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REVIEW PAPER
Cyanobacteria: potential candidates for drug discovery
Rakhi Bajpai Dixit M. R. Suseela
Received: 7 December 2012 / Accepted: 28 February 2013 / Published online: 27 March 2013
Springer Science+Business Media Dordrecht 2013
Abstract Cyanobacteria are a rich source of vast
array of bioactive molecules including toxins with
wide pharmaceutical importance. They show varied
bioactivities like antitumor, antiviral, antibacterial,
antifungal, antimalarial, antimycotics, antiprolifera-
tive, cytotoxicity, immunosuppressive agents and
multi-drug resistance reversers. A number of tech-
niques are now developed and standardized for the
extraction, isolation, detection and purification of
cyanobacterial bioactive molecules. Some of the
compounds are showing interesting results and have
successfully reached to phase II and phase III of
clinical trials. These compounds also serve as lead
compounds for the development of synthetic ana-
logues with improved bioactivity. Cyanobacterial
bioactive molecules hold a bright and promising
future in scientific research and great opportunity for
drug discovery. This review mainly focuses on
anticancerous, antiviral and antibacterial compounds
from cyanobacteria; their clinical status; extraction
and detection techniques.
Keywords Bioactive molecules Anticancerous Antiviral Antimicrobial Clinical trials Extraction methods
Introduction
Cyanobacteria are a group of photosynthetic prokary-
otes and are among the most successful and oldest life
forms present on earth (Gademann and Portmann
2008; Bajpai et al. 2010). They represent an excep-
tionally diverse but highly specialized group of micro-
organisms adapted to various ecological habitats.
They can be found in terrestrial, glaciers, aerial,
marine, brackish and fresh water environments. Cya-
nobacteria are often a main component of phytoplank-
ton in many freshwater and marine ecosystems.
Cyanobacteria produce one or a range of bioactive
compounds, which are potentially rich source of a vast
array of products with applications in feed, food,
nutritional, cosmetic, pharmaceutical and neutraceu-
tical industries (Tan 2007). Due to their high chemical
stability and water solubility, these compounds have
important implications. They have a bright future in
scientific research and for human welfare.
According to World Health Organisation (WHO),
approximately 80 % of the world population depends
on traditional remedies for their primary health care
needs. Since, thousands of years natural products have
been found to be used for treating various diseases and
they form a major milestone for modern therapeutics.
In the microbial world, especially cyanobacteria are
prolific producers of secondary metabolites, many of
which show various biological activities or bioactiv-
ity. Gerwick et al. (2008) found that secondary
metabolites are mostly isolated from the members of
R. B. Dixit (&) M. R. SuseelaAlgology Section, CSIR-National Botanical Research
Institute, Lucknow 226001, Uttar Pradesh, India
e-mail: [email protected]
123
Antonie van Leeuwenhoek (2013) 103:947961
DOI 10.1007/s10482-013-9898-0
-
oscillatoriales (49 %), followed by nostocales (26 %),
chroococcales (16 %), pleurocapsales (6 %) and
stigonematales (4 %). Cyanobacteria such as Ana-
baena, Nostoc, Microcystis, Lyngbya, Oscillatoria,
Phormidium and Spirulina produce variety of high
value compounds such as carotenoids, fatty acids,
lipopeptides, polysaccharides and other bioactive
compounds. Apoptogenic activity was more abundant
in the genera Anabaena and Microcystis compared to
Nostoc, Phormidium, Planktothrix, and Pseudoanaba-
ena (Oftedal et al. 2011). Interestingly synthesis of
these biomolecules remains an enigma and unresolved
puzzle to the scientific world.
A majority of these biomolecules are peptides and
are synthesized by large multimodular nonribosomal
polypeptide (NRPS) or mixed polyketide (PKS)-
NRPS enzymatic systems (Schwarzer et al. 2003). In
aquatic environments, these metabolites usually
remain within the microbial cells and are released in
substantial amounts on cell lysis (Chorus and Bartram
1999). Richard E. Moore (1970s to early 2000s),
revealed that the marine cyanobacteria are an excep-
tionally rich source of secondary metabolites (Car-
dellina and Moore 2010). Cyanobacterial secondary
metabolites includes different compounds like cyto-
toxic (41 %), antitumor (13 %), antiviral (4 %),
antimicrobial (12 %) and other compounds (18 %)
include antimalarial, antimycotics, multi-drug resis-
tance reversers, antifeedant, herbicides and immuno-
suppressive agents (Burja et al. 2001). Thus,
cyanobacteria continue to be explored and their
metabolites are now evaluated in number of biological
areas and they are becoming an exceptional source of
leading compounds for drug discovery (Singh et al.
2005, 2011; Nunnery et al. 2010; Bajpai et al. 2010).
Anticancerous, antiviral and antibacterial bioactive
molecules produced by various cyanobacteria are
listed in Table 1. These natural products not only serve
directly as drugs, but also being used as template for
the discovery and synthesis of new drugs.
Anticancerous compounds
A large number of cyanobacterial bioactive com-
pounds are found to target tubulin or actin filaments in
eukaryotic cells, making them an attractive source of
anticancer agents (Jordan and Wilson 1998). The
small anticancerous peptide, Dolastatin 10 and
Dolastatin 12 was isolated from Symploca sp. and
Leptolyngbya sp. (Kalemkerian et al. 1999; Catassi
et al. 2006). Curacin A shows antiproliferative activity
that has been isolated from cyanobacterium Lyngbya
majuscula (Nagle et al. 1995). It is also artificially
synthesized because of its pharmacological impor-
tance (Muir et al. 2002). Cryptophycin isolated from
Nostoc shows dose-dependent inhibition of L1210
leukemia cell line (Smith et al. 1994). Rickards et al.
(1999) isolated two compounds calothrixin A and B
from the organic extracts of Calothrix strains and
found that it inhibited the growth of human HeLa
cancer cells.
Apratoxin A from L. majuscula (Luesch et al.
2001a), Apratoxin BC from Lyngbya sp. (Luesch
et al. 2002a), Apratoxin D from L. majuscula and
Lyngbya sordid (Gutierrez et al. 2008), Apratoxin E
from Lyngbya bouilloni (Matthew et al. 2008) and
Apratoxins FG from L. bouilloni (Tidgewell et al.
2010) showed cytotoxicity to various cancer cell lines
i.e. U2OS osteosarcoma, HT29 colon adenocarci-
noma, HeLa cervical carcinoma, KB oral epidermoid
cancer, LoVo colon cancer, H-460 lung cancer and
HCT-116 colorectal cancer cells lines. Luesch et al.
(2000) isolated Lyngbyabellin B from L. majuscula, it
shows cytotoxic against KB and LoVo cells lines.
Likewise, symplocamide A, isolated from Symploca
sp. showed potent cytotoxicity to lung cancer cells and
neuroblastoma cells (Linington et al. 2008).
Malyngamide 3 and cocosamides B are recently
isolated from L. majuscula and it showed weak
cytotoxicity against MCF7 breast cancer and HT-29
colon cancer cells (Gunasekera et al. 2011). Oftedal
et al. (2010) have screened several cyanobacteria for
the acute myeloid leukemia (AML), which is the
second most common form of leukemia. They have
found that the aqueous cyanobacterial extract is most
effective in causing apoptosis to AML cell lines. The
combination of a moderate concentration of the
anticancer drug daunorubicin with cyanobacterial
extract induced a synergistic apoptotic response in
AML cells. It can be concluded that these cyanobac-
terial apoptogens have the ability to greatly improve
the therapeutic index of daunorubicin (Oftedal et al.
2010). Also, there was no correlation between mouse
toxicity and induction of apoptosis neither in T cell
lymphoma nor in AML-cells (Oftedal et al. 2011).
Bisebromoamide, a new cell toxin that inhibits
cancer cell lines, was obtained from an Okinawan
948 Antonie van Leeuwenhoek (2013) 103:947961
123
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Table 1 Bioactive molecules produced by various cyanobacteria
Bioactive molecules Cyanobacteria Bioactivity References
Symplocamide A Symploca sp. Anticancer Linington et al. (2008)
Symplostatin Symploca sp. Anticancer Luesch et al. (2002b)
Apratoxins Lyngbya majuscula, L. sordid,L. bouilloni
Anticancer Luesch et al. (2001a), Gutierrez
et al. (2008), Matthew et al. (2008),
Tidgewell et al. (2010)
Aplysiatoxin Lyngbya majuscula Anticancer Mynderse et al. (1977)
Lyngbyabellin B Lyngbya majuscula Anticancer Luesch et al. (2000)
Acutiphycin Oscillatoria acutissima Anticancer Barchi et al. (1984)
Dragonamide C, D Lyngbya polychroa Anticancer Gunasekera et al. (2008)
Cryptophycins Nostoc sp. Anticancer Moore et al. (1996)
Arenastatin A Dysidea arenaria Anticancer Moore et al. (1996)
Borophycin Nostoc linckia, N. spongiaeforme Anticancer Hemscheidt et al. (1994)
Homodolastatin 16 Lyngbya majuscula Anticancer Davies-Coleman et al. (2003)
Curacin A Lyngbya majuscula Anticancer Simmons et al. (2005)
Tjipanazoles Tolypothrix tjipanasensis Anticancer Bonjouklian et al. (1991)
Pitipeptolides A, B Lyngbya majuscula Anticancer Luesch et al. (2001c)
Aurilide Lyngbya majuscula Anticancer Han et al. (2006)
Carmabin A, B Lyngbya majuscula Anticancer McPhail et al. (2007)
Calothrixins A, B Calothrix sp. Anticancer Rickards et al. (1999)
Dolastatins Lyngbya sp., Symploca sp. Anticancer Fennell et al. (2003)
Biselyngbyaside Lyngbya sp. Anticancer Teruya et al. (2009b)
Ankaraholide A Geitlerinema sp. Anticancer Andrianasolo et al. (2005)
Malyngamide 3 Lyngbya majuscula Anticancer Gunasekera et al. (2011)
Cocosamides B Lyngbya majuscula Anticancer Gunasekera et al. (2011)
Bisebromoamide Lyngbya sp. Anticancer Teruya et al. (2009a)
Symplocamide A Symploca sp. Anticancer Linington et al. (2008)
Veraguamides Symploca cf. hydnoides Anticancer Salvador et al. (2011)
Largazole Symploca sp. Anticancer Taori et al. (2008)
C-phycocyanin Aphanizomenon flos-aquae Anticancer Tokuda et al. (1996)
Diacylglycerols Aphanizomenon flos-aquae Anticancer Tokuda et al. (1996)
Caylobolide Phormidium sp. Anticancer Salvador et al. (2010)
Coibamide Leptolyngbya sp. Anticancer Medina et al. (2008)
Hoiamide Association of Lyngbya majusculaand Phormidium gracile
Anticancer Choi et al. (2010)
Isomalyngamide Lyngbya majuscula Anticancer Chang et al. (2011)
Jamaicamides Lyngbya majuscula Anticancer Edwards et al. (2004)
Kalkitoxin Lyngbya majuscula Anticancer White et al. (2004)
Palauamide Lyngbya sp. Anticancer Zou et al. (2005)
Tasiamide Symploca sp. Anticancer Williams et al. (2003a)
Tasipeptins Symploca sp. Anticancer Williams et al. (2003b)
Wewakpeptins Lyngbya semiplena Anticancer Han et al. (2005)
Lagunamide Lyngbya majuscula Anticancer Tripathi et al. (2011)
Majusculamide Lyngbya majuscula Anticancer Pettit et al. (2008)
Malevamide Symploca hydnoides Anticancer Horgen et al. (2002)
Obyanamide Lyngbya confervoides Anticancer Williams et al. (2002)
Antonie van Leeuwenhoek (2013) 103:947961 949
123
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collection of Lyngbya sp. (Teruya et al. 2009a). It
inhibits the phosphorylation of extracellular signal-
related protein kinase (ERK). Veraguamides from
cyanobacterium Symploca cf. hydnoides showed mod-
erate to weak cytotoxic activity against HT29 colo-
rectal adenocarcinoma and HeLa cervical carcinoma
cell lines (Salvador et al. 2011). Taori et al. (2008)
reported that largazole isolated from Symploca sp.
shows cytotoxicity against transformed mammary
epithelial cell lines (MDA-MB-231). The molecular
target for largazole is found to be histone deacetylases
(HDACs), and it is categorized as a class I HDAC
inhibitor.
Some workers have also reported the anticancerous
activity of photosynthetic pigment. Li et al. (2010)
reported anti-tumor activities of C-phycocyanin (C-
PC) mediated photodynamic therapy in MCF-7 breast
cell lines. Aphanizomenon flos-aquae extract contain-
ing a high concentration of phycocyanin inhibited the
in vitro growth of tumor cell lines, Phormidium tenui
contain several diacylglycerols that inhibit chemically
induced tumors in mice (Tokuda et al. 1996).
Recently, Gantar et al. (2012) reported that C-PC in
combination with lower dose (10 % of typical dose) of
anticancer drug topotecan can kill cancer cells at
higher rate than used alone at full dose.
Cyanobacteria cyclopeptides as a lead compound
for cancer treatment
Cyanobacterial cyclopeptides, microcystins (MCs)
and nodularins at high concentration are considered
to be toxic to humans (Carmichael et al. 2001; Funari
and Testai 2008). MCs are the most common cyano-
bacterial toxin prevalent in the water bodies. They can
be ingested through contaminated drinking water
(Oberholster et al. 2004), fish (Poste et al. 2011) or
sea foods (Mulvenna et al. 2012). From a pharmaco-
logical point of view, MCs are stable hydrophilic
Table 1 continued
Bioactive molecules Cyanobacteria Bioactivity References
Palmyramide Lyngbya majuscula Anticancer Taniguchi et al. (2010)
Ulongapeptin Lyngbya sp. Anticancer Williams et al. (2003c)
Grassypeptolide Lyngbya majuscula Anti-proliferative Kwan et al. (2008)
Nostoflan Nostoc flagelliforme Antiviral Kanekiyo et al. (2005)
Ichthyopeptins Microcystis ichthyoblabe Antiviral Zainuddin et al. (2007)
Bauerines AC Dichotrix baueriana Anti-HSV-2 Larsen et al. (1994)
Sulfolipids Lyngbya lagerhimii, Phormidium tenue Anti-HIV Gustafson et al. (1989)
Calcium spirulan Spirulina platensis Anti-HIV Hayashi et al. (1996)
Cyanovirin Nostoc ellipsosporum Anti-HIV Dey et al. (2000)
Scytovirin Scytonema varium Anti-HIV Xiong et al. (2006)
Sulfoglycolipid Scytonema sp. Anti-HIV Loya et al. (1998)
Ambiguines Fischerella sp. Antibacterial Raveh and Carmeli (2007)
Bastadin Anabaena basta Antibacterial Miao et al. (1990)
Bis-(v-butyrolactones) Anabena variabilis Antibacterial Ma and Led (2000)
Hapalindole Nostoc CCC537, Fischerella sp. Antibacterial Asthana et al. (2009)
Abietane diterpenes Microcoleous lacustris Antibacterial Gutierrez et al. (2008)
Nostocine A Nostoc spongiaeforme Antibacterial Hirata et al. (2003)
Noscomin Nostoc commune Antibacterial Jaki et al. (2000)
Didehydromirabazole Scytonema mirabile Antibacterial Stewart et al. (1988)
Tolyporphin Tolypothrix nodosa Antibacterial Prinsep et al. (1992)
Muscoride Nostoc muscorum Antibacterial Nagatsu et al. (1995)
Ambiguine Fischerella ambigua Antibacterial Raveh and Carmeli (2007)
950 Antonie van Leeuwenhoek (2013) 103:947961
123
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cyclic heptapeptides causes cellular damage following
uptake via organic anion transporting polypeptides
(OATP) (Sainis et al. 2010; Fischera et al. 2005). Their
intracellular biological effects involve inhibition of
catalytic subunits of protein phosphatase 1 (PP1) and
PP2, glutathione depletion and generation of reactive
oxygen species (ROS) (Amado and Monserrat 2010).
However, there are certain OATPs which are prom-
inently expressed in cancer tissue as compared to
normal tissue, qualifying MCs as potential candidates
for cancer drug development (Sainis et al. 2010;
Monks et al. 2007).
In the era of targeted cancer therapy, cyanobacterial
toxins comprise a rich source of natural cytotoxic
compounds with a potential to target cancers express-
ing specific uptake transporters (Sainis et al. 2010).
Furthermore, a high proportion of these natural
products target eukaryotic cytoskeleton, such as
tubulin and actin microfilaments, making them an
attractive source of anticancer drugs (Tan 2010).
Antiviral compounds
The global spread of deadly viral diseases like HIV/
AIDS and avian influenza (H5N1 virus) etc. have
showed fatal consequences. Food and Drug Adminis-
tration (FDA) approved anti-HIV treatment highly
active antiretroviral therapy (HAART), is effective in
controlling the progression of HIV infections but
found to be toxic (Luescher-Mattli 2003). Thus, novel
drugs are now urgently required to combat deadliest
diseases. Antiviral compound isolated form cyano-
bacteria are usually found to show bioactivity by
blocking viral absorption or penetration and inhibiting
replication stages of progeny viruses after penetration
into cells. The protection of human lymphoblastoid T
cells from the cytopathic effect of HIV infection with
the extract of Lyngbya lagerheimeii and Phormidium
tenue has been reported by Gustafson et al. (1989). A
new class of HIV inhibitors called sulfonic acid,
containing glycolipid, was isolated from the extract of
cyanobacteria and the compounds were found to be
active against the HIV virus. Cyanovirin-N (CVN), a
peptide isolated from cyanobacteria, inactivates the
strains of HIV virus and inhibits cell to cell and virus to
cell fusion (Yang et al. 1997). In vitro and in vivo
antiviral tests suggested that the anti-HIV effect of
CVN is stronger than a well-known targeted (viral
entry) antibody (2G12) and another microbicide,
PRO2000 (Xiong et al. 2010).
Calcium spirulan (Ca-SP), a novel sulphated poly-
saccharide, is an antiviral agent. This compound
selectively inhibits the entry of enveloped virus
(Herpes simplex, humancytomegalo virus, measles
virus) into the cell (Hayashi et al. 1996). Rechter et al.
(2006) have analyzed polysaccharide fractions iso-
lated from Arthrospira platensis. These fractions
containing spirulan-like molecules showed a pro-
nounced antiviral activity against human cytomega-
lovirus, herpes simplex virus type 1.
Yakoot and Salem (2012) has conducted first
human trial to address the effect of Spirulina platensis
dried extract on virus load, liver function, health
related quality of life and sexual functions in patients
with chronic hepatitis C virus (HCV) infection. They
found the therapeutic potential of S. platensis in
chronic HCV patients, and in some cases (13 %) the
viral infection is complexly nullified. Mansour et al.
(2011) have found that the polysaccharides isolated
from Gloeocapsa turgidus and Synechococcus cedro-
rum showed higher antiviral activity against rabies
virus than that against herpes-1 virus. The exopoly-
saccharide from Aphanothece halophytica has an
antiviral activity against influenza virus A (H1N1),
which shows an 30 % inhibition of pneumonia in
infected mice (Zheng et al. 2006).
Antibacterial compounds
Noscomin from Nostoc commune exhibited antibac-
terial activity against Bacillus cereus, Staphylococcus
epidermidis, and Escherichia coli (Jaki et al. 2000).
Nostocarboline from Nostoc was found to inhibit the
growth of other cyanobacteria and green alga (Blom
et al. 2006). Hirata et al. (2003) found that nostocine A
isolated from Nostoc spongiaeforme exhibited growth
inhibitory stronger to green algae than to cyanobac-
teria. Asthana et al. (2009) have isolated hapalindole
(alkaloids) from Nostoc CCC537 and Fischerella sp.
and found antimicrobial activity against Mycobacte-
rium tuberculosis H37Rv, Staphylococcus aureus
ATCC25923, Salmonella typhi MTCC3216, Pseudo-
monas aeruginosa ATCC27853, E. coli ATCC25992
and Enterobacter aerogenes MTCC2822.
Ambiguine, a hapalindole-type alkaloid from Fi-
scherella ambigua shows antibacterial activity against
Antonie van Leeuwenhoek (2013) 103:947961 951
123
-
Cryptophycin 52 (C36H45ClN2O8 & 669.2 Da)
HN
O
O
H3C
O
ONHH3C CH3
O
O
O
H3 C
CH3Cl
OCH3
CH2S
CH3
N
H3CO
CH3
Curacin (C23H35NOS & 373.6 Da)
CH3
N
NH
N
N
CH3
CH3
H3C
O
H3C
H3C
O
H3C
CH3H3C
O
N
O
OO
H3C
H3C
N
O
O
OCH3
Dolastin 15 (C45H68N6O9 & 837 Da)
H3CN
HN
N
N
CH3
H3C CH3
OH3C CH3
O
CH3
CH3
CH 3
O
N
O
O
HN
H3C
CH 3
H3C
Tasidotin (C32H58N6O5 & 606.8 Da)
H3CN
HN
NN
CH3
H3C CH3
OH3C CH3
O
CH3
H3C CH3
OH O
NH
H3CO
CH3
O
Soblidotin (C36H61N5O6 & 660 Da)
H3C N
HN N
N
CH3
H3CCH3
OH3C
CH3
O
CH3
H3C
H3C
OCH3O NHH3CO
CH3
O
N
S
Dolastin 10 (C42H68N6O6S & 785 Da)
Cemadotin (C35H56N6O5 & 640.8 Da) H3C
N
NH
N
CH3
H3C
CH3 O
CH3
CH3
O
O
N
CH3
H3C
HN CH 3
O
O
N
Fig. 1 Structures of biomolecules which were in clinical trials
952 Antonie van Leeuwenhoek (2013) 103:947961
123
-
M. tuberculosis and against Bacillus anthracis (Raveh
and Carmeli 2007). Guo et al. (2009) have isolated
6-cyano-5-methoxy-12-methylindolo (2,3-a) carba-
zole from cyanobacteria and identified as a B. anthra-
cis inhibitor. The methanolic extract of S. platensis
showed broad spectrum antimicrobial activity and the
inhibition recorded was maximum for S. aureus
followed by E. coli, P. aeruginosa and S. typhi
(Kaushik and Chauhan 2008). Because of the growing
bacterial resistance against antibiotics and commercial
standard the search for new active substances with
antibacterial activity is urgently needed and cyano-
bacteria are the potential and promising candidates.
Cyanobacterial bioactive molecules under clinical
trials
The drug-development process normally proceeds
through various phases of clinical trials (phase 0 or
pre clinical, phase I, phase II and phase III). The FDA
must approve each phase before the study can
continue. Drugs are first tested in laboratory animal
(pre clinical phase) and in further phases healthy
human are tested. In phase I, II and III the number of
subjects range from 20 to 80, few dozen to 300 and
several hundred to 3,000 people, respectively. If the
drug successfully passes through all the phases it will
usually be approved by the National Regulatory
Authority (NRA) for use by the general population.
There are few prominent molecules from cyanobac-
teria such as dolastatins, cryptophycins, curacin and
their analogues which are in clinical trials as potential
anticancer drugs. The structures were drawn with the
help of ChemDraw (Fig. 1).
Dolastatins are the group of structurally unique
peptides which were first reported from marine animal
Dolabella auricularia (Pettit et al. 1987), using
microalgae as diet, but later on they were isolated
from the cyanobacteria Symploca (Luesch et al.
2001b). Dolastatins show anticancerous activity by
inhibiting microtubule assembly and many of its
analogues are in clinical trials. Till date there are
sixteen dolastatin forms isolated and are simply named
as dolastatin 1, 2, 3, and so on. Dolastatin 10 and 15 are
found to be showing promising results. National
Cancer Institute of US conducted the phase I clinical
trials of dolastatin 10 and progressed further to phase
II. Unfortunately, it was dropped from clinical trials,
due to some toxic effects (Simmons et al. 2005). This
finding results in the development of dolastatin 10
synthetic analogues like soblidotin, usually with
improved pharmacological and pharmacokinetic prop-
erties. Interestingly, its synthetic analogue soblidotin,
has cleared phase I and II successfully and now
undergoing phase III clinical trials under the supervi-
sion of Aska Pharmaceuticals, Tokyo, Japan (Bhatna-
gar and Kim 2010). The antitumor activity of
soblidotin, was found to be superior to existing
anticancer drugs, such as paclitaxel and vincristine
(Watanabe et al. 2006). The third generation dolastatin
15 analogues are cemadotin and tasidotin. Tasidotin is
antitumor agent and has cleared phase I trials (Mita
et al. 2006) and now undergoing phase II trials with
Genzyme Corporation, Cambridge, MA (Bhatnagar
and Kim 2010).
Cryptophycins are a group of cytotoxic depsipep-
tides, first isolated from Nostoc sp. as an antifungal
compound (Schwartz et al. 1990), later it was reported
to be effective against drug-resistant cancer cell lines
(Smith et al. 1994). Moore group (Chaganty et al.
2004; Golakoti et al. 1994, 1995) have isolated
twenty-six cryptophycins forms from Nostoc sp.
GSV 224. Of the various forms, cryptophycin 52
was found to be the most successful and evaluated in
phase II clinical trials for the treatment of platinum-
resistant ovarian cancer (DAgostino et al. 2006) and
advanced lung cancer (Edelman et al. 2003). Unfor-
tunately, the clinical trails were further discontinued
as it causes neuropathy and pain in the patients.
Magarvey et al. (2006) have analyzed cryptophycin
biosynthetic pathways that have opened more avenues
to create novel cryptophycin analogs (Sammet et al.
2010; Wei et al. 2012).
Another group, curacins are unique thiazoline-
containing lipopeptides that inhibits microtubule
assembly and it is a potent competitive inhibitor of
the binding of colchicine to tubulin (Blokhin et al.
1995). Gerwick group have isolated curacin A (Ger-
wick et al. 1994); curacin B and C (Yoo and Gerwick
1995); curacin D (Marquez et al. 1998) from Lyngbya
majuscule, which is prevalent in different water
bodies. Clinical development of curacin has been
hindered due to its low water solubility and thus it is
unable to produce activity during in vivo animal trails.
Hence, curacin was withdrawn from pre clinical
phase, but it served as a lead compound for the
development of synthetic analogs which are more
Antonie van Leeuwenhoek (2013) 103:947961 953
123
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water soluble (Wipf et al. 2004). Isolation of all
of these compounds offer great opportunity and a
platform for the discovery of promising anticancer
agents.
Methods used for isolation and detection of novel
biomolecules
There are number of methods used for the extraction of
valuable metabolites. The extraction can either be
simultaneous (extra and intracellular metabolites) or
sequential (intercellular metabolites only). In both
types of extraction first quenching is done with liquid
nitrogen to freeze the metabolic activity. In simulta-
neous extraction, quenching is immediately followed
with extraction using a suitable solvent (butanol/
acetone/hexane/chloroform/methanol/aqueous metha-
nol/water/hexane/dichloromethane), while in sequen-
tial extraction biomass separation is done after
quenching and then various fractions are collected
by extracting with solvents of decreasing polarity
sequentially (water, aqueous methanol, methanol,
hexane) (Fig. 2). Conventional extraction methods
employed are solidliquid extraction (SLE) or liquid
liquid extraction (LLE). SLE is usually done by
soxhlet apparatus, it is the process of removing a
solutes from a solid (fixed phase) or matrix by using of
liquid solvent (mobile phase). Whereas in LLE, both
phase are in liquid phase and the separation of the
solute depend on the distribution coefficient of the
solute in mobile phase. Both SLE and LLE require
high volumes of solvents, long extraction times and
reproducibility of the results are low.
Recently low cost, chemical free green extraction
(GE) methods are used such as supercritical fluid
extraction (SFE), pressurized liquid extraction (PLE).
In SFE, the dissolved solutes are separated from the
raw material using certain gases (act as solvent) above
critical points. Carbon dioxide (CO2) gas is commonly
used solvent for the extraction of biomolecules. Some
of the researchers are also using ethanol as cosolvent
along with the CO2 gas. Mendiola et al. (2007) have
used SFECO2 (220 bar, 26.7 C) with 10 % ofethanol (cosolvent) for the extraction of antimicrobial
component from S. platensis. Onofrejova et al. (2010)
Simultaneous quenching (freeze metabolic activity) and extraction
with suitable solvent
Sequential sampling (Intracellular metabolites only)
Cyanobacterial Culture
Simultaneous sampling (Intracellular and extracellular
metabolites)
Quenching (to freeze metabolic activity)
Sequential extraction with various solvents
Biomass separation (by centrifugation and washing)
Fig. 2 Extraction procedure commonly followed for the isolation of novel biomolecules from cyanobacteria
954 Antonie van Leeuwenhoek (2013) 103:947961
123
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have used combination of pressurized-liquid with
solid-phase extraction (PLESPE) for the isolation of
bioactive phenols freshwater algae.
There are number of analytical techniques available
for the detection and purification of biomolecules from
cyanobacterial extract (Fig. 3). Thin layer chromatog-
raphy (TLC) followed by spectrophotometric analysis
is the easiest technique used for primarily identifica-
tion and separation of bioactive molecules. Pelander
et al. (2000) have used high performance TLC plates
(HPTLC) for the separation of small cyanobacterial
peptides. However, TLC/HPTLC separation is non-
specific and less sensitive. Use of high performance
liquid chromatography (HPLC) for the identification
and quantification has increased greatly. Nowadays
more advance technique ultra performance liquid
chromatography (UPLC) is available, which can be
better option than HPLC. In order to get accurate
identification of bioactive product, liquid chromatog-
raphy is followed by mass spectrometry (LCMS)
(Harada et al. 2004). Different configurations of this
approach such as fast atom bombardment (FAB-LC
MS) (Kondo et al. 1995) and electrospray ionization
(ESI-LCMS) has been developed (Barco et al. 2002;
Spoof et al. 2003). Zhang et al. (2004) used LCMS
MS with electrospray ionization. Liquid chromatog-
raphy can also be coupled with quadruple time-of-
flight tandem mass spectrometry (LCQTof-MS) for
cyanobacterial cyclopeptides detection (Ferranti et al.
2009). Immunoassay techniques due to their high
sensitivity, specificity and operational simplicity are
widely used for the characterization of biomolecules.
Lindner et al. (2004) have developed the highly
sensitive enzyme-linked immunosorbent assays
(ELISA) for the detection and quantification of
cyanobacterial cyclopeptides.
Metabolites are also identified using matrix-
assisted laser desorption/ionization time-of-flight
mass spectrometry (MALDI-TOF MS). The technique
requires very small amount of sample without sepa-
ration or purification (Welker et al. 2002). Erhard et al.
(1997) used MALDI-TOF MS for identification of
secondary metabolites with intact cyanobacterial cells.
Resulting mass signals which are further characterized
by post source-decay fragmentation, and comparison
of observed fragment spectra with theoretical ones or
Cyanobacterial Extract
In Vivo assay
Chromatographic analysis
Mass spectral analysis Immunological assay
using ELISA
TLC/HPTLC
HPLC/UPLC-UV/PDA
Bioassay using bacterial/plant/animal system
In Vitro assay
GC-FID
MALDI-TOF MS
ESI-MS
DART-MS
DESI-MS
LC-MS
GC-MS
Fig. 3 Detection and purification methods for isolation of bioactive molecules from cyanbacterial extract
Antonie van Leeuwenhoek (2013) 103:947961 955
123
-
with those of pure reference compounds (Welker et al.
2004). In general, MALDI-TOF MS is used for the
identification of peptides; however this can also be
used for the identification of alkaloids (Araoz et al.
2008). In MALDI-TOF MS, the mass fragmentation
pattern of a particular analyte is distinctive, and may
vary according to the ionization mode used for mass
spectrometry and to the charge state of the molecule
(Antoine et al. 2006; Welker et al. 2006).
Desorption electrospray ionization mass spectrom-
etry (DESI-MS) is also an applied analytical technique
for chemical profiling, characterization and quantifi-
cation of low molecular-weight biomolecules
(Esquenazi et al. 2009). Another technique, direct
analysis in real time mass spectrometric (DART-MS)
technique is very much effective in chemical profiling
and fingerprinting of bioactive molecules without
prior sample preparation. Singh and Verma (2012)
have identified the Nostoc sp. on the basis of
characteristic chemical compounds (chemical finger-
printing) using DART-MS. All these techniques are
helpful for the identification and characterization of
bioactive molecules.
Conclusion
Cyanobacteria are the promising sources potentially
useful natural products. Microbial natural products
discovery opens a new era of research. Presently, the
isolation of number of natural products is increasing;
however, few compounds have reached the market.
Limited number of identified cyanobactererial bio-
molecules and analogues are in clinical trials and some
of them have passed different phases of clinical trials
to prove their candidature as potential drugs. In order
to exploit the new opportunities available, it will be
necessary to develop novel methodologies that allow
the isolation and culture of microorganisms, which
produce natural products unique to particular envi-
ronmental conditions. Thus, there is an urgent need for
extensive research in this new emerging field for drug
discovery.
Acknowledgments Authors are thankful to Director, CSIR-NBRI for all the facilities and constant encouragement. Rakhi
Bajpai Dixit is grateful to Department of Science and Technology
(DST, New Delhi), for providing financial assistance in the form
of a project (Ref. No. SR/FT/LS-111/2010).
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c.10482_2013_Article_9898.pdfCyanobacteria: potential candidates for drug discoveryAbstractIntroductionAnticancerous compoundsCyanobacteria cyclopeptides as a lead compound for cancer treatmentAntiviral compoundsAntibacterial compoundsCyanobacterial bioactive molecules under clinical trialsMethods used for isolation and detection of novel biomoleculesConclusionAcknowledgmentsReferences