Current Perspective of Natural Alkaloid Carbazole and its Derivatives as Antitumor

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Anti-Cancer Agents in Medicinal Chemistry, 2015, 15, 000-000 1
1871-5206/15 $58.00+.00 © 2015 Bentham Science Publishers
Current Perspective of Natural Alkaloid Carbazole and its Derivatives as Antitumor
Agents
Mahamadhanif S. Shaikh, Rajshekhar Karpoormath*
, Neeta Thapliyal, Rajesh A. Rane, Mahesh B. Palkar,
A.M. Faya, Harun M. Patel, Wesam S. Alwan, Kavita Jain and Girish A. Hampannavar
Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences,
University of KwaZulu-Natal, Westville Campus, Durban – 4000, South Africa
Abstract: Throughout our evolution, the importance of natural products for medicine and health has been
increasing and it continued to be a key source of new anticancer drugs, leads and new chemical entities.
Among natural products tricyclic heteroaromatic alkaloids such as carbazoles are an important class of natural
and semi-synthetic organic compounds. In the last few decades medicinal role of natural and semi-synthetic
carbazoles has expanded significantly, especially as a vital heterocyclic class of antitumor agents. Some of the
carbazoles that displayed potential anticancer activity have undergone clinical trials. However, complications
arising due to multidrug resistance in clinical trials led to very few of the selected carbazoles being approved for
cancer therapy. Planar, polycyclic and aromatic carbazoles exhibit anticancer activity via DNA intercalation.
Further many carbazoles can be cytotoxic by inhibiting DNA-dependent enzymes such as telomerase and
topoisomerase I/II.
Keywords: Anticancer agent, antitumor agent, carbazole alkaloids, review.
INTRODUCTION
Cancer has become the leading cause of death worldwide and
has seriously endangered the health as well as life of humans over a
prolonged period [1]. The design of cancer chemotherapy has
become ever more sophisticated but yet there is no cancer treatment
that is 100% effective against dispersed cancer. Single molecule
or pathway targeted cancer therapy has not resulted in any good
drug [2]. In general the agents acting on more than one target were
found to resolve the problem of drug resistance observed in single
target acting drugs [3]. The number of patients diagnosed with
different types of cancer has almost doubled in the last three
decades and is expected to rise even higher in coming years. Hence
there is an urgent need to develop new and efficient treatment
methods [4].
It is not surprising to note that among the various drugs used for
the treatment of cancer more than 80% belong to natural source.
Natural products are key inspiration for the search of novel
anticancer drugs and one such heteroaromatic tricyclic alkaloid is
carbazole, which has attracted much attention among the medicinal
chemist for its diverse biological activities. Notably, they are well
recognised for their potential anticancer activity [5]. Some
examples of natural Carbazoles with antitumor activity have been
depicted in Figure 1. These alkaloids include Staurosporine-1, a
glycosidic natural product obtained from the cultures of
actinomycete Streptomyces staurosporeus [6]; Clausine E,
Mukonine and Koenoline isolated from higher plants of the
Rutaceae family [7]; pyrrolo carbazoles reported for Chk1
inhibitors; UCN-01 an indolocarbazole natural product currently in
phase II clinical trials [8] and compounds a, b and c as retelliptine
(BD84) [9] analogs. Considering these significant facts, we
envisaged to write a review on the anticancer potential of carbazole
alkaloids and their synthetic derivatives from 2007 to mid 2014.
*Address correspondence to this author at the Department of Pharmaceutical
Chemistry, Discipline of Pharmaceutical Sciences, College of Health
Sciences, University of KwaZulu-Natal, Westville Campus, Durban – 4000,
South Africa; Tel: +27(0)312607179, +27721107207; Fax: +27(0)312607792;
E-mail: karpoormath@ukzn.ac.za, rvk2006@gmail.com
CARBAZOLES WITH ANTI-CANCER ACTIVITY
Cytotoxic activities of clausine E, mukonine and koenoline
bioisosteres (1-3) were reported against breast adenocarcinoma cell
line (MCF-7), sarcoma cell line (MES-SA) and three colorectal
carcinoma cell lines (HCT-116, SW-48 and SW-480). Clausine E
displayed prominent anticancer activity against MCF-7 breast
cancer line (IC50 = 0.6 ± 0.3 µM) at nanomolar concentrations.
Further, it has exhibited cytotoxic activity at micromolar
concentrations with IC50 values of 35 ± 1.0, 1.9 ± 0.2, 21 ± 7.0 and
4.8 ± 3.0 µM against MES-SA, HCT-116, SW-48 and SW-480 cell
lines respectively. Compound 1 showed appreciable anti-
proliferative activity against all the investigated cancer cell lines.
Significant growth inhibitory activity was expressed by compound
2 towards the colorectal and breast cancer cell lines (concentration
range 1–10µM). Mukonine and compound 3 exhibited weak
to moderate anti-cancer activity towards all the cancer cell lines
[10].
3-carbomethoxy-2-hydroxy-7-methoxycarbazole 4, a carbazole
alkaloid was isolated from the ethyl acetate extract of the stem bark
of the Malaysian Clausena excavate and was found to display
potent activity against T-Lymphoblastic leukaemia cell line (CEM-
SS)with an IC50 value of 8.2 µg/mL [11].
Huet et al. synthesized a number of aza heterocyclic carbazole
sulphonamides and screened for their antiproliferative activity
against CEM leukemia cells. Among the synthesized derivatives
compound 5 and 6 presented most potent cytotoxicity (IC50 = 122
nM and 101 nM). Further cytotoxic activities of compounds 5 and 6
against seven diﬀerent human tumor cell lines namely CEM, MCF-
7, T-lymphoid cell line (MOLT-3), hepatoma cell line (BEL-7402),
melanoma cell line (DND-1) and prostate cancer cell lines (PC-3
and DU-145)were also reported with sub-micromolar activities
against all the investigated cell lines [12].
Heat shock protein 90 (Hsp90) is considered to be a prominent
target to treat cancer and other diseases. A carbazole-based
molecule, compound 7 was reported to suppress Hsp90 at
nanomolar concentrations and was also observed to be significantly
cytotoxic towards a range of cancer cell lines [13] as depicted in
Table 1.
R. Karpoormath
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2 Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 15, No. 0 Shaikh et al.
Beata et al. have described the antiproliferative activity of novel
pyrido-carbazole derivatives against human kidney cancer (A498)
and human lung cancer (A549) cell lines. Here carbazoles 8, 9, 10
and 11 displayed higher cytostatic activities towards A549 and
A498 as compared to the reference compounds, ellipticine and
cisplatin. Compounds 8, 9, 10 and 11 also exhibited superior activity
against A549 cell line than the reference drug cisplatin. However,
only 8 exhibited higher activity compared to ellipticine [14].
Table 1. Anticancer activity of compound 7 against a range of
cancer cellines.
Assay IC50 (µM)
Hsp70 induction, A375 0.23±0.07
Her2 degradation 0.56±0.13
pErk inhibition, AU565 0.59±0.24
pS6 inhibition, A375 0.07±0.02
A375 proliferation 0.40±0.17
HT29 proliferation 0.37±0.10
LNCAP proliferation 0.70±0.26
MCF-7 proliferation 0.29±0.05
MDA-MB-231 proliferation 0.96±0.13
NCI-H460 proliferation 0.90±0.15
PC-3 proliferation 0.82±0.20
SK-MEL-5 proliferation 0.34±0.09
Fig. (1). Examples of natural carbazoles.

Current Perspective of Natural Alkaloid Carbazole and its Derivatives Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 15, No. 0 3
Table 2. Antiproliferative activity of pyrido-carbazole analogs (8-
11) against cell lines A498 and A549.
Compound A498 (µM) A549 (µM)
8 0.437±0.382 0.867±0.060
9 0.766±0.052 0.808±0.046
10 0.822±0.041 0.924±0.061
11 0.700±0.060 1.240±0.323
Cisplatin 1.180±0.110 1.320±0.281
Ellipticine 1.740±0.040 0.850±0.040
Novel tetra- and pentacyclic compounds with a carbazole-2,3-
dicarboximide core were screened for their in vitro tumor cell-
growth inhibitory activity against cervical carcinoma (KB-HeLa),
ovarian carcinoma (SK-OV-3), mouse lymphatic leukemia (L1210),
colon adenocarcinoma (RKOp27), CNS cancer (SF-268), non-
small-cell lung cancer (NCI-H460) and MCF-7 tumor cell lines via
the XTT assay at a concentration of about 10 µmol/L. Compound
12 showed the highest percentage of growth inhibition (GI) against
KB-HeLa, SK-OV-3, L1210 and MCF-7 (99, 85, 100 and 72
µmol/L respectively). Compound 13 displayed strong activity
towards SF-268, NCI-H460 and RKOp27 (% GI=72, 94 and 100
respectively) [15].
Interruption in microtubule polymerization can lead to
apoptotic cell death. Hence, tubulin interactive agents play an
important role in the management of cancer therapy. Some
carbazole compounds that influence tubulin polymerization kinetics
were synthesized and subsequently tested for their cytotoxic
activity in selected cancer cell lines. Compound 14 demonstrated
superior activity against human erythro-myeloblastoid-leukemia
(K562), human colon cancer (SW620), human colorectal
adenocarcinoma (HT-29) and MCF-7cell lines (IC50 = 5.5, 0.87, 15
and 3.2 nM) compared to the reference compound Colcemid [16].
Lemster et al. evaluated novel hetarene annelated carbazoles for
their cytotoxicity against sixty human tumor cell lines from the
following nine types of cancer viz., central nervous system (CNS)
lymphoma, colon cancer, leukaemia, melanoma, non-small cell
lung cancer, ovarian cancer, prostate cancer, renal cancer and breast
cancer by the SRB assay. Carbazoles 15, 16 and the chloro
derivative 17 were selected for NCI antitumor screening. Evaluation
of cytotoxicity of the synthesized compounds against HT-29 cell
line was also assessed. Compounds 17 and 18 were found to be the
most cytotoxic agents with GI50 (concentration at which 50% of
maximum cell proliferation is inhibited) equal to 1.08 ± 0.28 and
2.20 ± 1.07 µM respectively [17].
Hu et al. reported synthesis and in vitro anti-proliferative
evaluation of a new series of 2-substituted aminomethyl-9-alkyl-
1,2,3,4-tetrahydrocarbazole-1-ones against human gastric
adenocarcinoma (SGC), HCT-116, A549, K562 and a multi-drug
resistant subline KBVCR. Higher sensitivity was observed for these
compounds towards cell line HCT-116 (IC50 = 2.46 to 9.08 µM)
compared to the reference drug Taxol (IC50 = 4.37 µM).
Compounds 19 and 20 exhibited remarkable cytotoxicity against

A549 cell line (IC50 = 0.0703 and 0.7087 µM), which are
approximately 35 and 3.5 times more active than that of Taxol
(IC50 = 2.46 µM) [18]. Compound 21 exhibited the most potent
antiproliferative activity against the specified cell lines.
A new carbazole alkaloid antipathine A (22) was isolated from
the EtOH/CH2Cl2 extracts of Antipathes dichotoma, a black coral
found in the South China Sea. Compound 22 was screened for anti-
cancer activity against human stomach carcinoma (SGC-7901) and
human liver carcinoma (HepG2) cancer cell lines using MTT
method. It showed moderate cytotoxicity against SGC-7901 cell
line (IC50 = 67.38 µg/mL), while weak cytotoxicity was observed
against HepG2 cell line [19].
Yang et al. observed that the carbazole derivative 23 displayed
superior activity as compared to compound 24 against human breast
adenocarcinoma (MDA-MB-231), human prostate adenocarcinoma
(LNCaP), PC3 and DU145 cell lines with IC50 values 3.4, 9.3, 2.9
and 4.0 µM respectively, after 48h of pre-treatment [20].
Novel pyrrolo[2,3-a]carbazole derivatives were screened for
their in vitro antiproliferative activity against three human cancer
cell linesPC3, PA1 (ovarian carcinoma) and DU145 at 1 µM
concentration. Potent antiproliferative activities were found for

compounds 25, 26, 27 and 28 with IC50 values ranging from 1.0 to
4.0 µM against PC3 and DU145 and less than 0.8 µM for PA1 cell
line. Compounds 29, 30 and 31 exhibited less activity (IC50 = 2 to8
µM) for PC3 and DU145, while against PA1 cell line IC50 values
were 1.1 µM, 0.89 µM and 1.96 µM respectively [21] as compared
to compounds 25-28.
Bouaziz et al. synthesized novel oxazino carbazoles and
evaluated their cytotoxic activity against ﬁve human tumour cell
lines that included leukemic cell lines (CEM and Jurkat), breast
cancer cell line (MCF-7), Burkitt's lymphoma and colorectal cancer
cell line (Caco-2) using the WST-1 colorimetric assay at 100 µM.
Higher activities were displayed against the leukaemia cell lines in
comparison to the MCF-7 and CaCO-2 lines. Compound 32 was
moderately active against MCF-7 and CaCO-2 cell line displaying
IC50 values of 25.2 ± 0.2 and 37.0 ± 17.8 µM respectively. The best
anti-cancer activity was observed for 33 and 34 against all the three
tested leukemic cell lines with IC50 values around 12 µM [22].
The clinical approach of employing kinase inhibitors to inhibit
tumor angiogenesis has been validated as a strategy for anti-
angiogenic therapy. 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo
[5,4-a]pyrrolo[3,4-c]carbazoles 35 and 36 were tested against
recombinant human VEGF-R2 and TIE-2 employing a recombinant
human phospholipase C-γ in 2010. Both compounds 35 and 36
exhibited significant dual VEGF-R2 and TIE-2 receptor tyrosine
kinase inhibitory activity IC50 values of 10 nM and 3 nM for TIE-2 and
24 and 11 nM for VEGF-R2 respectively. Prominent concentration-
dependent inhibition of human umbilical vein endothelial cells
(HUVEC) capillary tube formation was also exhibited by the
synthesized compounds with EC50 0.6 and 2.0 nM relative to the
control, which was evaluated when there was no HUVEC
cytotoxicity present. Compounds 35 and 36 showed significant
inhibition of FGFR-3 (total or 100% inhibition), PDGFRβ ( > 90%
inhibition) and the src family (fyn, lck, lyn,blk and yes showing >
90% inhibition) when tested for selectivity against 60 tyrosine
kinases at 3 µM concentration. However, they failed to inhibit
EGFR or IR with IC50 values greater than 1 µM. Compounds 35
and 36 inhibited VEGF-R1 (IC50 = 28 nM and 16 nM) and VEGF-
R3 (IC50 = 5 nM and 9 nM) family members. These compounds thus
showed selective and prominent dual VEGF-R2/TIE-2 inhibitory
activity with remarkable enzyme and cellular potency [23].
Recently Chk1 inhibitors have been targeted because of their
potential application in anticancer chemotherapies. Chk1 inhibitory
activity of 5-substituted pyrrolo carbazole-1,3(2H,6H)-dione
derivative 37 was investigated and it was found to show potent
inhibitory activity (IC50 = 2.8 nM) [24].
Eight carbazole compounds isolated from crude ethyl acetate
extract of C. harmandiana roots (Rutaceae) exhibited cytotoxicity
against KB (oral human epidermal carcinoma), NCI-H187 (human
lung cancer) and MCF-7 cell lines with IC50 values ranging from 17
to 28 µg/mL using the resazurin microplate assay (REMA) method.
Among all the isolated compounds, compound 38 revealed most
potent cytotoxicity against NCI-H187 cell line (IC50 = 1.63 µg/mL).
Significant cytotoxicity was displayed by compound 39 against the
KB and MCF-7 cell line with an IC50 value of 1.74 and 2.21 µg/mL
[25].
Newly synthesized 11H-benzo[a]carbazole-5-carboxamide
derivatives were screened for their in vitro and in vivo antitumor

activity against HCT-15 (human colon tumor), B16F10 (mouse
melanoma), SKMel2 (human skin melanoma), SKOV3 (human
ovarian adenocarcinoma) and A-549 cancer cell lines by SRB assay
method. Most of the compounds demonstrated potent antitumor
activity. Compound 40 displayed remarkable anti-proliferative
effects against A-549, B16F10, HCT-15, SKOV3 and SKMel2 cell
lines with IC50 values of 4.04 ± 0.13, 2.85 ± 0.07, 3.45 ± 0.07,
10.03 ± 0.13 and 4.61 ± 0.10 µg/mL respectively. Compound 41
also excibited significant cytotoxicity against all the cell lines
studied. Selective cytotoxicity was shown by compound 42 against
HCT-15, B16F10, SKMel2 and A-549 cell lines with IC50 values of
22.51 ± 0.67, 19.36 ± 0.17, 48.21 ± 1.60 and 23.40 ± 2.20 µg/mL
respectively [26].
Novel tricyclic carbazoles (4a-k) were evaluated by Taj et al.for
their cytotoxicity against A498 and A549 cell lines. Partial activity
was reported for compounds 43 and 44 against A498 cell line with
LC50 > 70 µM. The corresponding GI50 values were 74.5 and 55.2
µM respectively. Compounds 43, 44 and 45 also showed partial
activity against A549 cell line with LC50 > 70 µM and GI50 values
were 75.7, 76.5 and 52.5 µM respectively [27].
In vitro and in vivo antitumor activity of novel 11H-benzo[a]
carbazole-5-carboxamide derivatives was screened against HCT-
116 and A549 cell lines using SRB assay. Compounds 46 and 47
showed significant in vivo anti-tumor activity against both HCT-
116 and A549 cell lines [28].

The mitotic kinesin, KSP (Kinesin spindle protein) has emerged
as an excellent target for the management of cancer. A number of
carbazole and carboline derivatives were synthesized and screened
for their KSP inhibitory activity. Lactam-fused carbazole and β-
carboline derivatives exhibited significant KSP inhibition and
mitotic arrest in prometaphase. Lactam-fused carbazole derivative
48 (IC50 = 0.031) was found to exhibit the best KSP ATPase
inhibitory activity, thus expressing cytotoxicity due to cell cycle
arrest at the mitotic phase. These carbazoles exhibited anti-cancer
activity by competitive KSP inhibition [29].
Uraiwan et al. reported anti-cancer activity of compounds 49
and 50 isolated from the roots of Clausena harmandiana against
KB and NCI-H187cell lines. It was found to display IC50 values of
1.32 and 1.68 µM against NCI-H187 and KB cancer cells [30].
A number of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and
carbazolyl-3,4-dihydro-ƒÒ-carboline analogs were synthesized and
screened for their in vitro antitumor activity towards Hepa (human
hepatoma), DLD (human colon adenocarcinoma), HepG2/A2
(human hepatoma), NCI-H661 (human lung large cell carcinoma)
and KB tumor cell lines. Compounds 51, 52, 53, and 54 exhibited
the most selective and potent activity against the cell lines studied.
Compound 51 shows prominent activity with IC50 values of 0.71,
1.09, 0.84 and 0.60 µg/mL for DLD, HepG2/A2, KB and NCI-H661
cell lines respectively. Compounds 52, 53 and 54 were found to be
most effective against KB (IC50 = 0.48 µg/mL), NCI-H661 (IC50 =
0.22 µg/mL) and Hepa(IC50 = 1.12 µg/mL) cells respectively [31].
Various carbazole–pyrrolo-benzodiazepine conjugates were
synthesized by Kamal et al., and evaluated for their anti-cancer
activity against selected cancer cell lines namely NCI-60, lung
cancer (HOP-62), nasopharyngeal cancer (Gurav), human ovarian
cancer (A-2780), cervical carcinoma (SiHa), colon cancer (Colo-
205), breast cancer (Zr-75-1), A-549, PC-3, KBand MCF7 at 4µM
concentration. Compounds 55–60 showed remarkable cytotoxicity
with GI50 values in the range < 0.1 to 2.21 µM. Among the series
compound 60 was found to exhibit the best anticancer activity
exhibiting IC50 values of 0.01, 0.09, 0.10, 0.11, 0.01, 0.01, 0.11,
0.07, 0.12 and 0.01 for HOP-62, A-549, KB, Gurav, A-2780, PC3,
SiHa, Colo-205, Zr-75-1 and MCF-7 cell lines respectively [32].
Mahanine (61), mahanimbicine (62) and mahanimbine (63)
were isolated from the ethanolic extract of the leaves of Murraya
koenigii (Rutaceae) and screened for their antiproliferative effect on
three tumor cell lines namely P388 (mouse leukemia) and
HeLa(cervix adeno carcinoma) and MCF-7 using MTT assay in a
dose-dependent manner. Mahanimbine (63) was found to exhibit
potent antitumor activity against all the three specified cell lines
displaying IC50 values of 1.98, 2.12, and 5.0 µg/mL for HeLa,
MCF-7 and P388 cell lines respectively. Mahanimbicine (62) was
found to show noticeable cytotoxic activity against the MCF-7 cell
line (IC50 = 17.0 µg/mL) and P388 cell line (IC50 = 18.31 µg/mL).
Little cytotoxic activity was displayed by mahanine (61) against all
the three cell lines showing IC50 values higher than 30.0 µg/mL
[33].
Pierce et al. reported that pyrimido indolocarbazole derivative
64 revealed significant in vitro cytostatic activity with a 58.9%
mean growth percentage against a selected number of human cancer
cell lines at 10 µM concentration. The GI50 and TGI (concentration
at 0% cell growth or total inhibition) values obtained by investigating
antiproliferative activity of compound 64 against the selected cell
lines as stated in the Table 3.Though aza indolocarbazole 65 was
observed to be less cytotoxic than analogue 64, but displayed
satisfactory anticancer activity against NCI-H522 (non-small cell
lung cancer) and UO-31 (renal cancer) at low micromolar range
[34].
A novel carbazole derivative 66 was synthesized and its
anticancer effects were investigated. It was found to sensitize etoposide,
doxorubicin and radiation-treated cancer cells by enhancing DNA
damage. The compound also demonstrated anticancer activity
against Hs578T (human breast cancer cell line) by enhancing DNA
damage and inducing cell cycle arrest at the S phase [35].
The in vitro cytotoxicity of 2-amino-8-chloro-4-phenyl-5,11-
dihydro-6H-pyrido[2,3-a]carbazole-3 carbonitrile was evaluated by

SRB assay against five cancer cell lines namely A-549, SKMel2,
B16F10, SKOV3 and HCT-15. Compound 67 displayed prominent
cytotoxic activity towards A-549, B16F10, and HCT-15 with an
IC50 value of 37.24 ± 0.56, 32.23 ± 1.02 and 30.65 ± 0.11 µg/mL
respectively. Moderate anti-cancer activity against SKMel2 cell line
was observed for compound 67 (IC50 = 42.22 ± 1.32 µg/mL) [36].
A number of indolocarbazoles were synthesized and examined
for their anti-proliferative effects against human colon
adenocarcinoma cell lines (LoVo and DLD-1), HUVECs and
Burkitt lymphoma cell lines (ST-486) using MTT assay.
Compounds 68 and 69 indicated potent anti-cancer activity against
HUVECs with IC50 of 0.1 µM. Best inhibitions for LoVo cell line
was observed for compound 68 (IC50 value = 0.3 µM). The in vivo
anti-angiogenic activity of the synthesized compounds in a murine
Lewis lung cancer model was also tested. The best selectivity was
exhibited by compound 69, which was 200 folds more active on
HUVECs as compared to human colon cancer cell lines at sub-
micromolar concentrations [37].
Selective inhibition of xanthine oxidase (XO) was reported for
cancer chemotherapy and derivatives of carbazole(N-benzamide/
amide derivatives) were synthesized and evaluated for their in vitro
XO inhibitory activity. The most significant XO inhibition was
shown bycyclopropyl ring bearing carbazole 70 (IC50 = 4.3 µM)
[38].
Novel N-10-substituted pyrrolo carbazole derivatives were
synthesized and evaluated for their in vitro anti-proliferative
activity against a human fibroblast primary culture as well as
three human cancer cell lines PA1 (ovarian cancer), PC3 and
DU145 (prostate cancer). Compound 71 displayed enhanced anti-
proliferative activities toward all the cell lines tested with IC50
values of 0.63, 0.48, 0.65 and 0.96 µM respectively [39].
Thirteen carbazole alkaloids isolated from the acetone extract
of Murrayaeuchrestifolia bark were evaluated against human
leukemia cell line HL-60 at 30 µM concentration. Murrayafoline-A
72 and murrayazolinine 73 exhibited significant growth suppression
in HL-60 cells by inducing apoptosis via the activation of the
caspase-9/caspase-3 pathway [40].
Maneerat et al. isolated four novel carbazole alkaloids from
Clausenawallines , along with eighteen known compounds from
the roots of Clausenawallichii, were investigated for their
antiproliferative activity against three human cancer cell lines. All
the compounds exhibited cytotoxic activity against NCI-H187 cell
line. Among all, compound 74 demonstrated most significant

cytotoxic activity against small-cell lung cancer (NCI-H187) and
oral cancer (KB), each with an IC50 value of 4.5 µM [41].
In vitro anticancer activity of compounds 75 and 76 was
evaluated against A549 cell lines by SRB assay method. These
compounds displayed significant anticancer activity with GI50
values of < 10 µg/mL drug concentration [42].
Cytotoxic activities of compounds 77, 78 and 79 were evaluated
against HeLa cervical cancer cell lines in µM concentrations and
the compounds exhibited reasonable cytotoxicity with an IC50
values ranging from 19.80 ± 0.06 µM, 17.46 ± 0.05 µM and 18.76
± 0.01 µM respectively after 72 h of treatment [43].
Table 3. Anti-cancer activity profile of compound 64.
Cell Line GI50 (µM) TGI50 (µM) LC50 (µM)
Breast cancer 2.13 44.10 >100
CCRF-CEM (Leukaemia) 3.41 >100 >100
SF-295 (CNS cancer) 3.68 12.90 76.7
NCI-H23 (Non small cell lung cancer) 3.51 >100 >100
NCI-H460 (Non small cell lung cancer) 3.06 >100 >100
OVCAR-3 (Ovarian cancer) 9.07 25.60 69.80
SK-OV-3(Ovarian cancer) 3.56 >100 >100
ACHN (Renal cancer) 1.11 >100 >100
CAKI-1 (Renal cancer) 1.33 >100 >100
UO-31 (Renal cancer) 1.37 >100 >100
HCT-116 (Colon cancer) 3.20 35.30 >100
HCT-15 (Colon cancer) 1.98 >100 >100
KM12 (Colon cancer) 3.24 32.30 >100
M14 (Melanoma) 3.36 89.60 >100
MDA-MB-435 (Melanoma) 3.39 22.30 >100
SK-MEL-2 (Melanoma) 1.90 7.59 76.5
SK-MEL-5 (Melanoma) 3.25 13.70 37.9
UACC-257 (Melanoma) 12.80 32.00 79.7

A novel carbazole alkaloid excavatine (80) was isolated from
the leaves and stems of Clausena excavate (Rutaceae), which is
commonly found in Xishuangbanna, China. This compound was
evaluated for its anti-proliferative activity against A549, BGC-823
and HeLa cancer cell lines by the SRB assay. It was found to
exhibit promising cytotoxic activity towards A549 and HeLa cell
lines with IC50 values of 5.25 and 1.91 µg/mL respectively [44].
Janus Kinase-Signal Transducers and Activators of Transcription
(JAK-STAT) signalling is associated with regulation of cell
proliferation, differentiation and apoptosis.STAT3 was found to be
over expressed in different tumour types such as breast carcinoma,
prostate cancer and leukemia. A new series of N-alkyl-carbazole
derivatives were evaluated for their antiproliferative activity on
STAT3. Compounds 81, 82 and 83 revealed prominent activity as
STAT3 DNA-binding activity at 50 µM with 50%, 95% and 90%
inhibition in THP-1 cell line respectively [45].
Various pyrido[3,2-α]carbazole derivatives and their analogues
were synthesized and subsequently tested for their anticancer
activity against A549 and colon cancer HT29 cells via SRB assay
after 72h of treatment. Among all the synthesized compounds the
highest cytotoxicity was displayed by compound 84, which was
almost 7 to 10 folds as potent as the reference drug R16 against
A549 (IC50 = 0.07 ± 0.07 µM) and HT29 (IC50 = 0.11 ± 0.08 µM)
cancer cell lines [46].
Certain 2-[(9-ethyl-9H-carbazol-3-yl)amino]-2-oxoethyl N,N-
disubstituted dithiocarbamates were screened for their anticancer
activity against A549 and C6 rat glioma cell lines using MTT assay
in a dose-dependent manner after 24 hour incubation period.
Compound 85 exhibited the maximum cytotoxic activity against C6
cancer cell line followed by compounds 86, 87 and 88 with IC50
values of 5.9, 20, 21.3 and 26.7 µg/mL respectively [47].
Novel hetero-annulated carbazoles were evaluated for their in
vitro anticancer activity against human cancer cell lines (HeLa and
MCF 7) via MTT assay. All the compounds displayed appreciable
activity especially against HeLa. The preeminent activity was
exhibited by compound 89 (IC50 = 8.11 µM) against HeLa which
was better than the standard drug ellipticine (IC50 = 9.81 µM).
Compound 90 (IC50 = 9.63 µM) and 91 (IC50 = 12.32 µM) also

depicted substantial anti-proliferative activity against HeLa .
However, moderate activity was observed for the compounds 89-91
against MCF 7 with IC50 values of 37.43, 34.54 and 46.63µM
respectively [48].
Two novel carbazole structured alkaloids Karapinchamines A
and B along with twelve known carbazole alkaloids were isolated
from the ethyl acetate-soluble fraction and methanolic extract of Sri
Lankan curry leaves Murraya koenigii. Inhibitory effects of each
alkaloid on melanogenesis were investigated in theophylline-stimulated
murine B16 melanoma 4A5 cells. At 10 µM concentration compounds
were found to suppress melanogenesis. The most significant
inhibitory activities were displayed by Koenimbine 92 (IC50 = 1.2
µM) and mahanimbine 93 (IC50 = 1.4 µM). Further mahanimbicine
94 and murrayamine-E 95 also exhibited significant melanogenesis
inhibitory activity (IC50 = 2.2 µM and 2.9 µM) [49].
Some carbazole chalcones were also tested for their anti-cancer
activity against cancer cell lines Hep 3BPN7 (liver cancer cell line),
HL60 P58 (leukaemia cancer cell line) and HeLa-B75 (cervix

cancer cell line).Compounds 96, 97, 98, 99, 100 and 101
demonstrated superior cytotoxicity against the Hep 3BPN7 (61.53
µM and 61.40 µM) and HeLa-B75 (56.31 µM) cell lines [50].
The cytotoxic activity of 9-[(6-chloropyridin-4-yl)methyl]-9H-
carbazole-3-carbinol (102) was evaluated against MCF-7 cells.
Compound 102 was found to suppress MCF-7 cell growth after 48
h of treatment with an IC50 of 20–30 µM by inducing cell arrest at
the S phase and triggering cell apoptosis. Compound 102 was also
found to inhibit cell proliferation, cell migration, and VEGF- or
bFGF induced tube formation in HUVECs. Thus indicating in vitro
anti-angiogenic activity [51].
Bisgerayafolines A, a dimeric carbazole alkaloid possessing
geranyl moieties was isolated from the CHCl3 extract of the fruit
pulp of Murraya koenigii. This compound was then tested for its
cytotoxic activity against AGS (stomach adenocarcinoma), HeLa
and HCT116 using the MTT assay. Compound 103 showed significant
cytotoxicity against the tested cell lines with IC50valuesof 23.2 ±
0.13, 17.2 ± 0.11 and 22.3 ± 0.25 µM respectively [52].
Novel 1,6-dihydropyrazolo carbazoles and 3,6-dihydropyrazolo
carbazoles were synthesized and tested for their in vitro
antiproliferative activities towards two prostatic cancer cell lines
LnCAP (androgen dependent cells) and PC3 (androgen independent
cells) via the colorimetric MTS assay at 10 µM concentration. After
72 hours of treatment compounds 104 and 105 displayed more than
70% growth inhibition for PC3 (IC50 = 3 µM and 2.30 µM) [53].
In vitro antitumor activity of newly synthesized carbazole
analogues were evaluated against HeLa, MDA MB231 and TCC-
SUP (bladder transitional cell carcinoma) cell lines. All the
compounds exhibited high inhibitory activity even at a low
concentration of 0.5 µM. Highest anti-proliferative effect was
displayed by compound 109 towards TCC-SUP cells [54].
In vitro antitumor activity of a novel pyridocarbazole-5-
carboxylate derivative was evaluated against a human cervical
cancer cell line (HeLa S-3) using MTT assay. Compound 110
displayed promising antitumor activity with an IC50 value of 1.30
µM [55].
Novel carbazole derivatives 111, 112, 113, 114 and 115 were
evaluated for their anti-proliferative activity against MCF7 cancer
cell line by the SRB assay method. Most potent activity was
exhibited by 115 with an LC50 value of 35.6 µg mL-1
, which was
slightly lower than that of the control compound Adriamycin (LC50
= 23.2 µg mL-1
) [56].
Novel guanidine derivatives of carbazole (116-119) were
evaluated for anti-proliferative activity against various cell lines.

Compounds 117, 118 and 119 displayed high inhibitory activity
towards KB human cell lines at 10 µM concentrations. These
compounds were further tested against HL60 cell line and the IC50
values observed were 3.1, 3.5 and 4 µM respectively. This showed
that compound 117 was highly active and found to exhibit potent
anti-cancer activity against MCF7, HCT116 and PC3 at 10 µM
concentration [57].
Biological activities of two newly synthesized dipyrrolo
carbazole stereoisomers were studied towards Chk1, GSK-3b, Pim-
1, Pim-2, and Pim-3 protein kinases. Chk1, Pim-1 and Pim-3 were
found to be the most inhibited kinases. Compound 120 exhibited
potent in vitro protein kinase inhibitory activity at sub-micromolar
range. Pim-3 kinase was the most inhibited kinase with an IC50
value of 0.31 µM. Compound 120 also demonstrated inhibitory
activities towards Chk1 and GSK-3b with IC50 values of 3.0 µM
and 9.0 µM respectively [58].
The in vitro cytotoxic activity of novel pyrido carbazole 121
was evaluated against MCF-7, HeLa and A549 by SRB assay.
Compound 121 showed almost equipotent cytotoxic activity (IC50 =
13.4 µM) with the standard Cisplatin (IC50 = 13.2 µM) against
HeLa. Moderate to good activity was observed against A549 and
MCF-7 cell lines with IC50 values of 87.2 µM and 30.4 µM
respectively [59].
Novel carbazole analogues bearing pyrazolo, pyrimido,
isoxazolo and pyrido moieties were reported for their in vitro anti-
proliferative activity against HeLa and AGS cancer cell lines.
Prominent growth inhibition was shown by these carbazoles on
HeLa cell line as compared to AGS cancer cell line. The most
significant anti-proliferative activity was exhibited by compounds
6-chloro-2-(3′,4′-diethoxy-benzylidene)-2,3,4,9-tetrahydro-carbazol-
1-one, 122 (IC50 = 0.37 µM) and 2-(3′,4′-diethoxy-benzylidene)-6-
methyl-2,3,4,9-tetrahydro-carbazol-1-one, 123(IC50 = 0.80 µM)
against HeLa cell line [60].
Compound 124 was found to exhibit antitumor activity (IC50 =
8 µM) against SKOV3 by MTT method [61].
It has been established that activation of signal transducers
(STAT3) attained via phosphorylation of Y705 residue by cytokine
receptor associated kinases promotes tumour growth and has been
implicated in various human cancers. A novel carbazole 125 was
found to strongly inhibit IL-6-induced activation of endogenous
STAT3-mediated transcription and phosphorylation of STAT3
(Y705) in a dose-related manner displaying anti-cancer activity in
triple-negative breast cancer (TNBC) cell lines HS578T and
SUM149PT. Compound 125 also exhibited anti-proliferative
activities towards squamous carcinoma cell linesA549 (GI50 = 2.5
µM) and A431(GI50 = 0.16 µM) as well as against a prostate cancer
cell line PC-3 (GI50 = 3 and 7.9 µM) using MTT assay after 72
hours of treatment [62].
The in vitro anticancer activities of a series of N-acyl
carbazoles 126-133 were evaluated via SRB assay against MDA-
MB231 and CAL 27 (human tongue squamous cell cancer) cell line
at 10 µM. After three days of treatment, compounds 126, 127, 128,
129, 130, 131, 132 and 133 were found to inhibit the growth of
CAL 27 cells (> 90% inhibition) significantly The effects were

consistent for 126, 128, 129, 130 and 133 in a dose-dependent study
with IC50 values for 128 and 133 to be 0.028 ± 0.002 and 0.45 ±
0.03 µM respectively. Compounds 127, 128, 129, 131 and 133 also
exhibited prominent cytotoxic activity against MDA-MB231 cells
[63].
CONCLUSION
Over the ensuing millennia, humankind discovered and made
use of an enormous range of natural compounds. Carbazoles
represent an important class of natural product alkaloids and the
carbazole scaffold is widely present in numerous biologically active
molecules with diverse pharmacological effects. In this review,
both naturally occurring and synthetic carbazole alkaloids along
with their respective anticancer activities reported from 2008 to mid
2014 potrayed. It is well known that carbazoles act as anticancer
agents by the DNA intercalation as well as by suppressing DNA-
dependent enzymes such as telomerase and topoisomerase I/II.
Future work related to these emerging natural and synthetic
carbazole lead compounds will be primarily focused on enhancing
the potency, specificity, improving pharmacokinetic properties,
metabolic stabilities and reducing toxic side effects. This could be
achieved by systematic and iterative optimization by medicinal
chemists, in an effort to discover advanced carbazole experimental
candidates with anticancer therapeutic and cancer chemopreventive
potential. This medicinal chemistry campaign can be further
facilitated by various computational studies such as docking,
quantitative-structure activity relationship pharmacophore modelling
and structure-based drug design approach including the X-ray co-
crystal studies.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
The authors sincerely thank the College of Health Science,
University of KwaZulu-Natal, Durban, South Africa for funding
this project.
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Received: October 10, 2014 Revised: April 04, 2015 Accepted: April 17, 2015

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