ArticlePDF AvailableLiterature Review

Abstract and Figures

Background: In the search of bioactive molecules, nature has always been an important source and most of the drugs in clinic are either natural products or derived from natural products. The ocean has played significant role as thousands of molecules and their metabolites with different types of biological activity such as antimicrobial, anti-inflammatory, anti-malarial, antioxidant, anti HIV and anticancer activity have been isolated from marine organisms. In particular, marine peptides have attracted much attention due to their high specificity against cancer cell lines that may be attributed to the various unusual amino acid residues and their sequences in the peptide chain. This review aims to identify the various anticancer agents isolated from the marine system and their anticancer potential. Method: We did literature search for the anticancer peptides isolated from the different types of microorganism found in the marine system. Total one eighty eight papers were reviewed concisely and most of the important information from these papers were extracted and kept in the present manuscript. Results: This review gives details about the isolation, anticancer potential and mechanism of action of the anticancer peptides of the marine origin. Many of these molecules such as aplidine, dolastatin 10, didemnin B, kahalalide F, elisidepsin (PM02734) are in clinical trials for the treatment of various cancers. Conclusion: With the interdisciplinary and collaborative research and technical advancements we can search more promising and affordable anticancer drugs in future.
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Current Protein and Peptide Science, 2017, 18, 1-20 1
REVIEW ARTICLE
1389-2037/17 $58.00+.00 © 2017 Bentham Science Publishers
Marine Peptides as Anticancer Agents: A Remedy to Mankind by Nature
Beena Negi, Deepak Kumar, and Diwan S. Rawat*
Department of Chemistry, University of Delhi, Delhi-110007 India
A R T I C L E H I S T O R Y
Received: February 11, 2016
Revised: June 25, 2016
Accepted: July 02, 2016
DOI: 10.2174/1389203717666160724
200849
Abstract: Background: In the search of bioactive molecules, nature has always been an important
source and most o f the drugs in clinic are either natural products or derived from natural products. The
ocean has played significant role as thousands of molecules and their metabolites with different types
of biological activity such as antimicrobial, anti-inflammatory, anti-malarial, antioxidant, anti HIV and
anticancer activity have been isolated from marine organisms. In particular, marine peptides have
attracted much attention due to their high specificity against can cer cell lines that may be attributed to
the various unusual amino acid residues and their sequen ces in the peptide chain. This review aims to
identify the various anticancer agents isolated from the marine system and their anticancer potential.
Methods: We did literature search for the anticancer peptides isolated from the different types of mi-
croorgan ism found in the marine system. Total one eighty nine papers were reviewed concisely and
most of the important information from these papers were extracted and kept in the present manu-
script.
Results: This review gives details about the isolation, anticancer potential and mechanism of action of
the anticancer peptides of the marine origin. Many of these molecules such as aplidine, dolastatin 10,
didemnin B, kahalalide F, elisidepsin (PM02734) are in clinical tri als for the treatment of various can-
cers.
Conclusion: With the interdisciplinary and collaborative research and technical advancements we can
search mo re promising and affordable anticancer drugs in future.
Keywords: Marine peptides, An ti-cancer agents, Milnamide B, Apratoxin, Kahalalide F, Dolastatin 10, Elisidepsin.
1. INTRODUCTION
Cancer is a major public health burden both in the
developed and developing countries [1]. It is characterized
by uncontrolled growth of cells and spreads in the body
through lymph or blood. The main types of cancer are lung,
liver, stomach, colorectal, breast and oesophageal cancer [2].
In 2012, 14.1 million new cancer cases and 8.2 million
cancer related deaths were reported worldwide. Out of these
65% (5.3 million) of the cancer deaths occurred in the less
developed regions of Africa, Asia and Central and South
America [3, 4]. The WHO has launched a global action plan
for the prevention and control of non-communicable diseases
2013-2030 that aims to reduce by 25% premature mortality
from cancer, cardiovascular diseases, diabetes and chronic
respiratory diseases. A limited number of effective antican-
cer drugs are currently available for the treatment of cancer
[5].Nature has always been an important source of bioactive
molecules and has led to the discovery of new molecular
*Address correspondence to this author at the Department of Chemistry,
University of Delhi, P.O. Box: 110007, New Delhi, India; Tel/Fax: + 91-11-
27667465; E-mail: dsrawat@chemistry.du.ac.in
structures which can be illustrated by the fact that the
majority of medicines used today are either natural products
or their derivatives. Thus natural product represents a sig-
nificant source of inspiration for the development of new
biologically important molecules with improved pharmacol-
ogical profile. The contribution of oceans in the development
of therapeutic agents cannot be forgotten, as thousands of
molecules and their metabolites with different types of bio-
logical activity such as antimicrobial, anti-inflammatory,
anti-malarial, antioxidant, anti HIV and anticancer activity
have been isolated from marine organisms. Some of these
active compounds have entered into preclinical and various
stages of clinical trials and it might be expected that this
number would increase in the future [6].
The oceans cover up nearly 70% of the earth’s surface
and have been considered as a vast resource for the finding
of potential anticancer agents. Since the marine environment
is much more diverse than the terrestrial environment,
therefore there is always a big scope to explore the biological
properties of marine natural products. During the last few
decades, numerous novel compounds have been found from
marine organisms with interesting biological activities
comprising different structural features. In particular, marine
2 Current Protein and Peptide Science, 2017, Vol. 18 No. 5 Negi et al.
peptides have attracted a great deal of attention due to their
potential effects in promoting health and reducing disease
risk. These peptides have been obtained from sponges,
mollusks, tunicates, bryozoans, algae, fish, soft corals, sea
slugs and other marine organisms. The various unusual
amino acid residues and their sequences are the key struc-
tural features which may be responsible for their potential
cytotoxic effects. Compared with the traditional cancer
treatments such as chemotherapy or radioactive treatment,
peptides show high specificity against cancer cells. These
characteristics ensure that the marine peptides have potential
for the prevention and treatment of cancer and they can be
used as molecular models in anticancer drug discovery.
The development of peptides derived from various
marine resources as anticancer drugs with their further
advancement for the treatment of cancer has been discussed.
2. PEPTIDES FROM SPONGES
Sponges belong to the phylum porifera. Worldwide,
nearly 10,000 sponges are found in marine environment.
Sponges are traditionally known as a vital source of novel
bioactive metabolites which possess a wide range of biologi-
cal activities and hence are considered as a gold mine for the
chemists. More recently, they have been explored to search
newer bioactive peptides. Active peptides from sponges are
mostly cyclic or linear peptides bestowed with unusual
amino acids and with uncommon condensation between the
amino acids.
Jaspamide is a cyclic depsipeptide and was isolated from
sponges of the genus Jaspis and Hemiastrella [7-9]. The
structure of jaspamide consists of a 15-carbon macrocyclic
ring having three amino acid residues. Jaspamide has a
strong antiproliferative activity against PC-3, LNCaP and
TSU-Pr1 (human immortalized prostate carcinoma cell lines)
and human Jurkat T cells [10, 11]. Recently Cio ca et al also
reported the apoptosis activity of jaspamide in human pro-
myelocytic leukemia cell line and T cells in brain tumor by
caspase-3 activation and decreasing in Bcl-2 protein expres-
sion [12, 13]. It was also observed that jaspamide induces a
caspases independent and caspases dependent pathway of
cell death, responsible for the observed cytoplasmic and
membrane changes in apoptosing cells, and PARP proteoly-
sis, respectively.
The marine sponge Jaspis splendans obtained from
Vanuatu yielded two new jaspamide derivatives, B and C
along with Jaspamide [14]. Jaspamide, Jaspamide B and
Jaspamide C exhibited cytotoxicity against the human
NSCLC-N6 cancer cell line with IC50 values 0.36, 3.3 and
1.1 µg/mL, respectively.
Hemiasterlins are tripeptides isolated from two distinct
species of sponge Auletta and Siphonochalina sp [15-17].
There are three different hemiasterlins (Hemiasterlin, Hemi-
asterlin A, Hemiasterlin C) with potential cytotoxic and anti-
tubulin activity. They are highly potent in suppression of
microtubule depolymerization presumably by binding to the
vinca alkaloid site of tubulin and cause mitotic arrest and cell
death [18]. A synthetic analogue of hemiasterlin, taltobulin
(HTI-286) has been synthesized in which the 3-substituted
indole ring was replaced by phenyl group. Loganzo et al
examined the anticancer potency of HTI-286 and it was ob-
served to inhibit the polymerization of purified tubulin and
also causes disruption of microtubule organization in cells,
and induces mitotic arrest, as well as apoptosis [19]. HTI-
286 inhibited the proliferation in 18 human tumor cell lines
with mean IC50 value of 2.5±2.1 nM and exhibits less inter-
action with the multidrug resistance protein (P-glycoprotein)
[20, 21] than the commonly used antimicrotubule agents
such as paclitaxel, vinblastine, docetaxel, vinorelbine and
others Moreover, HTI-286 inhibited the growth of human
tumor xenografts (e.g. HCT-15, DLD-1, MX-1W, and KB-8-
5) where paclitaxel and vincristine [22, 23] were found to be
ineffective against these cell lines probably due to inherent
or acquired resistance associated with P-glycoprotein.
Geodiamolides A-G are cyclic peptides which were iso-
lated from the Caribbean sponge Geodia sp [24-27]. Further
examination of the sponge Geodia sp. furnished other related
compounds, geodiamolides H and I [28]. Geodiamolide H
showed in vitro cytotoxicity towards various human cancer
cell lines e.g. non-small cell lung cancer, HOP 92 (TGI =
1.18 x 10-7 M), central nervous system, SF-268 (TGI = 1.53
x 10-7 M), ovarian cancer, OV Car-4 (1.86 x 10-8 M), renal
cancer, A498 (9.48 x 10-8 M) and UO-31 (1.85 x 10-7 M) and
breast cancer MDA-MB-231/ATCC (4.33 x 10-7 M) and HS
578T (2.45 x 10-7 M). Geodiamolide I was completely de-
void of activity.
The anticancer activity of geodiamolides A, B, H and I
were also examined against sea urchin eggs (Lytechinus
variegatus), and human breast cancer cells lines (T47D and
MCF7) [29]. The activity of these compounds was supposed
to be mediated by disorganization of actin filaments of can-
cer cells of T47D and MCF7, while microtubule organization
was not affected. Freitas et al investigated the effects of geo-
diamolide H on migration and invasion of Hs578T cells.
Geodiamolide H was found to significantly decrease the mi-
gration and invasion of Hs578T cells probably due to modi-
fications in actin cytoskeleton [30].
A cyclodepsipeptide, arenastatin A was isolated from ma-
rine sponge Dysidia arenaria which showed extremely po-
tent cytotoxicity against KB cells with IC50 5 pg/mL [31].
The primary mechanism of action of arenastatin A was sug-
gested by the inhibition of microtubule assembly through
binding to the rhizoxin/maytansine site on tubulin [32, 33].
However, arenastatin A was found to exhibit weak in vivo
anti-tumor activity which could be attributed due to rapid
metabolism of the 15,20-ester linkage in aren astatin A [34].
To overcome this problem, a 15,20-triamide analog was syn-
thesized, in which the labile ester function was replaced by
an amide group. This analog was found to show sufficient
stability but again unfortunately weaker cytotoxic activity
(IC50 = 6 ng/mL) than that of arenastatin A. Moreover, the
same research group synthesized two other analogues of are-
nastatin by replacing the isobutyl group at the C-15 position
by bulky substituents such as iso-propyl and the tert-butyl
groups [35]. Although both the derivatives gradually me-
tabolized, they were shown to be more stable than arenas-
tatin. The iso-propyl and the tert-butyl analogues displayed
moderate cytotoxicity against KB-3-1 cells with IC50 values
30 and 10 ng/mL, respectively. Again, in order to increase
metabolic stability and water solubility of arenastatin A, Ko-
Marine Peptides as Antic ancer Agents Current Protein and Peptide Science, 2017, Vol. 18, No. 5 3
bayashi et al further synthesized several 15,20-triamide ana-
logues of arenastatin A with a polar substituent on the phenyl
ring [36]. The two analogues with diethylamine and MOM-
ether substituent on the phenyl ring were found to be the
most potent cytotoxic compounds (IC50 = 0.18 and 0.61
ng/mL, respectively) with good solubility and stability. The
in vivo anti-tumor activity of the intraperitoneally applied
diethylamine analog was tested in subcutaneously implanted
murine sarcoma S180 cells. It inhibited the growth of the
tumor at a dose of 1 mg/kg with comparable efficacy to that
of 5 mg/Kg doxorubicin, without any acute toxicity.
HN
O
O
O
N
OH
O
NH
HN
O
Br
Jaspamide (Jasplakinolide)
HN
O
O
O
N
OH
O
NH
HN
O
Br
Jaspamide B
O
HN
O
O
O
N
OH
O
NH
HN
O
Br
Jaspamide C
HO
N
H
NOH
R2
O
OO
NH
N
Hemiasterlin; R1 = R2 = CH3
Hemiasterlin A; R1 = H, R2 = CH3
Hemiasterlin C; R1 = CH3, R2 = H
R1
NOH
O
OO
NH
HTI-286
NN
O R1
O
O
O
NHR2
O
H
X
OH
Geodiamolide A; R1 = Me, R2 = Me, X = I
Geodiamolide B; R1 = Me, R2 = Me, X = Br
Geodiamolide C; R1 = Me, R2 = Me, X = Cl
Geodiamolide D; R1 = Me, R2 = H, X = I
Geodiamolide E; R1 = Me, R2 = H, X = Br
Geodiamolide F; R1 = Me, R2 = H, X = Cl
HN O
O
O
N O
NH
X
HO
O
Geodiamolide G; X = I
Geodiamolide J; X = Br
Geodiamolide K; X = Cl
OHN O
O
O
N O
NH
X
HO
OH
O
Geodiamolide H; X = I
Geodiamolide I; X = Br
O
O HNO
O OHN
O
OMe
O
Arenastatin A
Fig. (1).
Homophymines, B-E and A1-E1 are cyclodepsipeptides
isolated from the sponge Homophymia sp [37] which showed
highly potent anticancer activity against various cancer cell
lines in nano molar range. Homophymines A1-E1 having the
4-amino-6 carbamoyl-2,3-dihydroxyhexanoic acid moiety,
displayed better activity than the corresponding Homo-
phymines A-E which consists of the same moiety in its car-
boxy form. The homophymines do not show significant ef-
fect of caspases 3 and 7 activation which indicates that ho-
mophymines display a toxic rather than anti-proliferative
activity.
Discodermins A-H were obtained from sponges of the
genus Discodermia sp [38-40]. These compounds contain
some rare amino acids present in the chain and the macro-
cyclic ring present in the structure is formed by the lactoni-
zation of the amino acid, threonine with the carboxy termi-
nal. Sato et al also investigated the permeabilizing effect of
discodermin A on the plasma membrane and found that dis-
codermin A interacts with plasma membrane phospholipids
with its six successive hydrophobic amino residues at N-
terminal [41]. Discodermins A-H also inhibited the devel-
opment of starfish embryos (IC50 = 0.02-20 µg/mL). In addi-
tion, discodennins F, G and H were cy totoxic against P388
leukemia cells with IC50 values of 0.1, 0.4 and 0.1 µg/mL,
respectively [42].
R1
HN
NH
HN
O
HN
H2N
OH
O
O
O
O
NH2
O
O
HO
OH
HN
O
O
NH
O
R2HN
H2N
N
O
HN
O
HO
O
NH
NH
O
MeO
O
O
N
Me
H2N
O
OH O
OH O
OH O
Homophymine A; R1 = OH
Homophymine A1; R1 = NH2
Homophymine B; R1 = OH
Homophymine B1; R1 = NH2
Homophymine C; R1 = OH
Homophymine C1; R1 = NH2
OH O
Homophymine D; R1 = OH
Homophymine D1; R1 = NH2
OH O
Homophymine E; R1 = OH
Homophymine E1; R1 = NH2
R2
N
H
H
NN
H
H
NN
H
H
NN
O
R4
O
R3
O
O
OSO3
-
OO
O
Me
O NH2
HN
NH
NH2
H2N
O
N
Me
O
H
N
N
O
NH
O
HN
R1
O
H
NHO
OH
NH
O
NH2
O
O
R2
Discodermin A; R1 = H, R2 = H, R3 = Me, R4 = Me; Discodermin B; R1 = H, R2 = H, R3 = H, R4 = Me
Discodermin C; R1 = H, R2 = H, R3 = Me, R4 = H; Discodermin D; R1 = H, R2 = H, R3 = H, R4 = H
Discodermin F; R1 = H, R2 = H, R3 = Me, R4 = Et; Discodermin G; R1 = Me, R2 = H, R3 = Me, R4 = Me
Discodermin H; R1 = H, R2 = OH, R3 = Me, R4 = Me
N
H
H
NN
H
H
NN
H
H
NN
O
O
O
O
OSO3
-
OO
O
Me
O NH2
NH
NH2
H2N
O
N
Me
O
H
N
N
O
NH
O
HN
O
H
NHO
OH
NH
O
NH2
O
O
O
H2N
Discodermin E
Fig. (2).
Phakellistatin 1, a cyclic heptapeptide was isolated from
two Indo-Pacific sponges, Phakellia costata and Stylotella
aurantium which displayed growth inhibitory activity against
murine leukemia (P-388) cell line with ED50 value of 7.5
µg/mL [43]. Two new members of the phakellistatin group,
phakellistatin 2 and phakellistatin 3 were isolated from the
marine sponge Phakellia carteri by Pettit and co-workers
[44, 45]. Phakellistatin 2 and 3 showed growth inhibitory
against P388 cell line with ED50 value 0.34 and 0.33 µg/mL,
respectively. Phakellistatin 2 also showed good activity
against ovarian (OVCAR-3), brain (SF-295), renal (A498),
lung (NCI-H460), colon (KM2OL2) and melanoma (SK-
MEL-S) cell lines with log10 GI50 values of 1.0, 3.0, 2.1, 2.0,
2.8, 1.0 µg/mL, respectively.
Pettit et al. further isolated three new congeners, Phakel-
listatin 4, 5 and 6 from Phakellia costata [46-48]. Phakel-
listatin 4 and 5 were screened against the NCI human cancer
cell lines and displayed mean pan el GI50 values of 0.6 and
3.0 µM, respectively. Phakellistatin 6 was found to display a
good level of cancer cell growth inhibition against the mur-
4 Current Protein and Peptide Science, 2017, Vol. 18 No. 5 Negi et al.
ine P388 lymphocytic leukemia (ED50 = 0.185 µg/mL), ovar-
ian (OVCAR-3, GI50 = 0.025 µg/mL), CNS (SF-295, GI50 =
0.041 µg/mL), renal (A498, GI50 = 0.078 µg/mL), lung
(NCI-H460, GI50 = 0.019 µg/mL), colon (KM2OL2, GI50 =
0.021 µg/mL) and melanoma (SK-MEL-S, GI50 = 0.032
µg/mL) cancer cell lines.
Phakellistatins 7-9 were isolated from the Federated
States of Micronesia (Chunk) marine sponge Phakellia co-
stata [49]. All the three compounds have very similar struc-
ture and also display quite comparable cytotoxicity against
the P388 cell in vitro with ED50 = 3.0, 2.9 and 4.1 µg/mL,
respectively.
N
H
N
O
NH
O
NO
N
OHN
O
O
OH
NH
O
Phakellistatin 3
NH
H
HO
H
N
H
N
O
NHO
NO
NH
O
HN O
O
N
OOH
Phakellistatin 1
H
N
NO
HN O
N
O
N
H
O
NH
O
O
N
O
HO
Phakellistatin 2
N
H
N
O
NH
O
N
O
H
N
OHN
O
O
N
O
Phakellistatin 6
HN
H
N
NO
HN O
H
N
O
N
H
O
NH
O
O
HO
N
O
OH
Phakellistatin 4
N
H
H
N
O
NH
O
N
H
O
H
N
OHN
O
O
N
O
Phakellistatin 5
H2NO
H3CS
NH
NH
O
O
NH
O
N
O
N
O
H
N
O
N
O
HN
O
O
NO
NH
HO
Phakellistatin 7
NH
NHO
O
NH
O
N
O
N
O
H
N
O
N
O
HN
O
O
NO
NH
HO
Phakellistatin 8
NH
NHO
O
NH
O
N
O
N
O
H
N
O
N
O
HN
O
O
NO
NH
HO
Phakellistatin 9
Fig. (3).
Phakellistatin 10-14 were isolated from the sponge
Phakellia fusca [50-53]. Phakellistatin 10, Phakellistatin 11
and 12 inhibited the growth of murine P-388 lymphocytic
leukemia with ED50 values 2.1, 0.20 and 2.8 µg/mL, respec-
tively. Phakellistatin 13 showed strong cytotoxic activity
against the BEL-7404 human hepatoma cell line with an
ED50 < 10-2 µg/mL, but was not active against the HL-60
cell line. Phakellistatin 14 showed cancer cell growth inhibi-
tory activity (ED50 = 5 µg/mL) against the murine lympho-
cytic leukemia P388 cell line and a panel of human cancer
cells (GI50 = 0.75-3.4 µg/mL).
Phakellistatins 15-18 were isolated from the South China
Sea sponge P. fusca [54]. All the compounds were tested for
cytotoxic activity in vitro. Phakellistatin 15 exhibited cyto-
toxicity ag ainst cancer cell line P388 with an IC50 value of
8.5 µM. Phakellistatin 16 showed cytotoxicity against cancer
cell lines P388 and BEL-7402 with IC50 values 5.4 and 14.3
µM, respectively, whereas phakellistatins 17 and 18 showed
no cytotoxicity against these cancer cell lines.
Phakelistatin 14
O
N
HO
H
N
HN
O
OH
HN
O
O
N
NH
N
H
H2N
NH
O
NH
HO
O
N
H
O
NH
O
HO OOH
Pro
Phakellistatin 16
trans-Pro (major conformer)
cis-Pro (minor conformer)
N
O
H
N
O
N
H
O
NH
HN O
N
O
O
N
OH
N
O
HN
Phakellistatin 17
O
N
H
N
O
NH O
N
O
HN O
N
O
O
H
N
O
N
O
HN
Phakellistatin 15
HN O
NH
O
H
N
SO
O
HN O
H
N
N
ONHO
OCH3
O
H
N
O
N
O
HN
O
N
O
NH
O
O
O
N
N
H
HO Phakellistatin 18
Phakelistatin 12
HN
H
N
OO
NH
ON
O
NO
HN
O
N
O
NH
O
O
N
O
NH
OH
OH
H
N
N
O
HN O
NH
ONHO
N
O
ONH
O
OH
HN
Phakellistatin 13
Fig. (4).
Callyaerin G, an optically active cyclic peptide was
isolated from Indonesian sponge Callyspongia aerizusa [55].
Callyaerin G was found to be cytotoxic towards the mouse
lymphoma cell line (L5178Y) and human cervix carcinoma
(HeLa) cells with ED50 of 0.53 and 5.4 µg/mL, respectively,
while inactive against rat brain tumour (PC12) in the
microculture tetrazolium (MTT) assay at concentrations of 3
and 10 µg/mL.
Recently, Ibrahim et al have isolated new cyclic peptides,
Callyaerins A-F and H from the same sponge Callyspongia
aerizusa [56]. The callyaerins contains a cyclic peptide
system of 5-9 amino acids along with a side chain containing
2-5 amino acid residues. The cytotoxicity of callyaerins A-F
and H was examined against L5178Y (mouse lymphoma),
and HeLa (human cervix carcinoma) and PC12 (rat brain
tumour) cell lines. Callyaerins E and H showed potent
activity towards L5178Y cell line with ED50 values of 0.39
and 0.48 µM, respectively. The remaining compounds were
found to be less active towards this cell line with ED50 values
ranging from 2.92 to 4.14 µM, except callyaerin F which
was found to be totally inactive. Among all the callyaerins,
callyaerin E was the most active compound while callyaerin
F showed the least activity. The structure-activity
relationship indicates that increasing the number of proline
residues in the cyclic moiety increases anticancer activity
and replacement of a proline moiety with a hydroxyproline
reduces the anticancer activity.
Milnamide A, a cytotoxic tripeptide was isolated from
Papua New Guinean collections of the Axinellida sponge
Auletta cf. constricta [57]. Milnamide A displayed signifi-
cant cytotoxic activity against several cancer cell lines such
as A549 (IC50 = 4.1 µg/mL), HT-29 (IC50 = 2.8 µg/mL),
B16/F10 (IC50 = 3.3 µg/mL) and P388 (IC50 = 0.74 µg/mL).
Marine Peptides as Antic ancer Agents Current Protein and Peptide Science, 2017, Vol. 18, No. 5 5
A reinvestigation of Auletta sp. yielded a related compound,
milnamide C along with the known compounds milnamide A
and milnamide B (hemiasterlin) [58]. Milnamide B and mil-
namide C were evaluated for their cytotoxicity towards
MDA-MB-435 cancer cells and displayed IC50 values of 0.15
ng/mL and 0.32 µg/mL, respectively. Both the compounds
showed the inhibition of microtubule polymerization. The
sponge Cymbastela collected in Milne Bay, Papua New
Guinea furnished milnamide, milnamide D along with al-
ready known milnamide A [59]. Milnamide A and milna-
mide D were tested against two colorectal cancer cell lines
(HCT-116, wild type, and p53-deficient mutant). Milnamide
D (IC50 = 66.8 nM) was significantly more potent than mil-
namide A (IC50 = 1652.6 nM). When tested for antitubulin
activity both the compounds showed strong inhibitory activ-
ity towards tubulin polymerization with IC50 values of 6.02
µM and 16.90 µM, respectively.
Two new linear peptides, Microcionamides A and B were
isolated from the Philippine Sponge Clathria (Thalysias)
abietina [60]. Microcionamides A and B showed significant
cytotoxicity toward human breast tumor cell lines MCF-7
and SKBR-3. Microcionamide A was active against MCF-7
and SKBR-3 cells with IC50 values of 125 and 98 nM, re-
spectively, whereas Microcionamide B d isplayed activity
with IC50 values of 177 and 172 nM against MCF-7 and
SKBR-3 cells, respectively. Furthermore, both compounds
were shown to induce apoptosis within 24 h in MCF-7 cells
at 5.7 µM concentration. Extensive DNA fragmentation,
which is also considered as a significant biochemical marker
of apoptotic cells, was detected in a TUNEL assay and by
Hoescht staining of peptide-treated MCF-7 and SKBR-3
cells, respectively.
Calyxamides A and B were isolated from the marine
sponge Discodermia calyx collected near Shikine-jima
Island, Japan [61]. These are the first cytotoxic cyclic pep-
tides isolated from the Japanese marine sponge, D. calyx and
contain 5-hydroxytryptophan and thiazole moieties. Calyx-
amides A and B showed moderate cytotoxicity against P388
murine leukemia cells, with IC50 values of 3.9 and 0.9 µM,
respectively.
Williams et al isolated two cyclic heptapeptides, rol-
loamides A and B from the Dominican marine sponge Eury-
pon laughlini [62]. Rolloamide A exhibited significant
growth suppression activity against a panel of histologically
diverse cancer cell lines with IC50 values ranging from 0.17
to 5.8 µM.
Four cyclic peptides, kapakahines A-D were isolated
from the marine sponge Cribrochalina olemda [63, 64].
These peptides lack an amide linkage between two
tryptophan residues and the ring is closed by a bond from the
indole nitrogen of Trp-1 to the β-carbon of Trp-2. Kapakahi-
nes A, B, and C showed moderate cytotoxicity against P388
murine leukemia cells at IC50 values of 5.4, 5.0 and 5.0
µg/mL, respectively, while kapakahine D did not show any
cytotoxicity upto 10 µg/mL concentration.
A marine sponge of the genus Theonella collected from
southwestern Japan yielded a linear decapeptide, koshika-
mide A1 which exhibited cytotoxic activity against P388
leukemia cells with an IC50 value 2.2 µg/mL [65]. Further
examination of the extract from the same sponge afforded a
closely related compound, koshikamide A2. It was identified
as linear undecapeptide by spectroscopic methods and
showed moderate cytotoxic activity against P388 leukemia
cells with an IC50 value 6.7 µg/mL [66].
Koshikamide B was isolated from a marine sponge
Theonella sp [67]. Koshikamide B displayed anticancer ac-
tivity against murine leukemia cells (P388) and the human
colon tumor (HCT-116) cell line with IC50 values of 0.45 and
7.5 µg/mL, respectively.
A new cyclic peptide, scleritodermin A was isolated from
the marine sponge Scleritoderma nodosum. The structure of
Scleritodermin A was found to have a novel conjugated thia-
zole moiety 2-(1-amino-2-p-hydroxyphenylethane)-4-(4-
carboxy-2,4-dimethyl-2Z,4E-propadiene)-thiazole (ACT), L-
proline, L-serine, and the unusual amino acids keto-allo-
isoleucine and O-methyl-N-sulfo-D-serine [68]. The com-
pound demonstrated in vitro cytotoxicity against a panel of
human tumor cell lines (IC50 < 2 µM), including colon carci-
noma HCT116, ovarian carcinoma A2780, and breast carci-
noma SKBR3. Compound was also tested for its ability to
promote or inhibit calf brain tubulin polymerization. Al-
though, compound did not promote tubulin polymerization,
it did inhibit GTP-induced tubulin polymerization 50% at a
concentration of 10 µM.
NO
HN
O
NH
N
O
O
N
NH
O
HN
NH
O
H
N
O
H
NO
N
H
O
H
N
O
O
H2N
O
Callyaerin E
N
O
N
N
OO
N
NH
O
O
NH
H
H
N
O
NO
O
HN N
H
OH
N
O
O
N
H
ONH2
Callyaerin G
N
H
N COOH
O
O
N
N
H
N
H
N COOH
O
O
N
N
H
O
N
H
N COOH
O
O
N
N
H
Milnamide D
Milnamide A
Milnamide C
N
H
N COOH
O
O
HN
N
H
Milnamide B
S
S
NH
N
H
HN
HN
H
NO
HN
O
O
O
O
O
HN
O
NH2
S
S
NH
N
H
HN
HN
H
NO
HN
O
O
O
O
O
HN
O
NH2
Microcionamides A Microcionamides B
Fig. (5).
6 Current Protein and Peptide Science, 2017, Vol. 18 No. 5 Negi et al.
H
H
NN
H
H
NN
H
H
N
O
NH2
O
OH
O
O
O O
O
NH
H
N
SMeO
O
H
N
HN
O
HN
OH Calyxamide A
H
H
NN
H
H
NN
H
H
N
O
NH2
O
OH
O
O
O O
O
NH
H
N
SMeO
O
H
N
HN
O
HN
OH Calyxamide B
NH
O
HN
O
N
O
N
O
HN
H
N
O
O
NH
O
OH
Rolloamide B
N
HO
H
N
O
N
O
N
O
NNH
O
O
N
H
O
N
HO
H
N
O
N
O
N
O
NNH
O
O
N
H
O
Rolloamide A (Minor conformer)
Rolloamide A (Major conformer)
N
NO
N
H
OH
N
O
N
O
O
NH
O
N
O
H
N
O
H2N
N
HO
Kapakahine A
N
NO
NH
O
O
HN O
N
H
O
NH
NH2
O
N
Kapakahine B
N
NO
N
H
OH
N
O
N
O
O
NH
O
N
O
H
N
O
NH
N
HO
Kapakahine C
OH
H
N
NO
N
H
OH
N
O
N
O
O
NH
O
N
O
H
N
O
NH
N
HO
Kapakahine D
OH
H
H
Fig. (6).
3. PEPTIDES FROM ASCIDIANS
A number of cyclic and linear peptides and depsipeptides
with novel structural features have also been discovered in
ascidians usually called tunicates.
One of the important classes of cyclic depsipeptides
isolated from the Caribbean tunicate Trididemnun solidum is
didemnins. Firstly, didemnins were isolated from tunicate
Trididemnum solidum in 1981 [69, 70], but later obtained
from other species of the same genus [71-73]. Until today,
many new members of the didemnin family have been
obtained from the tunicate Trididemnun solidum as well as a
large number of didemnin analogues have been prepared
synthetically or semi-synthetically and evaluated for their
cytotoxic activity [74, 75]. Didemnin B along with some
other promising marine derived anticancer compounds was
examined against human prostatic cancer cell lines (DU145,
PC-3 and LNCaP-FGC) [76]. Didemnin B was found to be
most effective inhibitory agents in the proliferation of
prostate cancer cell than vincristine, vinorelbine or taxol at
concentration levels between 5 and 50 pmol/mL. However,
neurotoxic side effects were also observed at these
concentrations.
NO
HN
O
NH
N
O
O
N
NH
O
HN
NH
O
H
N
O
H
NO
N
H
O
H
N
O
O
H2N
O
Callyaerin E
N
O
N
N
OO
N
NH
O
O
NH
H
H
N
O
NO
O
HN N
H
OH
N
O
O
N
H
ONH2
Callyaerin G
N
H
NN N N
O
O
OCONH2
O
O
O
O
N
HO
H
NMeO
CONH2O
NN
OCONH2
Koshikamide A1
N
H
Me
NN
Me
Me
NN
Me
Me
NN
H
H
N
O
O
O
O
O
O
CONH2O
O
CONH2
MeO
H
N
H
Me
N
CONH2
O
HN
ONH
O
H
H
O
O
O
O
N
H
OCONH2
MeN
H
O
NH
O
H
N
H
NH2NO
O O
HN
NH
OH
O
Koshikamide B
OO
HN
O
N
S
NH
O
O
NH
O
N
OH
O
N
ONHSO3Na
H3CO
Scleritodermin A
Fig. (7).
In the preclinical study, it was observed that didemnin B
exhibit potent dose dependent anticancer activity and
tolerable toxicity which ensured this co mpound to be
evaluated in phase I clinical trials. It was the first compound
from a marine source entering into the clinical trials for
human diseases. In the initial stage of phase I clinical trials
of didemnins different schedules of administration were
evaluated [77-79]. The most commonly reported side effects
were the dose-dependent nausea and vomiting. Based on
potent activity against a variety of cancer cells it underwent
the phase II human clinical trial studies u sing different type
of cancers. Unfortunately, the phase II trials of didemnins B
displayed poor efficacy at the recommended doses with
relatively higher level of toxicity [80-83] and hence further
trials were terminated by National Cancer Institute [84, 85].
Detailed mechanistic study revealed that didemnin B in-
hibited RNA, DNA and proteins synthesis [86, 87]. The
inhibition of protein could be due to the binding of
didemnins to ribosome-EF-1α complex [88, 89]. Moreover,
the activity of FK-506 binding proteins is modulated by
didemnin B as part of its immunomodulatory process leading
to cell death through apoptosis [90]. The experience gained
from the study conducted on didemnins B helped in
designing new molecules which has resulted the discovery of
potent related molecule aplidine.
A second-generation didemnin, namely aplidine
(dehydrodidemnin B) was obtained from the Mediterranean
tunicate, Aplidium albicans [91]. It exhibited potent
cytotoxic activity against various human cancer cell lines
such as lung, breast and melanoma cancers. Aplidine was
Marine Peptides as Antic ancer Agents Current Protein and Peptide Science, 2017, Vol. 18, No. 5 7
found to be more active as compared to didemnin [92].
Aplidine was found to be well tolerated with negligible
toxicity and some side effects such as nausea, asthenia,
vomiting, and hypersensitivity reactions but no
hematological toxicity and no alopecia [93-97]. The phase II
clinical trial studies are underway for renal, head and neck,
and medullary thyroid in Europe and Canada [98-100].
The cell cycle arrest, inhibition of the synthesis of DNA
and protein, and inducing apoptosis of cancer cells are the
main pathways by which aplidine acts on cancer cells [101].
Aplidine leads to apoptosis in MDA-MB-231 breast cancer
cells which causes activation of the epidermal growth factor
receptor (EGFR), the non-receptor protein-tyrosine kinase
Src, and the serine/threonine kinases JNK and p38 MAPK
[102]. Two important mechanisms which are responsible for
the activation of JNK are the rapid activation of Rac1 small
GTPase and down regulation of MKP-1 phosphatase.
Furthermore, aplidine inhibits the enzyme, ornithine
descarboxylase, which is considered as an important enzyme
in the formation and growth of tumor cells [101].
Vervoort et al reported the isolation of two new cytotoxic
depsipeptides, tamandarins A and B from a marine Ascidian
of the family Didemnidae [103]. Tamandarin A was tested
for its cytotoxic activity towards three cancer cell lines: the
pancreatic carcinoma BX-PC3, the prostate carcinoma
DU145 and the head and neck carcinoma UMSCC10b.
Tamandarin A showed a 50% reduction in overall cell sur-
vival (IC50) at a concentration of 1.79, 1.36, and 0.99 ng/mL,
respectively.
A new cytotoxic cyclic heptapeptide, mollamide was iso-
lated from the ascidian Didemnum molle [104]. It showed
anticancer activity against a variety of cancer cell lines such
as human lung carcinoma and human colon carcinoma. Mol-
lamide was active against P388 (murine leukemia) with IC50
value of 1 µg/mL and against A549 (human lung carcinoma),
HT29 (human colon carcinoma) and CV1 (monkey kidney
fibroblast) cell lines with IC50 value of 2.5 µg/mL. It inhib-
ited RNA synthesis, with an IC50 of approximately 1 µg/mL.
Two new mollamides, B and C were isolated from the
Indonesian tunicate Didemnum molle and showed cytotoxic
activity against several cancer cell lines [105]. Mollamide B
was tested against four cancer cell lines viz the non-small
cell lung cancer cell line H460, the breast cancer cell line
MCF7 and the CNS cancer cell line SF-268 at 100 µM. Mol-
lamide B showed significant percentage growth inhibition
and evaluated further in the 60-cell-line panel by the Na-
tional Cancer Institute (NCI). No signif icant activity was
observed against any of the cell lines. At the same time, Mol-
lamide C was tested against two leukemias (murine L1210
and human CCRF-CEM), five solid tumors (murine colon
38, human colon HCT-116, human lung H125, human breast
MCF-7, and human prostate LNCaP), and a murine and hu-
man normal cell (hematopoietic progenitor cell, CFU-GM)
in a disk diffusion assay. Mollamide C showed a unit zone
differential value of 100 against L1210, human colon HCT-
116, and human lung H125 and a value of 250 against mur-
ine colon 38 and was not considered to be solid tumor selec-
tive.
In 1996, Bowden and co-workers isolated trunkamide A
from the colonial ascidian Lissoclinum sp. obtained from the
Great Barrier Reef, Australia [106]. It has shown very prom-
ising cytotoxic activity against P-388 (suspension culture of
a lymphoid neoplasm from DBA-2 mouse), A-549 (mono-
layer culture of a human lung carcinoma), HT-29 (monolayer
culture of a human colon carcinoma and MEL-28 (mono-
layer culture of a human melanoma), with an IC50 values of
0.5, 0.5, 0.5 and 1.0 µg/mL, respectively [107].
N
O
N
NH
OO
O
O
O
NHR
O
O
O
HO NH
OMe
O
NHMe
O
N
O
N
O
N
O
OH
O
OH
Didemnin A
Didemnin B
Didemnin C
R
O
N
H
OH
O
O
N
H
O
O
HN
O
O
NO
O
N
N
O
O
N
O
O
MeO
Aplidine
O
NH
OH O
HN
O
R
O
N
H
O O
O
N
ON
CH3
O
N
N
O
OCH3
O
HO
Tamandarin A; R = CH3
Tamandarin B; R = H
NH
N
N
H
HN
N
HN
O
H
ON
H
O
H
O
H
O
H
O
H
H
H
H
mollamide
NS
H
N
ONH
O
N
O
HN
HN
OO
O
NS
H
N
ONH
O
NH
O
HN
N
OO
O
mollamide B mollamide C
H
N
NH
HN
HN
N
NH
Ph
O
O
O O
O
O
O
O
S
N
Trunkamide A
Fig. (8).
Lissoclinamid es comprise the another family of cyclic
peptides isolated from ascidians Lissoclinum patella which
shows significant anticancer as well as other pharmacologi-
cal properties against human fibroblast and bladder carci-
noma cell lines and normal lymphocytes [108]. Ireland et al
isolated and reported the cytotoxic activity of lissoclinamides
1-3 which displayed moderate cytotoxicity against L1210
cells with IC50 values >10 pg/mL [109].
Further investigation of Lissoclinum patella yielded two
new lissoclinamides, lissoclinamides 4 and 5 [110]. Lissocli-
namide 4 reduced survival in both T24 and MRC5CVl cells
to approximately 5% of the untreated values at 5 pg/mL
(IC50 = 0.8 µg/mL). Interestingly lissoclinamide 5, which
differs from lissoclinamide 4 only by the presence of a thia-
zole instead of a thiazoline ring, is much less cytotoxic.
Hawkins et al isolated two new lissoclinamides from the
same species, lissoclinamides 7 and 8 [111]. The cytotoxicity
of these compounds was tested against bladder carcinoma
cells (T24), SV40-transformed fibroblasts (MRC5CV1) and
normal peripheral blood lymphocytes. Lissoclinamide 7 ex-
8 Current Protein and Peptide Science, 2017, Vol. 18 No. 5 Negi et al.
hibited very potent activity with IC50 values of 0.06, 0.04 and
0.08 µg/mL against (T24), SV40-transformed fibroblasts
(MRC5CV1) and lymphocytes, respectively, while lissocli-
namide 8 showed mild activity IC50 values of 6, 1 and 8
µg/mL, respectively.
HN
NH
N
N
H
O
S
O
N
O
O
O
S
NR1
N
R2
Ulicylamide
R1R2
Lissoclinamide 1
HN
NH
N
N
H
O
S
O
N
O
O
O
S
NR1
N
R2
Lissoclinamide 2
R1R2
Lissoclinamide 3
N
H
S
O
N
O
N
O
HN
N
S
N
N
H
OO
N
H
S
O
N
O
N
O
HN
N
S
N
N
H
OO
Lissoclinamide 4
Lissoclinamide 7
N
H
S
O
N
O
N
O
HN
N
S
N
N
H
OO
Lissoclinamide 5
N
H
S
O
N
O
N
O
HN
N
S
N
N
H
OO
Lissoclinamide 8
Fig. (9).
Vitilevuamide, a bicyclic peptide was isolated from two
marine ascidians, Didemnum cuculiferum and
Polysyncranton lithostrotum [112]. It showed cytotoxic
activity in several human tumor cell lines with LC50 values
ranging from 6 to 311 nM. Vitilevuamide displayed in vivo
activity against P388 lymphocytic leukemia, increasing the
lifespan of leukemic mice 70% at 30 µg/Kg. The LC50 values
of 6 nM, 124 nM, 311 nM, 311 nM were obtained for HCT
116 human colon tumor, A5249 lung cancer, SK Mel-5
malanoma tumor and A498 kidney cancer cell lines,
respectively. An LC50 value of 3.1 µM was obtained for
CHO cells treated with zitilevuamide for only 1 h instead of
72 h. Vitilevuamide inhibits tubulin polymerization and can
arrest the cell cycle of target cells in the G2/M phase. Viti-
levuamide shows non-competitive inhibition of vinblastine
binding to tubulin. It also affects the GTP binding, suggest-
ing the possibility that vitilevuamide inhibits tubulin polym-
erization via an interaction at a unique site.
Three cyclic peptides, patellamides A-C comprising of
fused oxazoline-thiazole units were isolated from Lisso-
clinum patella collected at Eil Malk Island, Palau Islands
[113]. Patellamides A, B and C exhibited approximately
equal activities against L1210 murine leukemia cells with
IC50 values of 3.9, 2.0 and 3.2 µg/mL, respectively. In addi-
tion, Patellamide A also inhibited the human ALL cell line
(T cell acute leukemia) CEM with IC50 values of 0.028
µg/mL.
Patellamide D, E and F have been isolated from the as-
cidian Lissoclinum patella [114-116]. Patellamide D showed
marginal cytotoxicity against lymphocytic leukemia cells
(PS) with ED50 value 11 µg/mL. Patellamide E was weakly
cytotoxic (IC50 = 125 µg/mL) against human colon tumor
cells in vitro. Patellamide F showed a LC50 value of 13 µM
in NCI 60 human tumor cell line panel.
Further investigation of the extracts of Lissoclinum pa-
tella collected in Pohnpei, Federated States of Micronesia
yielded a new analogue, Patellamides G along with the
known compounds, patellamides A, B, and C [117]. All the
compounds were evaluated for anti-MDR activity ag ainst
vinblastine-resistant CCRF-CEM human leukemic lym-
phoblasts. The IC50 for vinblastine against the drug resistant
cells (CEM/VBL100) was found to be 90 nM, whereas in the
presence of 2.5 µg/mL concentration of patellamides A-C
and patellamides G, the IC50 values for vinblastine was 90,
12, 12 and 60 nM, respectively. Thus Patellamides B and C
exhibited in vitro modulation of multidrug resistance in
CEM/VBL100 cells and reduced drug resistance about eight-
fold.
NH
N
H
HN
H
N
O
S
N
O
N
O
O
N
S
N
O
O
Patellamide B
Patellamide C
NH
N
H
HN
H
N
O
S
N
O
N
O
O
N
S
N
O
O
N
O
NH
HN
O
O
O
O
NH
OH
O
O
HN
O
HN
O
NH
N
NH
O
O
Ph
HN
O
O
OH
S
HN
NH
O
O
O
H
N
HO
N
H
O
O
Ph
Vitilevulamide
NH
N
H
HN
H
N
O
S
N
O
N
O
O
N
S
N
O
O
Patellamide A
N
H
O
N
S
O
N
NH
O
S
NH
N
O
O
N
HN
H
O
Patellamide D
N
H
O
N
S
O
N
NH
O
S
NH
N
O
O
N
HN
H
O
Patellamide E
HN
O
NS
O
N
NH
O
SN
NH
O
O
N
H
N
H
O
Patellamide F
HN
O
NS
N
H
NH
O
S N
NH
O
O
NHN
H
O
OH
O
Patellamide G
Fig. (10).
4. ANTICANCER MARINE PEPTIDES FROM
MULLUSKS
Several cytotoxic cyclic peptides such as solastatins, kha-
lalides and others have also been found in mollusks.
Dolastatins are a group of cyclic and linear peptides iso-
lated from the mar ine mollusk Dolabella auricularia. In
1981, Pettit et al isolated a series of these compounds, Do-
lastatin 1-9 from Dolabella auricularia [118]. All of these
compounds exhibited very promising anticancer activity be-
ing Dolastatin 1 the most active one. It was found to cause an
88% life extension (at a dose 11 µg/kg) with the murine
P388 lymphocytic leukemia and found to afford a curative
response (33%) with a dose of 11 µg/kg (with T/C 240 to
T/C 139 at 1.37 µg/mL) against the murine B16 melanoma.
Thereafter, a new and exceptionally potent analogue, Do-
lastatin s 10 was isolated from Dolabella auricularia [119]. It
Marine Peptides as Antic ancer Agents Current Protein and Peptide Science, 2017, Vol. 18, No. 5 9
was the most active antineoplastic compound till date and
was found to show a 17-67% curative response at 3.25-26
µg/Kg against the NCI human melanoma xenograph (nude
mouse), 42-1 with 38% life extension at 1.44-11.1 µg/Kg
using the B16 melanoma, and 69-102% life extension at 1-4
µg/kg against the PS leukemia (ED50 of 4.6×105 µg/mL).
Later on many analogues of Dolastatins were isolated from
the same mollusk [120-122]. Most of the compounds of this
series inhibit cell proliferation and induce apoptosis in vari-
ous malignant cell and cancer cell lines [123]. In addition to
this, dolastatins also exhib ited synergistic antitumor activity
with tubulin interactive agent’s vinca alkaloids and bry-
ostatin-1 [124, 125].
Based on the initial screening Dolastatins 10 and 15 were
selected for more detailed analyses in the full 60 cell line
screen [126, 127]. The panel average GI50 for dolastatin 10
was in the 0.1 nanomolar range, while individual cell lines
were 3-10 fold more sensitive than the panel average. Dolas-
tatin 15 was somewhat less potent with panel average GI50 in
the 1 nanomolar range. Dolastatin 10 has also shown the
ability to prevent tubulin polymerization, whereas dolastatin
15 relatively weak but still a very strong inhibitor of mitosis.
Because of its good preclinical activity profile, dolastatin 10
was selected for the phase I clinical trials [128].
Bai et al reported that dolastatin 10 inhibits the growth of
L1210 murine leukemia cells [129]. Dolastatin 10 induces
apoptosis associated with a decrease in Bcl-2 level and an
increase in p53 expression in the lymphoma cell line [130].
In addition to this it inhibits microtubule assembly, and tubu-
lin-dependent GTP hydrolysis also. Dolastatin 15 induces
apoptosis of myeloma cells via activation of both mitochon-
drialand Fas (CD95)/Fas-L (CD95-L)-mediated pathways
[131].
Recently, Pettit et al synthesized auristatin TP, a tyra-
mide phosphate modification of dolastatin 10 and aminoqui-
noline (AQ) auristatin conjugates auristatin-2AQ and aur-
istatin-6AQ [132]. Each of the new auristatins displayed very
strong cancer cell growth inhibition against a panel of mur-
ine and human cancer cell lines. Compounds auristatin-TP
(b), auristatin-TP (c), auristatin-2AQ and auristatin-6AQ
were evaluated against the murine P388 lymphocytic leuke-
mia cell line and showed excellent activity. Auristatins-TP
(b), auristatin-2AQ and auristatin-6AQ were also tested
against several human cancer cell lines such as lung (NCI-
H460), colon (KM20L2), prostate (DU-145), pancreas
(BXPC-3), breast (MCF-7), CNS (SF-268) and displayed
very strong activity, especially compounds auristatin-TP (b)
and auristatin-6AQ in pico molar range. These in vitro data
were quite comparable to those of dolastatin 10 which had
GI50 values in the range 10-2-10-3 nM against similar human
cell lines.
More recently, Gajula et al have synthesized eight ana-
logues (D1-D8) of dolastatin 10 containing several unique
amino acid subunits [133]. All eight compounds (D1-D8)
inhibited the proliferation of HeLa cell lines but compounds
D1, D2, D3 and D5 were found to be more active with IC50
values of 8.7±0.3, 8.8±0.3, 9.9±0.4, and 6.8±0.2 nM, respec-
tively. Moreover, D5 inhibited th e proliferation of HeLa,
MDA-MB-231, and MCF-7 cells in culture with IC50 values
of 6.8±0.2, 13±5, and 15±7 nM, respectively. Furthermore,
these compounds were evaluated for their inhibitory activ ity
of tubulin polymerization. The 19, 21, 10, and 37 % inhibi-
tion was observed for the compounds D1, D2, D3 and D5,
respectively. D5 bound to purified tubulin with a dissociation
constant of 29.4±6 µM, indicating that it binds to tubulin
with low affinity. D5 perturbed microtubules of both inter-
phase and mitotic cells; however, the depolymerizing effect
of D5 on microtubules was more pronounced in the mitotic
cells as compared to that of the interphase cells. D5 in-
creased the accumulation of checkpoint proteins BubR1 and
Mad2 at the kinetochoric region and caused G2/M block in
these cells. The blocked cells underwent apoptosis with the
activation of Jun N-terminal kinase. These results suggested
that D5 exerts its antiproliferative action by inhibiting micro-
tubule dynamics.
N
H
NNN
O
O
O O O O
H
N
H
S N
Dolastatin 10
N
H
NNN
O
O
O
Dolastatin 15
O
N
O
O
O
O
O
N
H
NNN
O
O
O
H
O
NH
O
Auristatin-TP
OPOR2
OOR1
(a), R1 = R2 = Li+; (b), R1 = R2 = Na+
(c), R1 = R2 = K+; (d), R1 = R2 = H, morpholine
(e), R1 = R2 = H, quinine; (f), R1 = R2 = H, TRIS
(g), R1 = R2 = H, serine; (h), R1 = R2 = H, nitroarginine
N
H
NNN
O
O
O
H
OON
Auristatin 2-AQ
N
H
NNN
O
O
O
H
OO
N
Auristatin 6-AQ
O
O
O
R
N
HN
N
HN
O
HN
O
O
O
O
N
S
H3CO
H3CO
R
N
HN
N
HN
O
HN
O
O
O
N
S
H3CO
H3CO
D3; R = H
D4; R = Me
O
O
D1; R = H
D2; R = Me
H
N
HN
N
HN
O
HN
CH3
O
O
O
H3CO
H3CO
D5; 2S
D6; 2R
OCH3
H
N
HN
N
HN
O
HN
CH3
O
O
O
H3CO
H3CO
D7; 2S
D8; 2R
OCH3
2
OO
Fig. (11).
A number of Kahalalides have been isolated from the sa-
coglossan mollusk Elysia rufescens. Kahalalides A-F were
obtained from the sacoglossan mollusk Elysia rufescens,
whereas kahalalide G was isolated from the diet of the ani-
mal, a green algae Bryopsis sp [134, 135]. Further analysis of
the mo lluskan extract revealed two new acyclic peptides,
kahalalide H and kahalalide J [136]. Kahalalide F was found
to be most active peptide in the series and showed good level
of activity against A-549, HT-29, LOVO, P-388 and KB
with IC50 values of 2.5, 0.25, <1.0, 10 and >10 µg/mL, re-
spectively.
In 2006, two new kahalalide analogues, kahalalides R
and S were isolated from E. grandifolia along with two
known congeners, kahalalides F and D, and examined for
their cytotoxicity tow ards L1578Y, HeLa and PC12 cancer
cell lines [137]. Kahalalide R was found to exert comparable
10 Current Protein and Peptide Science, 2017, Vol. 18 No. 5 Negi et al.
or even higher cytotoxicity than kahalalide F toward the
MCF7 human mammary carcinoma cell line. Kahalalides F
and R showed comparable cytotoxic activity towards MCF7
cells with IC50 values of 0.22 and 0.14 µmol/L, respectively.
Kahalalides S was less cytotoxic in MCF7 cell lines with
IC50 value 3.55 µmol/L, respectively. Kahalalide R displayed
cytotoxic toward the mouse lymphoma L1578Y cell line
with IC50 value of 4.28 nmol/mL nearly identical to that of
kahalalide F, with an IC50 4.26 nmol/mL, whereas both the
compounds were found to be inactive toward HeLa, H4IIE,
and PC12 cancer cell lines.
HN
H
NN
H
H
N
O
O
O
OO
O
H
N
OH
N
H
O
O
O
HN
HO
Kahalalide A
HN
H
N
N
H
H
N
O
O
O
O
O
O
H
N
N
H
O
O
O
N
HO
Kahalalide B
HN
H
NN
H
H
N
O
O
O
O
O
H
N
O
O
O
NH
Kahalalide C
HO
OH
N
H
NH2
HN
O
N
O
N
H
H
N
O
O
H
N
O
N
H
Kahalalide D
O
H
NN
H
H
N
O
OO
N
H
N
O
O
O
N
H
O
HN
Kahalalide E
NH
NH2
Fig. (12).
Rocha et al. examined the mode of action of kahalalide F
(KF) and it was found to interact with cellular lysosomes that
might lead to intracellular acidification and cell death. These
results suggested that cells with high lysosomal activity,
such as prostate cancer cells, would probably a suitable can-
cer cells to explore the activity of this peptide [138]. Several
other mechanisms of action have also been proposed for the
antitumor activity of KF, such as inhibition of the erbB2
tyrosine kinase activity, inhibition of transforming growth
factor-α (TGFα) gene expression, cell cycle block in the G0
G1 stage, and blockage of epidermal growth factor (EGF)
receptors [139-141]. In addition, KF induces non-p53-
mediated apoptosis without causing damage to DNA, and a
selective cytotoxic effect on neu+ cells overexpressing Her2
without inhibiting autophosphorylation or MEK kinase activ-
ity [142].
Kahalalide F exhibits potent in vitro cytotoxic activity
against various cell lines such as prostate, breast, colon car-
cinomas, neuroblastoma, chondrosarcoma, and osteosarcoma
with IC50 ranging from 0.07 mM (PC3) to 0.28 mM (DU145,
LNCaP, SKBR-3, BT474, MCF7). Importantly, non-tumo r
human cells such as MCF10A, HUVEC, HMEC-1, and
IMR90 were found to be 5-40 times less sensitive to the drug
(IC50 = 1.6-3.1 µM) [142].
Sewell et al investigated the cytotoxicity of KF on a
panel of hepatoma cell lines and compared it with other cell
lines from breast, ovary, prostate and colon cancers [143].
They took two hepatoma cell lines, KF-sensitive HepG2
(IC50 = 0.3 µM) and KF-resistant PLC/PRF/5C (IC
50 = 5
µM) in order to identify the key elements of KF-induced cell
death. KF induced extensive cell swelling and blebbing in
both the cell lines. These cellular changes were associated
with ATP depletion in a concentration-dependent fashion in
both HepG2 and PLC/PRF/5C cells but the depletion was
slower in case of PLC/PRF/5C cells. Important membrane
alterations were also observed in HepG2 cells after treatment
with KF. It increased permeablity to propidium iodide (PI)
and large molecules such as annexin V and LDH. Con-
versely, the permeability of PLC/PRF/5C cells was limited
to PI w ithout permeation to AV or release of LDH unless
high concentrations of KF were used (>10 µM).
O
NH
N
H
O
O
NH O
H
N O
HN
O
NH
O
O
NH
NO
NH H
NHN
OH
N
O
NH
O
O
Kahalalide F
O
O
ONH
N
H
O
HO
NH O
H
NO
HN
O
NH
O
ONH
NO
NH
O
H
NHN
HO
O
H
N
O
NH
O
O
Kahalalide G
HO
H
NN
H
N
HN
O
O
OH OO NH
HO
HN
O
HN O
O
OH
O
HN O
OH
O
HO
OH
Kahalalide H
H
NN
H
N
HN
O
O
OH OO NH
HO
HN
O
HN O
H
N
O
HN O
OH
O
HO
OH
Kahalalide J
O
OHO
NH2
Kahalalides R; R = H
Kahalalides S; R = OH
O
H2NH2N
N
HN
NH
HN
NH
HN
O
O
O
O
O
O
O
N
H
O
HN
O
H
N
ON
H
O
OH
NH3
OHN O
HN
O
H
N
O
F3CO
O
Elisidepsin
O
HN
N
H
HN O
O
O
HN
HN
O
H2N
N
O
HN
O
NH
OO
O
NH
H
N
O
O
HN
O
NH
O
HN O
NH
HO
OO
R
Fig. (13).
KF was licensed to PharmaMar by University of Hawaii
in the 1990s, and preclinical studies were conducted. On
successful completion of preclinical studies in December
2000 this compound entered in phase I clinical trials in
Europe for the treatment of androgen independent prostate
cancer [144]. Kahalalide F exhibited good activity profile
and low toxicity with few side effects such as fatigue, head-
ache, vomiting etc in phase I clinical trial studies. Thus kaha-
lalide F results show promising results in phase I clinical
trial alone or with other anticancer agents [145] and dis-
played no hematological toxicity, suggesting further clinical
testing either as a single agent or in combination. Currently,
this compound is undergoing phase II clinical trials for the
treatment of lung and prostate cancers, and melanoma [146].
Marine Peptides as Antic ancer Agents Current Protein and Peptide Science, 2017, Vol. 18, No. 5 11
Elisidepsin (PM02734) is a synthetic marine-derived cy-
clic peptide of the Kahalalide F family and is currently being
evaluated in phase I/II clinical trials [147]. PM02734 is a
potent cytotoxic agent both in vitro and in vivo in human
nonsmall-cell lung cancer (NSCLC) cell lines. Preclinical
studies have shown strong activity of KF against cell lines
and tumor specimens derived from different human solid
tumors, including non-small cell lung cancer (NSCLC), pros-
tate, breast, ovarian, and colon carcinomas.
Ling et al examined the cytotoxic activity of PM02734
(elisidepsin) against human H322 and A549 NSCLC cell
lines and observed that it did not cause nuclear
fragmentation, PARP cleavage, or caspase activation which
suggests that classical apoptosis is not the mechanism of
action of this compound [147,148]. In contrast, PM02734-
induced cell death was associated with several features of
autophagy, impaired autophagy clearance, inhibition of the
Akt/mTOR pathway, and activation of death associated
protein kinase (DAPK). In vivo, PM02734 effectively
inhibits A549 tu mor growth in association with induction o f
autophagy without causing significant toxicity.
Recent studies have revealed a direct correlation between
elisidepsin sensitivity and the expression of the ErbB3
receptor in a panel of NSCLC and other cell lines [149].
Treatment with Elisidepsin induced down-regulation of
ErbB3 protein expression in most cell lines. Furthermore,
elisidepsin was more effective in the induction of ErbB3
dephosphorylation and degradation than that of ErbB2
(HER2) and ErbB1 (EGFR) in human NSCLC cell lines.
Recently, Serova et al examined the cytotoxicity of elis-
idepsin in a panel of 23 human cancer cell lines and corre-
lated with mutational state, mRNA and protein expression of
selected genes [150]. Elisidepsin showed potent cytotoxic
activity in all the cancer cell lines with IC50 values ranging
from 0.4 to 2 µM. Elisidepsin was found to be more active in
cells harboring epithelial phenotype with high E-cadherin,
ErbB3, Muc1 expression, whereas the presence of KRAS
activating mutations was associated with resistance to this
compound. Combinations of elisidepsin with lapatinib and
several chemotherapies including 5-FU and oxaliplatin re-
sulted in synergistic effects that offer the potential of clinical
use of elisidepsin in combination settings.
5. PEPTIDES FROM CYANOBACTERIA
Cyanobacteria have been a source of bioactive marine
peptides. The compounds isolated from cyanobacteria have
widely been studied for their cytotoxic effects [151].
Leusch and Moore et al isolated a new cyclodepsipep-
tide, apratoxin A from the marine cyanobacterium Lyngbya
majuscule [152]. This compound showed very promising
cytotoxic activity against the LoVo and KB cancer cell lines
with IC50 values of 0.36 and 0.52 nm, respectively. However,
it was moderately active in vivo against a colon tumor and
ineffective against a mammary tumor. Apratoxin A was
poorly tolerated in mice, probably due to its intrinsic toxicity
to normal cells and lack of selectivity for tumor cell lines.
Preliminary studies suggested that apratoxin A neither af-
fects microtubule polymerization dynamics nor topoi-
somerase I. Further biological analysis revealed that
apratoxin A inhibits cell proliferation by causing cell cycle
arrest in the G1 phase [153].
Subsequently additional analogues of apratoxin A
namely, apratoxin B and apratoxin C were isolated from the
two collections of Lyngbya sp. made in Guam and Palau in
2002 [154]. Both, apratoxins B and C exhibited low
cytotoxicity than apratoxin A. In 2008, apratoxin D was
obtained form an extracts of the Papua New Guinea marine
cyanobacteria Lyngbya majuscule and Lyngbya sordid [155].
Apratoxin D displayed potent in vitro cytotoxic activity
against H-460 human lung cancer cells with IC50 value of 2.6
nM.
A new apratoxin class of cytotoxins, apratoxin E was
obtained from the marine cyanobacterium Lyngbya
bouillonii from Guam [156]. Apratoxin E displayed strong
cytotoxic activity against several cancer cell lines such as
HT29 colon adenocarcinoma, HeLa cervical carcinoma, and
U2OS osteosarcoma cells with IC50 value of 21, 72 and 59
nM, respectively.
In 2010, two new and highly potent analogues, apratoxin
F and G have been isolated form collection of Lyngbya
bouillonii made in Palmyra Atoll [157]. Both the compounds
were tested against H-460 and HCT-116 cancer cell lines.
IC50 value of 2 and 14 nm was observed for apratoxin F and
G against H-460 and apratoxin, whereas IC50 value of 36.7
nm was observed against HCT-116 cancer cell line for
apratoxin G.
A marine cyanobacterium Lyngbya majuscula collected
from Papua New Guinea led to the isolation of aurilides B
and C [158]. Both aurilides B and C showed in vitro
cytotoxicity toward NCI-H460 human lung tumor and the
neuro-2a mouse neuroblastoma cell lines. Aurilide B was
approximately 4-fold more active than aurilide C towards
these cell lines. The LC50 for aurilide B was 0.01 and 0.04
µM for neuro-2a and H460 cells, respectively, and 0.05 and
0.13 µM for aurilide C. Based on these results, aurilide B
was further evaluated in the NCI 60 cell line panel and found
to exhibit a high level of cytotoxicity (mean panel GI50
concentration < 10 nM) and to be particularly active against
leukemia, renal, and prostate cancer cell lines. In the
microfilament disruption assay, aurilide B induced loss of
the microfilament network in A-10 smooth muscle cells at
2.9 µM.
Lyngbyabellin A was isolated from the marine
cyanobacterium Lyngbya majuscula [159]. Lyngbyabellin A
showed moderate cytotoxicity against KB cells (a human
nasopharyngeal carcinoma cell line) and LoVo cells (a
human colon adenocarcinoma cell line), with IC50 values of
0.03 µg/mL and 0.50 µg/mL, respectively. While testing in
in vivo system it was found to be toxic to mice. The lethal
dose varied from 2.4 to 8.0 mg/kg. Lyngbyabellin A was
shown to be a potent disrupter of the cellular microfilament
network in A-10 cells at a concentration of 0.01-5.0 µg/mL
[160].
In the same year, lyngbyabellin B along with
lyngbyabellin A was isolated from the marine
cyanobacterium Lyngbya majuscula collected from at Apra
Harbor, Guam and near the Dry Tortugas National Park,
Florida [161]. Lyngbyabellin B is slightly less cytotoxic in
12 Current Protein and Peptide Science, 2017, Vol. 18 No. 5 Negi et al.
vitro than lyngbyabellin A with IC50 values of 0.10 and 0.83
µg/mL against KB and LoVo cells, respectively.
H
N
N
N
O
S
O
O
N
R1N
OO
O
OH
R2
O
Apratoxin A; R1 = Me, R2 = Me
Apratoxin B; R1 = H, R2 = Me
Apratoxin C; R1 = Me, R2 = H H
N
N
N
O
S
O
O
NN
OO
O
O
Apratoxin E
H
N
N
N
O
S
O
O
NN
OO
O
OH
O
Apratoxin D
H
N
N
N
O
S
O
O
NN
OO
O
OH
O
Apratoxin F
H
N
N
N
O
S
O
O
NN
OO
O
OH
O
Apratoxin G
O
O
NH
OH O O
N
O
NH
O
N
O
O
N
O
O
O
NH
OH O O
N
O
NH
O
N
O
O
N
O
O
O
NH
OH O O
N
O
NH
O
N
O
O
N
O
Aurilide Aurilide CAurilide B
Fig. (14).
Two new analogues, lyngbyabellin C [162] and
lyngbyabellin D [163] were isolated from cyanobacterium
Lyngbya sp. Lyngbyabellin C exhibited IC50 values of 2.1
µM against KB and 5.3 µM against LoVo cells.
Lyngbyabellin D displayed an IC50 value of 0.1 µM against
the KB cell line.
Five new lyngbyabellin analogs, lyngbyabellins EI were
isolated from the marine cyanobacterium Lyngbya majuscule
[164]. All five lyngbyabellins showed cytotoxicity to NCI-
H460 human lung tumor and neuro-2a mouse neuroblastoma
cell lines with LC50 values between 0.2 and 4.8 µM.
Lyngbyabellin E and H were found to be more active against
the H460 cell line with LC50 values of 0.4 and 0.2 µM,
respectively, compared to LC50 values of 1.2 and 1.4 µM in
the neuro-2a cell line. Lynbyabellin I showed the most
potent activity towards neuro-2a cells (LC50 0.7 mM).
Lyngbyabellin G was the least active compound among all
the lyngbyabellins with LC50 values of 2.2 and 4.8 µM
against H460 and neuro-2a cells, respectively.
Two new cyclic hexapeptides, venturamide A and B were
obtained from the marine cyanobacterium Oscillatoria sp.
venturamides A and B exhibited mild activity when tested
against MCF-7 cancer cells with IC50 value of 13.1 and > 54
µM, respectively [165].
O
O O OCl Cl
S
N
NS
HN
O
O
N
H
HO
Lyngbyabellin B
O
O O OCl Cl
S
N
NS
HN
O
O
N
H
H
HO
Lyngbyabellin A
O Cl
O O OCl
S
N
NS
O
O
HO
Lyngbyabellin C
OH
O
O
O
O
Cl
Cl
S
N
N
S
O
O
HO
MeO
Lyngbyabellin D
HO
O
O
HN
O
O
OO
O
O
S
N
N
S
O
O
OH
R
Lyngbyabellin F; R = OH
Lyngbyabellin I; R = H
O
H
N
O
O
O
O
O
Cl
O O OCl
S
N
NS
O
O
HO
Lyngbyabellin G
OH
OO
O
O
S
N
N
S
O
O
R
Lyngbyabellin E; R = OH
Lyngbyabellin H; R = H
O
O
H
N
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Fig. (15).
A cyclic depsipeptide, pitiprolamide was isolated from
the marine cyanobacterium Lyngbya majuscule collected at
Piti Bomb Holes, Guam [166]. Pitiprolamide showed weak
cytotoxic activity against HCT116 colorectal carcinoma and
MCF7 breast adenocarcinoma cell lines (IC50 33 µM for
both).
A cyclic depsipeptide, Coibamide A was isolated from
the marine cyanobacterium Leptolyngbya sp [167].
Coibamide A displayed potent cytotoxicity to NCI-H460
lung cancer cells and mouse neuro-2a cells (LC50 < 23 nM).
It does not interfere with tubulin or actin in cytoskeletal
assays. Flow cytometric studies showed that Coibamide A
causes a significant dose dependent increase in the number
of cells in the G1 phase of the cell cycle with little change in
G2/M and a loss of cells in S phase. Coibamide A was
further evaluated against the NCI 60 cancer cell lines and
exhibited potent activity and high selectivity towards certain
cancer cell lines. Coibamide A showed highest potency
(GI50) towards MDAMB-231 (2.8 nM), LOX IMVI (7.4
nM), HL-60(TB) (7.4 nM) and SNB-75 (7.6 nM), and good
histological selectivity for breast, CNS, colon and ovarian
cancer cells.
Seven new cyclic depsipeptides, veraguamides A-G were
obtained from cyanobacterium Symploca cf. hydnoides
collected from Cetti Bay, Guam [168]. These compounds
were evaluated for their cytotoxic activity against HT29
colorectal adeno carcinoma and HeLa cervical carcinoma cell
lines. All the compounds showed moderate to weak activity.
Veraguamides D and E were found to be more active than
the other derivativ es with IC50 value of 0.84, 1.5 µM against
HT29, respectively and 0.54, 0.83 µM against HeLa,
respectively.
6. ANTICANCER PEPTIDES FROM FUNGI
Marine derived fungi are also a rich source of structurally
diverse and biologically active secondary metabolites.
Marine Peptides as Antic ancer Agents Current Protein and Peptide Science, 2017, Vol. 18, No. 5 13
NH
O
N
O
N
O
N
O
O
O
N
ONH
O
O
O
Pitiprolamide
N
H
O
N
S
O
N
NH OHN
S
N
O
Venturamide B
OH
N
H
O
N
S
O
N
NH OHN
S
N
O
Venturamide A
NN
O
R6
O
O
R1
N
H
O
N
OR3
R5
R4
O
O
R2
O
Veraguamide A; R1= , R2 = H, R3 = H, R4 = Et, R5 = Me, R6 = H
Veraguamide B; R1= , R2 = H, R3 = H, R4 = Me, R5 = Me, R6 = H
Veraguamide C; R1= , R2 = H, R3 = H, R4 = Et, R5 = Me, R6 = H
Veraguamide D; R1= , R2 = H, R3 = H, R4 = Et, R5 = Me, R6 = Me
Veraguamide E; R1= , R2 = Me, R3 = Me, R4 = Et, R5 = Me, R6 = H
Veraguamide F; R1= , R2 = H, R3 = H, R4 = Ph, R5 = H, R6 = H
Veraguamide G; R1= , R2 = H, R3 = H, R4 = Et, R5 = Me, R6 = H
Br
Br
N
NH
N
N
N
H
N
O
O
O
H
O
OO
O
O
H
N
O
NN
O
O
ON
O
O
O
O
Coibamide A
Veraguamide A-G
Fig. (16).
Scopularide A and B, cyclic depsipeptides were obtained
from marine fungi Scopulariopsis brevicaulis, which was
isolated from the marine sponge Tethya aurantium [169].
Both the compounds significantly inhibited the growth of
several cancer cell lines. Scopularide A inhibited the growth
of Colo357, Panc89 (pancreatic tumor cells), and HT29 (co-
lon tumor cells) by 36, 42 and 37%, respectively at 10
µg/mL concentration, whereas Scopularide B at the same
concentration inhibited the growth by 26, 49 and 24%, re-
spectively.
Cordyheptapeptide A was isolated from the insect
pathogenic fungus Cordyceps sp. BCC 1788 [170]. Isaka et
al has also reported the isolation of cordyheptapeptides B
along with cordyheptapeptides A from the same fungus
Cordyceps sp. but different strain BCC 16176 [171].
Cordyheptapeptide A and B exhibited potent cytotoxic
activity against KB (oral human epidermoid carcinoma), BC
(human breast cancer), NCI-H187 (human small cell lung
cancer) and Vero (African green monkey kidney fibroblasts)
cell lines with IC50 values of 0.78, 0.20, 0.18, 14 µM and 2.0,
0.66, 3.1, 1.6 µM, respectively.
Three new cycloheptapeptides, cordyheptapeptides CE,
were isolated from the fermentation extract of the marine-
derived fungus Acremonium persicinum SCSIO 115 [172].
These three compounds were evaluated for their cytotoxic
activities against human gliob lastoma (SF-268), human
breast cancer (MCF-7) and human lung cancer (NCI-H460)
cell lines. Cordyheptapeptide E was found to be the most
potent out of three showing IC50 values of 3.2, 2.7, and 4.5
µM against SF-268, MCF-7 and NCI-H460, respectively.
Cordyheptapeptide C also disp layed significant activity
against SF-268 and MCF-7 and NCI-H460 cells with IC50
values of 3.7, 3.0 and 11.6 µM, respectively, while
cordyheptapeptide D exhibited mild activity against all the
three cancer cell lines.
A new cyclic tetrapeptide, asperterrestide A, was isolated
from the fermentation broth of the marine-derived fungus
Aspergillus terreus SCSGAF0162 [173]. It was tested for its
cytotoxicity towards human leukemic monocyte lymphoma
U937, erythroid leukemic K562, gastric carcinoma BGC-
823, acute lymphoblastic leukemia MOLT-4, breast
adenocarcinoma MCF-7, and lung carcinoma A549 cell
lines. The IC50 values of 1.9, 4.9, 3.5, 1.8, 5.0, and 3.6 nM
were obtained for U937, K562, BGC-823, MOLT-4, Mcf7,
and A549 cell lines, respectively.
Two new cyclic tetrapeptides, microsporins A and B,
were isolated from culture extracts of the marine-derived
fungus Microsporum cf. gypseum obtained from a sample of
the bryozoan Bugula sp. collected in the U.S. Virgin Islands
[174]. Both the compounds were evaluated for cytotoxic
activity against human colon adenocarcinoma (HCT-116), as
well as against the National Cancer Institute 60 cancer cell
lines. Microsporin A showed in vitro cytotoxicity against
HCT-116 with IC50 value 0.6 µg/mL, and a mean IC50 value
of 2.7 µM in the NCI 60 cell lines. Microsporin B showed
reduced in vitro cytotoxicity against HCT-116 (IC50 8.5
µg/mL). Both the compounds were also found to be potent
inhibitor of histone deacetylase.
HN
HN
N
H
H
N
NH
O
O
O
O
H
O
H
OO
H
R
Scopularide A; R = Et
Scopularide B; R = H
H
H
N
NH
O
O
HN
O
N
O NH
N