R1 =R2=H
HO
OH
NH
N
N H Hyrtinadine A
Figure(13): natural bis-indole alkaloids as anticancer agents FigureMarine 13 Marine natural bis-indole alkaloids as anticancer
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 bis-indole 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
O
N H
Hyrtiosins B
agents
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
9 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
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
tive configuration at C-8 and C-8 named (±) Gelliusines A and B. Gelliusines A and B showed anticancer 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. O
H N
O
R1
CHO N H H H H
OH
N
N Me R3
N
N H
OH O
O
HH R2
O
Coproverdine
N 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: R1=H, R2 =CH3, R3=OH, R4 =H
Me
Staurosporine G
FigureFigure (14):Chemical structures ofof marine staurosporines and coproverdine. 14 Chemical structures marinenatural naturalproducts, products, staurosporines and coproverdine H2N H N HO
O
NH2 OH
HO
NH
NH2
HN HO
O
N N H
N H
N H NH
N H Br
Br N H
H2N (±) Gelliusines
Hyrtioerectine A
Bengacarboline
Figure 15 Molecular structures of Hyrtioerectine A, Bengacarboline (±) Gelliusines Figure(15): Molecular structures of Hyrtioerectine A, Bengacarboline and (±) 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,
Figure 16 Chemical structure of Dendridine A and Chetomin
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 [1 26, 1 28] . 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
10 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
for spinocerebellar ataxias (SCA17). The development of indole-based compounds offers a promising strategy for the treatment of polyglutamine (polyQ) diseases via ac-
tivation of haperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models[127]. O
HN
NH N H
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 anticancer activity.
Figure 17 Chemical structure of some cycloalkano indoles have anticancer activity
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 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].
P
Au P
Au
N O
N O O
O
Fig. ( 18 ): Gold-containing indoles compounds
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 anticancer 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 CH3
H3 COOC
R1
R1 CH3
N
R1= H, CH3 , CF3
R1
5-(2-Carboxyethenyl) indole derivatives
R1= H, F 2,3-Dimethylindole
N H
R2
N H
R3 R1= H, F, CH3, OCH3 R2 = H, F, R3 = H,F R4 = H, CH3, Ph, PhCN Tetrahydrocarbazole
Figure 19: Simple indoles recently evaluated for anticancer activity.
Figure 19 Simple indoles recently evaluated for anticancer activity
Kumar et al.[131] have synthesized 2,3-dimethyl- indoles 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 anticancer activity against five different cell lines such as kidney adenocar-
cinoma (ACHN), pancreas carcinoma (Panc1), lung carcinoma (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 carci-
11 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
noma cell line with IC50 value 2.7, 3.1, 2.8 and 3.2 nmol/L. Tetrahydrocarbazole (R1 = OCH3, R2 = F, R3 = 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.
11.
12.
13.
14.
15.
Conflict of interest The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.
16.
References 17. 1.
2.
3.
4.
5.
6.
7.
8. 9.
10.
Ahmad A, Sakr WA, Rahman KW. Mechanisms and therapeutic implications of cell death induction by indole compounds. Cancers (Basel). 2011; 3(4): 2955– 2974. Fischer E, Jourdan F. Ueber die Hydrazine der Brenztraubensäure. Berichte der deutschen chemischen Gesellschaft. 1883; 16(2): 2241–2245. Yuan LJ, Liu JB, Xiao XG. Biooxidation of indole and characteristics of the responsible enzymes African Journal of Biotechnology 2011; 10(86): 19855–19863. Boone CW, Kelloff GJ, Malone WE. Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: a review. Cancer Res 1990; 50(1): 2–9. Ahmad A, Sakr WA, Rahman KM. Novel targets for detection of cancer and their modulation by chemopreventive natural compounds. Front Biosci 2012;4: 410– 425. Hrnčiřík K, Valušek J, Velíšek J. A study on the formation and stability of ascorbigen in an aqueous system. Food Chem 1998; 63(3): 349–355. Heber D, Bowerman S. Applying science to changing dietary patterns. J Nutr 2001; 131(Suppl 11): 3078S– 3081S. Terry P, Wolk A, Persson I, et al. Brassica vegetables and breast cancer risk. JAMA 2001; 285(23): 2975–2977. van Poppel G, Verhoeven DT, Verhagen H, et al. Brassica vegetables and cancer prevention. Epidemiology and mechanisms. Adv Exp Med Biol 1999;472:159–168. Verhagen H, Poulsen HE, Loft S, et al. Reduction of oxi-
18.
19.
20. 21. 22.
23.
24.
25.
26.
dative DNA–damage in humans by brussels sprouts. Carcinogenesis 1995; 16(4): 969–970. Keck AS, Finley JW. Cruciferous vegetables: Cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr Cancer Ther 2004; 3(1):5–12. El Sayed M. Development of novel indolyl-derived biologically active compounds [Ph.D]. Martin Luther University; 2013. El Sayed M. Development of novel indolyl-derived biologically active compounds. Saarbrücken: LAP LAMBERT Academic Publishing; 2015. Wikipedia contributors. Indole alkaloid [Internet]. Wikipedia. [cited 1 May 2015]. Available from: https:// en.wikipedia.org/wiki/Indole_alkaloid. El Sayed M, Mahmoud K, Hilgeroth A. Glacial acetic acid as an efficient catalyst for simple synthesis of dindolylmethanes. Curr Chem Lett 2014; 3(1): 7–14. El Sayed MT, Ahmed KM, Mahmoud K, et al. Synthesis, cytostatic evaluation and structure activity relationships of novel bis-indolylmethanes and their corresponding tetrahydroindolocarbazoles. Eur J Med Chem 2015; 90: 845–859. El Sayed MT, Mahmoud K, Ahmed KM, et al. First oxidized tetraindoles with antimicrobial evaluation and structure activity relationship. J Harmon Res Pharm 2014; 3(4): 167–176. El Sayed MT, Mahmoud K, Ahmed KM, et al. Novel aspects of domino reaction of indoles with homo–phthalaldehyde and tere–phthalaldehyde. Glob J Sci Front Res 2014; 14(6): 15–22. El Sayed MT, Mahmoud K, Hilgeroth A, et al. Synthesis of novel indolo-spirocyclic compounds. J Heterocyclic Chem 2015. Dewick P. Medicinal natural products. Chichester, West Sussex, England: Wiley; 2002. Begley T. Wiley encyclopedia of chemical biology. Hoboken, N.J.: John Wiley & Sons; 2009. Ahmad A, Sakr WA, Rahman KW. Mechanisms and therapeutic implications of cell death induction by indole compounds. Cancers (Basel) 2011; 3(3): 2955– 2974. Süzen S, Büyükbingöl E. Anti-cancer activity studies of indolalthiohydantoin (PIT) on certain cancer cell lines. Farmaco 2000; 55(4): 246–248. Giagoudakis G, Markantonis SL. Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen. Pharmacotherapy 2005; 25(1):18–25. Büyükbingöl E, Süzen S, Klopman G. Studies on the synthesis and structure-activity relationships of 5- (3'indolal)-2-thiohydantoin derivatives as aldose reductase enzyme inhibitors. Farmaco 1994; 49(6): 443– 447. Süzen S, Büyükbingöl E. Evaluation of anti-HIV activity
12 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
27.
28.
29.
30.
31.
32.
33.
34.
35. 36.
37.
38.
39.
of 5-(2-phenyl-3′-indolal)-2 thiohydantoin. Farmaco 1998; 53(7): 525–527. Olgen S, Altanlar N, Karatayli E, et al. Antimicrobial and antiviral screening of novel indole carboxamide and propanamide derivatives. Z Naturforsch C 2008; 63(3-4): 189–195. Gurkok G, Altanlar N, Suzen S. Investigation of antimicrobial activities of indole-3-aldehyde hydrazide/hydrazone derivatives. Chemotherapy 2009; 55(1): 15–19. Panchal RG, Ulrich RL, Lane D, et al. Novel broadspectrum bis-(imidazolinylindole) derivatives with potent antibacterial activities against antibiotic-resistant strains. Antimicrob Agents Chemother 2009; 53(10): 4283–4291. Chavan RS, More HN, Bhosale AV. Synthesis and evaluation of analgesic and anti-inflammatory activities of a novel series of 3-(4,5-dihydropyrazolyl)-indoles. Int J Pharm Biomed Res 2010; 1(4): 135–143. Kameyama T, Amanuma F, Okuyama S, et al. Pharmacological studies of furo [3,2-b] indole derivatives. I. Analgesic, anti-pyretic and anti-inflammatory effects of FI302,N-(3-piperidinopropyl)-4-methyl-6-trifluoromethyl-f uro [3,2-b]indole-2-carboxamide, in experimental animals. J Pharmacobiodyn 1985; 8(6): 477–486. Sridhar SK, Pandeya SN, Bajpai SK, et al. Synthesis antibacterial and antiviral activities of isatin derivatives. Indian Drugs 1999; 36(6): 412–414. Adel AE, Naida AA, El-Taber ZS, et al. Synthesis and biological activity of some new spio-[indoline-3, 2-thiazolidine]-2, 4,-diones. Alex J Pharm Sci 1997; 7: 99–103. Gitto R, De Luca L, Ferro S, et al. Development of 3-substituted-1H-indole derivatives as NR2B/NMDA receptor antagonists. Bioorg Med Chem 2009; 17(4): 1640– 1647. Kumar A, Saxena KK, Gurtu S, et al. Indian Drugs 1986; 24: 1–5. Hu W, Guo Z, Yi X, Guo C, et al. Discovery of 2-phenyl-3-sulfonylphenyl-indole derivatives as a new class of selective COX-2 inhibitors. Bioorg Med Chem 2003; 11(24): 5539–5544. Kalgutkar AS, Crews BC, Rowlinson SW, et al. Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA 2000; 97(2): 925–930. Hu W, Guo Z, Chu F, et al. Synthesis and biological evaluation of substituted 2-sulfonyl-phenyl-3-phenyl- indoles: a new series of selective COX-2 inhibitors. Bioorg Med Chem 2003; 11(7): 1153–1160. Caron S, Vazquez E, Stevens RW, et al. Efficient synthesis of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]- acetic acid, a novel COX-2 inhibitor. J Org Chem 2003; 68(10): 4104–4107.
40.
41.
42.
43.
44.
45.
46.
47.
48. 49.
50.
51.
52.
Pandya P, Islam MM, Kumar GS, et al. DNA minor groove binding of small molecules, Experimental and computational evidence. J Chem Sci 2010; 122(2): 247–257. Karaaslan C, Suzen S. Electrochemical Behavior of Biologically Important Indole Derivatives. Int J Electrochem 2011; 2011:1–10. Ahmad A, Sakr WA, Rahman KMW. Novel targets for detection of cancer and their modulation by chemo preventive natural compounds. Front Biosci (Elite Ed) 2012; 4: 410–425. Sarkar FH, Li Y. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Cancer Treat Rev 2009; 35(7): 597–607. Sarkar FH, Li Y, Wang Z, et al. Cellular signaling perturbation by natural products. Cell Signal 2009; 21(11): 1541–1547. Moiseeva EP, Almeida GM, Jones GD, et al. Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther 2007; 6(7): 3071–3079. Cover CM, Hsieh SJ, Tran SH, et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 1998; 273(7): 3838–3847. Rahman KW, Sarkar FH. Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3'- diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res 2005; 65(1): 364–371. Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. J Nutr 2004; 134(Suppl 12): 3493S–3498S. Wang Z, Yu BW, Rahman KM, et al. Induction of growth arrest and apoptosis in human breast cancer cells by 3,3-diindolylmethane is associated with induction and nuclear localization of p27kip. Mol Cancer Ther 2008; 7(2): 341–349. Sarkar FH, Li Y, Wang Z, et al. NF-kappaB signaling pathway and its therapeutic implications in human diseases. Int Rev Immunol 2008; 27(5): 293–319. Kong D, Li Y, Wang Z, et al. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 2007; 67(7): 3310–3319. Bhuiyan MM, Li Y, Banerjee S, et al. Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells. Cancer Res 2006; 66(20): 10064– 10072.
13 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64. 65.
66.
Ahmad A, Sakr WA, Rahman KMW. Role of nuclear factor-kappa B signaling in anticancer properties of indole compounds. J Exp Clin Med 2011; 3(2): 55–62. Rahman KM, Banerjee S, Ali S, et al. 3,3'-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res 2009; 69(10): 4468–4475. Bhatnagar, N, Li X, Chen Y, et al. 3,3'-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. Cancer Prev Res 2009; 2(6): 581–589. Ahmad A, Kong D, Sarkar SH, et al. Inactivation of uPA and its receptor uPAR by 3,3'-diindolylmethane (DIM) leads to the inhibition of prostate cancer cell growth and migration. J Cell Biochem 2009; 107(3): 516–527. Ahmad A, Kong D, Wang Z, et al. Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells. J Cell Biochem 2009;108(4): 916–925. Li Y, Wang Z, Kong D, et al. Regulation of FOXO3a/ beta-catenin/GSK-3beta signaling by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells. J Biol Chem 2007; 282(29): 21542–21550. Gupta MK, Qin RY. Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol 2003; 9(6): 1144–1155. Khwaja FS, Wynne S, Posey I, et al. 3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway in prostate cancer cells. Cancer Prev Res (Phila) 2009; 2(6):566–571. Lei P, Abdelrahim M, Cho SD, et al. Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3'-indoly)-1-(psubstituted phenyl)methanes. Mol Cancer Ther 2008; 7(10): 3363–3372. Csipo I, Montel AH, Hobbs JA, et al. Effect of Fas+ and Fas- target cells on the ability of NK cells to repeatedly fragment DNA and trigger lysis via the Fas lytic pathway. Apoptosis 1998; 3(2):105–114. Los M, Walczak H. Caspases—Their role in cell death and cell survival. Georgetown, Tex., USA.: Landes Bioscience; 2002. Hague A, Paraskeva C. Apoptosis and disease: a matter of cell fate. Cell Death Differ 2004; 11(12): 1366–1372. Wattenberg LW, Loub WD. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res 1978; 38(5): 1410–1413. Bradfield CA, Bjeldanes LF. Effect of dietary indole3-carbinol on intestinal and hepatic monooxygenase, glutathione S-transferase and epoxide hydrolase activities in the rat. Food Chem Toxicol 1984; 22(12): 977–982.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
Bradlow HL, Sepkovic DW, Telang NT, et al. Indole3-carbinol. A novel approach to breast cancer prevention. Ann N Y Acad Sci 1995; 768: 180–200. Chen I, Safe S, Bjeldanes L. Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem Pharmacol 1996; 51(8): 1096–1076. Vang O, Jensen MB, Autrup H. Induction of cytochrome P450IA1 in rat colon and liver by indole-3-carbinol and 5,6-benzoflavone. Carcinogenesis 1990; 11(8): 1259– 1263. Hong C, Kim HA, Firestone GL, et al. 3,3'- Diindolylmethane (DIM) induces a G(1) cell cycle arrest in human breast cancer cells that is accompanied by Sp1mediated activation of p21(WAF1/CIP1) expression. Carcinogenesis 2002; 23(8): 1297–1305. Firestone GL, Bjeldanes LF. Indole-3-carbinol and 3-3'-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr 2003; 133(Suppl 7): 2448S– 2455S. Grubbs CJ, Steele VE, Casebolt T, et al. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res 1995; 15(3): 709–116. Chinni SR, Li Y, Upadhyay S, et al. Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene. 2001; 20(23): 2927–2936. Chen DZ, Qi M, Auborn KJ, et al. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr 2001; 131(12): 3294– 3302. Dashwood RH, Fong AT, Williams DE, et al. Promotion of aflatoxin B1 carcinogenesis by the natural tumor modulator indole-3-carbinol: influence of dose, duration, and intermittent exposure on indole-3-carbinol promotional potency. Cancer Res 1991; 51(9): 2362–2365. Kim DJ, Han BS, Ahn B, et al. Enhancement by indole3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model. Carcinogenesis 1997; 18(2):377–381. Maciejewska D, Niemyjska M, Wolska I, et al. Synthesis, Spectroscopic Studies and Crystal Structure of 5,5′- Dimethoxy-3,3′-methanediyl-bis-indole as the Inhibitor of Cell Proliferation of Human Tumors. Z Naturforsch 2004; 59b: 1137–1142. Hannongbua S, Prasithichokekul S, Pungpo P. Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations. J Comput Alded Mol Des 2001; 15(11): 997–1004.
14 doi: 10.18282/amor.v1.i1.12
El Sayed MT, et al.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
Kim DJ, Han BS, Ahn B, et al. Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model. Carcinogenesis 1997; 18(2): 377–381. Mousavi SH, Moallem SA, Mehri S, et al. Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form. Pharm Biol 2011; 49(10): 1039–1045. Hong C, Firestone GL, Bjeldanes LF. Bcl-2 familymediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol 2002; 63(6): 1085–1097. Hong C, Kim HA, Firestone GL, et al. 3,3'- Diindolylmethane (DIM) induces a G(1) cell cycle arrest in man breast cancer cells that is accompanied by Sp1mediated activation of p21(WAF1/CIP1) expression. Carcinogenesis 2002; 23(8): 1297–1305. Rahman KM, Aranha O, Glazyrin A, et al. Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. Oncogene 2000; 19(50): 5764–5771. Rahman KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr Cancer 2003; 45(1): 101–112. Rahman KM, Li Y, Sarkar FH. Inactivation of akt and NF-kappaB play important roles during indole-3carbinol-induced apoptosis in breast cancer cells. Nutr Cancer 2004; 48(1): 84–94. Rahman KW, Sarkar FH. Inhibition of nuclear translocation of nuclear factor-{kappa} B contributes to 3,3'- diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res 2005; 65(1): 364–371. Rahman KW, Li Y, Wang Z, et al. Gene expression profiling revealed survivin as a target of 3,3'-diindolylmethane-induced cell growth inhibition and apoptosis in breast cancer cells. Cancer Res 2006; 66(9): 4952– 4960. Ali S, Varghese L, Pereira L, et al. Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents. Cance Lett 2009; 278(2): 201–209. Chen Y, Xu J, Jhala N, et al. Fas-mediated apoptosis in cholangiocarcinoma cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like inhibitory protein. Am J Pathol 2006; 169(5): 1833–1842. Pappa G Lichtenberg M. Iori R et al. Comparison of growth inhibition profiles and mechanisms of apoptosis induction in human colon cancer cell lines by isothiocyanates and indoles from Brassicaceae. Mutat Res 2006; 599(1-2): 76–87. Kim EJ, Park SY, Shin HK, et al. Activation of caspase-8 contributes to 3, 3'-Diindolylmethane-induced apop-
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
tosis in colon cancer cells. J Nutr 2007; 137(1): 31–36. Frydoonfar HR, McGrath DR, Spigelman AD. Inhibition of proliferation of a colon cancer cell line by indole3-carbinol. Colorectal Dis 2002; 4(3): 205–207. Suzui M, Inamine M, Kaneshiro T, et al. Indole3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int J Oncol 2005; 27(5): 1391–1399. Savino JA 3rd, Evans JF, Rabinowitz D, et al. Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane. Mol Cancer Ther 2006; 5(3): 556–563. Stresser DM, Williams DE, Griffin DA, et al. Mechanisms of tumor modulation by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats. Drug Metab Dispos 1995; 23(9): 965–975. Abdelrahim M, Newman K, Vanderlaag K, et al. 3,3'-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis 2006; 27(4): 717–728. Banerjee S, Wang Z, Kong D, et al. 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res 2009; 69(13): 5592–5600. Frydoonfar HR, McGrath DR, Spigelman AD. The effect of indole-3-carbinol and sulforaphane on a prostate cancer cell line. ANZ J Surg 2003; 73(3): 154–156. Savino JA 3rd, Evans JF, Rabinowitz D, et al. Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane. Mol Cancer Ther 2006; 5(3): 556–563. Chinni SR, Li Y, Upadhyay S, et al. Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 2001; 20(23): 2927–2936. Le HT, Schaldach CM, Firestone GL, et al. Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem 2003; 278(23):21136–21145. Hahn DA. Hexamethylmelamine and pentamethylmelamine: an update. Drug Intel Clin Pharm 1983; 17(6): 418–424. Foster BJ, Clagett-Carr K, Hoth D, et al. Pentamethylmelamine: review of an aqueous analog of hexamethylmelamine. Cancer Treat Rep 1986; 70(3): 383–389. Ferrer S, Naughton DP, Threadgill MD. Labelled compounds of interest as antitumour agents–VIII. Synthesis of 2H-isotopomers of pentamethylmelamine and of a potential prodrug thereof. J Label Compd Radiopharm 2002; 45(6): 479–484. Janssen Pharmaceutica. Indole derivatives as anticancer
15 doi: 10.18282/amor.v1.i1.12
Indoles as anticancer agents
agents. United States; 20110294846, 2011. 106. Chang QS, Zhang QL, Wen QL, et al. Synthesis and preliminary cytotoxic evaluation of substituted indoles as potential anticancer agents. Chin Chem Lett 2007; 18(8): 899-901. 107. Wu YS, Coumar MS, Chang JY, et al. Synthesis and evaluation of 3-aroylindoles as anticancer agents: metabolite approach. J Med Chem 2009; 52(15): 4941–4945. 108. Tiwari VK, Mishra BB. Opportunity, challenge and scope of natural products in medicinal chemistry. Kerala: Research Signpost; 2011. 109. Urban S, Blunt JW, Munro MH, et al. Coproverdine, a novel, cytotoxic marine alkaloid from a new zealand ascidian. J Nat Prod 2002; 65(9): 1371–1373. 110. Murray LM, Lim TK, Hooper JNA, et al. Isobromotopsentin: a new bis(indole) alkaloid from a deep-water marine sponge spongosorites sp. Aust J Chem 1995; 48: 2053. 111. Sakemi S, Sun HH. Nortopsentins A, B, and C. Cytotoxic and antifungal imidazolediylbis[indoles] from the sponge Spongosorites ruetzleri. J Org Chem 1991; 56(13): 4304– 4307. 112. Tsujii S, Rinehart KL, Gunasekera S. Topsentin, bromotopsentin, and dihydrodeoxybromotopsentin: antiviral and antitumor bis(indolyl)imidazoles from Caribbean deep-sea sponges of the family Halichondriidae. Structural and synthetic studies. J Org Chem 1988; 53(23): 5446–5453. 113. Casapullo A, Bifulco G, Bruno I, et al. New Bisindole Alkaloids of the Topsentin and Hamacanthin Classes from the Mediterranean Marine Sponge Rhaphisia lacazei. J Nat Prod 2000; 63(4): 447–451. 114. Morris SA, Andersen RJ. Nitrogenous metabolites from the deep water sponge Hexadella sp. Can J Chem 1989; 67(4): 677–681. 115. Endo T, Tsuda M, Fromont J, et al. Hyrtinadine A, a bis-indole alkaloid from a marine sponge. J Nat Prod 2007; 70(3): 423–424. 116. Schupp P, Eder C, Proksch P, et al. Staurosporine derivatives from the ascidian eudistoma toealensis and its predatory flatworm pseudoceros sp. J Nat Prod 1999; 62(7): 959–962. 117. Schupp P, Steube K, Meyer C, et al. Anti-proliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm. Cancer Lett 2001; 174(2): 165–172. 118. Wang HY, Cai B, Cui CB, et al. Vitexicarpin, a flavonoid from Vitex trifolia L., induces apoptosis in K562 cells via mitochondria-controlled apoptotic pathway. Acta pharmaceutica Sinica 2005; 40(1): 27–31.
119. Youssef DT. Hyrtioerectines A-C, cytotoxic alkaloids from the red sea sponge hyrtioserectus. J Nat Prod 2005; 68(9): 1416–1419. 120. Evans W. Alkaloids. In: Evans W, Evans D, Trease G, ed. by. Trease and Evans Pharmacognosy. 6th ed. Edinburgh: Saunders/Elsevier; 2009. 121. Foderaro TA, Barrows LR, Lassota P, et al. Bengacarboline, a New β-Carboline from a Marine Ascidian Didemnum sp. J Org Chem 1997; 62(17): 6064– 6065. 122. Bifulco G, Bruno I, Minale L, et al. (+/-)-Gelliusines A and B, two diastereomeric brominated tris-indole alkaloids from a deep water new caledonian marine sponge (Gellius or Orina sp.). J Nat Prod 1994; 57(9): 1294–1299. 123. Tsuda M, Takahashi Y, Fromont J, et al. Dendridine A, a bis-indole alkaloid from a marine sponge Dictyodendrilla Species. J Nat Prod 2005; 68(8): 1277– 1278. 124. Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 2004; 6(1): 33–43. 125. Lee CH, Yao CF, Huang SM, et al. Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models. Cancer 2008; 113(4): 815–825. 126. Hong BC, Jiang YF, Chang YL, et al. Synthesis and Cytotoxicity Studies of Cyclohepta[b]indoles, Benzo[6,7] Cyclohepta[1,2-b]Indoles, Indeno[1,2-b]Indoles, and Benzo[a]Carbazoles J Chin Chem Soc 2006; 53(3): 647– 662. 127. Kung PJ, Tao YC, Hsu HC, et al. Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models. Drug Des Dev Ther 2014; 8: 1929–1939. 128. Yamuna E, Zeller M, Adero PO, et al. Synthesis of thienoand benzocyclohepta[b]indoles: Gewald reaction and regioselective cycloaddition of acetylenic esters ARKIVOC 2012; 2012(vi): 326–342. 129. Craig S, Gao L, Lee I, et al. Gold-containing indoles as anticancer agents that potentiate the cytotoxic effects of ionizing radiation. J Med Chem 2012; 55(5): 2437–2451. 130. Han KL, Wang HM, Song BB, et al. Design, synthesis and biological activity evaluation of novel anticancer agent 5-(2-carboxyethenyl)indole derivatives. J Chem Pharm Res 2014; 6(9): 376–380. 131. Kumar TOS, Mahadevan KM, Kumara MN. Synthesis and cytotoxic studies of 2,3-dimethylindoles and tetrahydrocarbazoles. Int J Pharm Pharm Sci 2014; 6(2): 137– 140.
16 doi: 10.18282/amor.v1.i1.12
