Available online at www.sciencedirect.

com

ScienceDirect
Procedia Chemistry 14 (2015) 484 492

2nd Humboldt Kolleg in conjunction with International Conference on Natural Sciences,

HK-ICONS 2014

Status of Drug Discovery Research Based on Marine Organisms

from Eastern Indonesia

Yosmina H. Tapilatua*
a
Deep Sea Research Center , Indonesian Institute of Sciences (LIPI),
Jl. Y. Syaranamual Guru-guru Poka, Ambon 97233, Indonesia

Abstract

Despite the vastness of Eastern Indonesian Waters (EIW), no review has been done on the status of drug discovery research
based on marine organisms from this area. The aim of this paper is to briefly discuss the challenges and perspectives on drug
discovery research based on marine organisms in these indigenous waters. The emphasis is on the last 20 year period (1993 to
2013). Research activities completed during this period suggest that marine organisms from EIW could be utilized as an
important natural resource for future drug discovery and development. However, lack of facilities, as well as competent human
resources, significantly hinder progress on drug discovery research. More in-depth study especially on deep-sea natural products
needs to be carried out to solidify the research on the potential for marine organisms from EIW to contribute to the future of drug
discovery.
2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
2015 Y.H. Tapilatu. Published by Elsevier B.V.
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer-reviewunder
Peer-review underresponsibility
responsibility of the
of the Scientific
Scientifi Committee
c Committee of HK-ICONS
of HK-ICONS 2014 2014.

Keywords: Drug discovery; Eastern Indonesian Waters; marine organisms; pharmacologic activity.

Nomenclature
IC50 concentration of a compound required for 50 % inhibition in vitro, [g mL1 or M]
IC90 concentration of a compound required for 90 % inhibition in vitro, [g mL1 or M]
ED50(or EC50) dose (or concentration) of a compound required for causing 50 % of maximum effect

* Corresponding author. Tel.: +62 911 322 676; fax: +62 911 322 700.
E-mail address: yosmina.tapilatu@lipi.go.id, yosmina.lipi.ambon@gmail.com

1876-6196 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer-review under responsibility of the Scientific Committee of HK-ICONS 2014
doi:10.1016/j.proche.2015.03.065
 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492 485

for any measured biological effect of interest, [g mL1 or M]

MIC minimum inhibitory concentration of an anti microbial that will inhibit the visible
growth of a microorganism after overnight incubation, [g mL1]
LC50 concentration of a compound in air exposed for 4 h to kill 50 % of population during
observation, [ppm or L L1]

1. Introduction

Ocean comprises more than 80 % of the total eastern Indonesian area. As a consequence, Eastern Indonesian
Waters (EIW) have great potential in terms of marine biota biodiversity. Drug discovery based on marine
biodiversity has been a relatively rapid growing field over the last five decades. Indonesia was among countries with
sharp increases of new Marine Natural Product (MNP) discovered over the last two decades (1990 to 2009)1. There
are at least three reviews (Dewi et al.2, Chasanah3, Putra and Jaswir4) that covered about isolation of bioactive
compounds from marine organisms collected in Indonesian waters. However, limited information exists on the status
of drug discovery research based on marine organisms from EIW. There was only one review5 that covered about
EIW and its potential as MNP producers, including all those that do not have pharmacologic activity. To our
knowledge, trends of isolating compounds with pharmacologic activity from samples collected from the
aforementioned area have not been previously reviewed. This initial discovery is essential in advocating
conservation of these marine resources.
The purpose of this paper is to briefly review recent research on drug discovery based on marine organisms in
EIW. This mini review provides information applicable to future bioprospecting efforts addressing previously
unexplored regions in these indigenous waters.

2. Materials and methods

Information from the year 1993 to 2013 were obtained and assembled by surveying existing reviews (Dewi et al.2,
Chasanah and Dewi5). When particular information was insufficient or omitted, the original article was tracked
through Thomson Reuters and Science Direct and consulted to ensure the accuracy of data. It was not always
possible to retrieve all missing information by consulting the original article, as some of those works were only
accessible in abstract, while others provided no detailed information about the sampling site. Articles in Indonesian
were searched using common search engine. The EIW were defined as waters extended from Makassar Strait to
Banda and Arafura Seas horizontally, and from Pacific Ocean and Celebes Sea to Banda Sea vertically (Fig. 1).

Fig. 1. Indonesian map. Eastern Indonesian Waters (EIW) were indicated with black line.

3. Results and discussion

Drug discovery research activities in EIW during the last two decades were pushed forward notably by strong
collaborative projects, between Indonesian researchers from various universities and research institution and
international researchers. From 112 MNP reported to be isolated from marine organisms in EIW from 1993 to 20135,
486 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492

only 46 % (51 compounds) showed various potential pharmacologic activities (Table 1). Both new and previously
discovered MNP do not always exhibit pharmacologic activity. This activity was influenced largely by
environmental conditions where the samples were collected 6, and it could be the plausible explanation as to why
only 46 % of MNP isolated indicated this potential.

Table 1. Recapitulation of Marine Natural Product (MNP) with pharmacologic activity isolated from EIW marine organisms.

Sampling Organism/ Pharmacologic Type of assay:

Drug class Compound Chemistry Year Ref
location Species activity result

First decade (1993 to 2003)

7
North Anticancer Sponge/ Manadic acids A Fatty acid Moderately active Undetermined 1995
Sulawesi Plakortis sp. and B against various
antitumor cell lines

8
North Anticancer Sponge/Pla- Elenic acid (R-2,4- Fatty acid Inhibitor of IC50: 0.1 mg 1995
Sulawesi kinastrella sp. dimethyl-22-(p- Topoisomerase II mL1
hydroxyphenyl)-
docos-3(E)-enoic
acid

9
North Anticancer Soft coral/ Secosterol Sterol Inhibitor of human Undetermined 1998
Maluku Lobophytum ovarian tumor and
sp. human leukemia cell
lines

10
North Antibacterial Sponge/ Halicotriol A and B Terpene Inhibitor (weak) of Undetermined 2000
Maluku Haliclona sp. ketide Bacillus subtilis and
Staphyloccocus
aureus

11
Sulawesi Antiviral Sponge/ Microspinosamide Peptide Inhibitor of the EC50: 0.2 g 2001
Sidonops cytopathic effect of mL1
microspinosa HIV-1 infection in an
XTT-based in vitro
assay

12
North Anticancer Sponge/ Bitungolides Polyketide Inhibitor of dual- Undetermined 2002
Sulawesi Theonella specificity
swinhoei phosphatase VHR

13
South Anticancer Sponge/ Barangcadoic acid Terpenoid Inhibitor of RCE Undetermined 2002
Sulawesi Hippospongia A, Rhopaloic acids protease activity
sp. DG

14
East Anticancer Sponge/ Labuanine A Pyridoacri- Neuronal IC50: 0.03-3 2003
Nusa Biemna fortis dine alkaloid differentiation M
Tenggara inducers (50%)
against a murine
euroblastoma cell
line, Neuro 2A

15
Central Anticancer Sponge/ Puupehenones Meroses- Undetermined Undetermined 2003
Sulawesi Hyrtios sp. quiterpene

(continued on next page)

 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492 487

Table 1. Continued
Sampling Organism/ Pharmacologic Type of assay:
Drug class Compound Chemistry Year Ref
location Species activity result

16
North Antimicro- Sponge/ Manadomanza- Manzamine Inhibitor (strong) of MIC Mtb: 1.9, 2003
Sulawesi bial Acanthostro- mines A and B alkaloid Mycobacterium 1.5 and 0.91 g
ngylophora sp. tuberculosis (Mtb), mL1
active against HIV-1
and AIDS
opportunistic fungal
infections

Second decade (2004 to 2013)

17
East Anticancer Sponge/ 5-epismeno- Sesquiter- Differentiation- IC50: 2 M 2004
Nusa Dactylospo- spongorine pene ami- inducing substances
Tenggara ngia elegans noquinone to K562 cells into
erythroblast

18
Central Anticancer Sponge/ Kendarimide A Linear Multidrug resistant IC50: 6 M 2004
Sulawesi Haliclona sp. Peptide modulator in tumor
cell KB-C2

19
North Antifungal Sponge/ Naamine G Alkaloid Strong antifungal Undetermined 2004
Sulawesi and Leucetta activity against phy-
anticancer chagosensis topathogenic fungus
Cladosporium herba-
rium; mild cytotoxi-
city against mouse
lymphoma (L5178Y)
and human cervix
carcinoma (HeLa)
cell lines

20
North Anticancer Sponge/ Plakorstatins 1and Polyketide Inhibitor (moderate) ED50: 1.1 and 2004
Sulawesi Plakortis 2 (plakortide) of murine P388 0.91 g mL1
nigra lymphocytic
leukemia cell line

21
North Antiparasitic Sponge/ Manzamine E, Manzamine Inhibitor of Mtb and Undetermined 2004
Sulawesi (malaria) Acanthostro- 12,34-oxamanza- alkaloid Plasmodium sp.
and ngylophora sp. mine E and 6-
Antibacteria hydroxymanzamine
(TBC) E

22
South Anticancer Sponge/ Luffariellolide, Terpenes Cytotoxic against the Undetermined 2004
Sulawesi Acanthoden- Luffariellolide 25- mouse lymphoma
drilla sp. O-methyl deriva- L5187Y cell line
tive, acantholide
E (5)

(continued on next page)

488 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492

Table 1. Continued
Sampling Organism/ Pharmacologic Type of assay:
Drug class Compound Chemistry Year Ref
location Species activity result

22
South Antimicro- Sponge/ Acantholide B (2), Terpenes Inhibitor of Gram Undetermined 2004
Sulawesi bial Acanthoden- luffariellolide, and positive and negative
drilla sp. luffariellolide 25- bacteria (S. aureus,
O-methylcongener B. subtilis, Esche-
3 richia coli), yeast
(Candida albicans),
& the plant patho-
genic fungus (Clado-
sporium herbarum)

23
Sulawesi Anticancer Sponge/ Halenaquinone, Sesquiter- Inhibitor of IC50: 0.7 M, 2005
Xestopongia Adociaquinone B pene recombinant human 0.07 M and
sp. and 3-ketoadocia- quinone Cdc25B in vitro 0.2 M
quinone B

24
Sulawesi Antibacteria Sponge/ Sarasinosides J and Terpenoid Inhibitor of B. subti- Undetermined 2005
Melophlus A1 lis & Saccharomyces
sarassinorum cerevisae

25
North Anticancer Sponge/ Coelodiol and Terpenoid Inhibitor of the Undetermined 2006
Sulawesi Coelocarteria coeloic acid MKN-45 cell line
cfr. Singa- (human gastric
porensis adenocarcinoma)
growth

26
North Antiparasitic Sponge/ Ircinal A Manzamine Leishmanicidal IC50: 0.9 g 2006
Sulawesi (leishmania- Acanthostro- alkaloid activity mL1; IC90: 1.7
sis) ngylophora sp. g mL1

26
North Alzheimers Sponge/ Manzamine Y Manzamine Inhibitor (significant) Undetermined 2006
Sulawesi treatment Acanthostro- alkaloid of GSK3 activity, an
ngylophora sp. enzyme implicated in
Alzheimer's disease
pathology

27
Sulawesi Anticancer Sponge/ Naamidines H and Alkaloid Inhibitor of human IC50: 5.6, 15 2007
Leucetta I cervix carcinoma g mL1
chagosensis (HeLa) cells

28
East Anticancer Sponge/ Cortistatins J Alkaloid Cytostatic anti IC50: 8 nM 2007
Nusa Corticium proliferative activity
Tenggara simplex against human
umbilical vein
endothelial cells
(HUVECs)

(continued on next page)

 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492 489

Table 1. Continued
Sampling Organism/ Pharmacologic Type of assay:
Drug class Compound Chemistry Year Ref
location Species activity result

29
North Anticancer Ascidian/ Lissoclibadins 4-7 Alkaloid Inhibitor of chinese EC50: 0.71, 2007
Sulawesi and anti- Lissoclinum hamster V79 cells 0.06, 0.06 and
microbial cf. Badium colony formation, 0.17 M (V79
inhibitor (weak) of cells)
S. aureus, E. coli and
Saccharomyces
cerevisiae

30
Papua Antiparasitic Sponge/ 2-(4-isobutyl- Terpenoid Inhibitor of P. IC50: 7.13 g 2013
(malaria) Xestopongia phenyl) propanoic falciparum 3D7 mL1
sp. acid growth

31
Maluku Antibacteria Sea weed/ Undetermined Undeter- Inhibitor of E. coli LC50: 108.29 2013
Porphyra sp. mined growth ppm

32
Maluku Antibacteria Bacteria/ 1-octadecene Hydro- Undetermined Undetermined 2013
Streptomyces carbon
sp.
BKBL7B.Ac

32
Maluku Antibacteria Bacteria/ Methylisoborneol terpenoid Inhibitor (weak) of Undetermined 2013
Streptomyces alcohol other marine bacteria
sp. isolates
BKBL8B.Ac

There were 17 MNP isolated from the first decade (1990 to 2003). The number was doubled (34) on the second
decade (2004 to 2013). This may be attributed to the new development in analytical technology1 and increased
accessibility of sampling area in EIW.
Most of them (82 %) were isolated from Sulawesi waters, all provinces (North, South, Central and not detailed
ones) included (Fig. 2a). Sulawesi waters are regarded as the center of global coral reef diversity due to its highest
number of species, comparable to the Caribbean Sea33. In Spermonde archipelago alone (south western Sulawesi) for
example, a beta diversity research team in 2006 identified 15 842 individual sponges to a total of 151 species
belonging to 68 genera and 37 families34. It is possible that samples were collected in this part of EIW during the last
two decades because of this reason.

a b

Fig. 2. Percentage of marine natural products (MNP) with potential pharmacologic activity isolated based on
(a) location and (b) source of organism (n = 51).
490 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492

Sponges (phylum Porifera) notably from class Demospongiae accounted for more than 80 % of the total number
of compounds isolated from EIW (Fig. 2b). Isolations of MNP were focused mainly on sponges because members of
this phylum were known to be prolific producers of MNP with pharmacologic activity. Nevertheless, recent studies
indicate that it is in fact their microbial symbionts that could play more important roles in producing these
metabolites6.
More than half of these compounds (63 %) belonged to the Anticancer drug class (Fig. 3a). The increased demand
for discovering new anticancer drugs substantially influenced the research activities involved in finding potent cures
based on the study of MNP.

a b

Fig. 3. Percentage of MNP with potential pharmacologic activity isolated based on

(a) drug class and (b) chemical structure (n = 51).

Almost 50 % of these compounds were classified as terpenes/terpenoids, followed by alkaloids and polyketides
(Fig. 3b.). It is interesting to note that despite the predominance of alkaloids and/or its derivative compounds
discovered in EIW, terpenes and/or terpenoids and their derivatives comprised the majority that did exhibit
pharmacologic activity.
Exploratory works carried out in recent years (eg. Bredholt et al.35, Turk et al.36) show the potential of yet
untapped resources of deep-sea biodiversity. The deep sea (marine environment deeper than 200 m) is a vast and
relatively untapped reservoir of unique molecular, structural and biological diversity. However, of the 30 000 MNP
reported, less than 2 % were derived from deepsea organisms37. With the advancement of deepsea exploration
technology in recent years, there is now more opportunity to isolate MNP with pharmacologic activity from this part
of EIW.
Deep sea covers a generous portion of EIW, notably in the Banda Sea, the Strait of Makassar and the Pacific
Ocean. An attempt of isolating exopolysaccharide-producing bacteria from Banda Sea sediment collected from 400
m38 yielded on one isolate capable of producing this compound (Fig. 4). Bacterial exopolysaccharide has wide range
of application in biotechnology, including pharmacy.

Fig. 4. Crude exopolysaccharide extracted from a bacterial isolate culture broth (Banda Sea sediment, depth: 400 m)

4. Conclusion and perspective

Almost half (46 %) of MNP isolated in EIW from 1993 to 2013 were compounds with pharmacologic activity.
This indicates that the biologically diverse marine organisms in these waters are potential producers of these types of
compounds. On another subject, the untapped marine biodiversity from the deep-sea region in EIW are also potential
 Yosmina H. Tapilatu / Procedia Chemistry 14 (2015) 484 492 491

producers of MNP with pharmacologic activity. Future studies on deep-sea derived MNP with pharmacologic
activity will only be possible within regional and/or international collaborative research scheme, because a large
infrastructure of equipment and human resources will be needed to accomplish them.

Acknowledgements

This mini review was made possible with financial support from Deep Sea Research Center LIPI to YHT. This is
contribution number 6 from Marine Microbiology and Biotechnology Laboratory, Deep Sea Research Center LIPI.

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