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Novel and highly potent antitumournatural products from cnidarians ofmarine originBoris Pejina, Milos Mojovicb & Aleksandar G. Savica

a Department of Life Sciences, Institute for MultidisciplinaryResearch – IMSI, University of Belgrade, Kneza Viseslava 1, 11030Belgrade, Serbiab Faculty of Physical Chemistry, University of Belgrade, Studentskitrg 12-16, 11158 Belgrade, SerbiaPublished online: 30 Jul 2014.

To cite this article: Boris Pejin, Milos Mojovic & Aleksandar G. Savic (2014): Novel and highlypotent antitumour natural products from cnidarians of marine origin, Natural Product Research:Formerly Natural Product Letters, DOI: 10.1080/14786419.2014.934241

To link to this article: http://dx.doi.org/10.1080/14786419.2014.934241

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REVIEW

Novel and highly potent antitumour natural products from cnidarians ofmarine origin

Boris Pejina*, Milos Mojovicb and Aleksandar G. Savica*

aDepartment of Life Sciences, Institute for Multidisciplinary Research – IMSI, University of Belgrade,Kneza Viseslava 1, 11030 Belgrade, Serbia; bFaculty of Physical Chemistry, University of Belgrade,Studentski trg 12-16, 11158 Belgrade, Serbia

(Received 1 May 2014; final version received 10 June 2014)

This article covers the 2003–2012 literature published for marine natural productsfrom the phylum Cnidaria. The focus is on new and highly potent antitumoursubstances, together with details related to the organism sourced. It describes 12promising bioactives isolated from 7 species.

Keywords: invertebrata; cancer; secondary metabolites; new leads

1. Introduction

The phylum Cnidaria (10,860 species) is a diverse group of relatively simple animals united

by the ability to synthesise a highly complex cellular product, the cnida (WoRMS 2014).

All cnidarians possess cnidae; no loss of the feature has been documented. They include corals,

hydroids, jellyfishes, sea anemones and sea fans which are abundant and common in marine

environments (Daly et al. 2007). The ability of cnidarians to produce powerful toxins and venoms

has been well documented (Turk & Kem 2009). However, further research has demonstrated that

marine natural products produced by their representatives are more than toxins and venoms

(Rocha et al. 2011). Compared with the performed studies on marine sponges so far (Sladic &

Gasic 2006; Pejin et al. 2008; Pejin, Iodice et al. 2014; Blunt et al. 2014), limited research has

been undertaken into the bioactive substances of cnidarians from the same environment.

This article covers 12 new and highly potent antitumour compounds of cnidarian origin

published from 2003 to 2012 (Table 1). The natural products herein have shown activity against

various tumour cell lines such as A-431, DU-145, HeLa, HeLa-Apl, HT-29, IGROV, K-562, P-

388 and SK-BR3.

2. Results and discussion

Acylspermidines A–C (Figure 1), isolated from an Okinawan collection of Sinularia sp. soft

coral collected at a depth of 10m of Chatan, Japan were all potently cytotoxic towards A-431

cells (epidermoid carcinoma; IC50 value of 17 ng/mL) (Ojika et al. 2003; Blunt et al. 2005). In

comparison, the anticancer agent cisplatin inhibited the growth of these cells at an IC50 value of

3mg/mL under the same culture conditions. Acylspermidine C was found to induce apoptotic

DNA fragmentation and condensation of chromatin in A-431 cells. Spermidines and its

q 2014 Taylor & Francis

*Corresponding authors. Email: borispejin@imsi.rs; brspjn@gmail.com; asavic@imsi.rs; enzo1320@yahoo.com

Natural Product Research, 2014

http://dx.doi.org/10.1080/14786419.2014.934241

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analogues are known for decades mimicking the natural polyamines in regulatory functions

(Seiler 2005).

(Z)-sarcodictyin A (Figure 2) is a potent cytotoxic diterpenoid isolated from a Japanese

collection of Bellonella albiflora (Nakao et al. 2003). The animal specimens were collected by

hand using scuba off Shishi-jima Island in the Amakusa Islands. Its absolute stereochemistry

was related to sarcodictyin A by transesterification and comparison of CD spectra. This natural

product was cytotoxic against HeLa cells with an IC50 value of 90 ng/mL. (Z)-sarcodictyin A

Table 1. Selected antitumour natural products from marine cnidarians.

2003 Acylspermidines A–C; (Z)-sarcodictyin A2004 Cembrane 7,8-dihydroflabellatene A2005 None (Blunt et al. 2007)2006 Annulin C; 2-hydroxygarveatin E; garveatin E2007 Cembranoid C; michaolides B and F2008 None (Blunt et al. 2010)2009 None (Blunt et al. 2011)2010 Pachyclaidin A2011 None (Blunt et al. 2013)

Figure 1. Acylspermidines A–C.

Figure 2. (Z)-sarcodictyin A and cembranes 7,8-dihydroflabellatene A and B.

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exhibited cytotoxicity against HeLa cells comparable to that of sarcodictyin A, thereby

indicating that the geometry of the double bond was not important for activity. Pharmacological

effect of sarcodictyn A corresponds to clinically used drug taxol acting by stabilising

microtubules (Faulkner 2000).

Cembranes 7,8-dihydroflabellatene A and B (Figure 2) were isolated from extracts of a sea

pen Gyrophyllum sibogae (Reyes et al. 2004; Blunt et al. 2006). The biological material was

collected by trawling at depths ranging from 666 to 943m in international waters near

Madagascar, South Africa. Cembrane 7,8-dihydroflabellatene A exhibited potent antiprolifera-

tive activity against a panel of 13 tumour cell lines; GI50 values for some of the lines evaluated

are as follows: prostate DU-145 (82.0 nM), ovary IGROV (90.3 nM), leukaemia K-562

(62.7 nM) and colon HT-29 (14.5 nM). Except these tumour cells, the other nine (ovary

IGROVET, breast SK-BR3, melanoma SK-MEL-28 and NSCL/A549/, pancreas PANC1, colon

LOVO and LOVO-DOX and cervix HeLa and HeLa-APL) have been included in the screening.

Although mechanism of action for the given cembranes has yet remained unknown, it is worth

noting that a cembrane from the octocorals Eunicea succinea and Eunicea mammosa affects

mammalian GABAA receptors (Li et al. 2008).

The search for new inhibitors of indoleamine-2,3-dioxygenase (IDO; proposed to play a

central role in evasion of T-cell-mediated immune rejection) has led to the isolation of a number

of known metabolites in addition to the new natural products annulin C, 2-hydroxygarveatin E,

garveatin E and garvin C (Figure 3) from the hydroid Garveia annulata (Barkley Sound, BC,

USA; collected by hand using scuba, at a depth of 10–20m) (Pereira et al. 2006; Blunt et al.

2008). Most of the known IDO inhibitors are tryptophan analogues, which are active only at

Figure 3. Annulin C, 2-hydroxygarveatin E, garveatin E and garvin C.

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concentrations of ,10mM and greater, making them marginal drug candidates. Annulin C and

related compounds were the most potent inhibitors (submicromolar) identified in the study.

Three of this four novel natural products (namely, annulin C, 2-hydroxygarveatin E and

garveatin E) are shown to be more active (Ki 0.14, 1.40 and 3.10mM, respectively) than

1-methyltryptophan (Ki < 6.60mM) which is one of the most potent IDO inhibitors reported

to date in the literature.

Lobophytum michaelae (Ken-tin, southern Taiwan; at a depth of 2–3m) yielded the

moderately to potently cytotoxic michaolides A–K (Figure 4) (Wang et al. 2007; Blunt et al.

2009). Michaolides B and F exhibited potent cytotoxicity against colon HT-29 and leukaemia

P-388 cell lines, while michaolides I and K exhibited moderate cytotoxicity against the same

tumour cells. Hydroxylation at C-14 together with an a-exo-methylene-g-lactone and a 3,4-

trisubstituted epoxy may be important for potent cytotoxicity. However, the mechanism of

action of michaolides needs to be investigated in detail.

Of four new cembranoids A–D (Figure 5) isolated from the hybrid soft coral Sinularia

maxima £ Sinularia polydactyla (collected at Piti Bomb holes, a shallow reef on the leeward

side of Guam; hybrids were verified by classical taxonomic procedures such as spicule

morphology) strong cytotoxic activity towards tumour cell lines was observed for

cembranoid C (Kamel et al. 2007; Blunt et al. 2009). This compound exhibited strong

cytotoxicity against the growth of ovary cancer IGROV, breast cancer SKBR3, melanoma

Figure 4. Michaolides A–K.

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SK-MEL-28, pancreas PANC1, colon LOVO and LOVO-DOx and cervix HeLa and HeLa-

Apl cell lines with GI50 values of 0.520, 0.039, 0.540, 0.580, 0.510, 0.750, 0.480 and

0.560mM, respectively.

In addition to eleven known diterpenes, five new eunicellins pachycladins A–E (Figure 6)

were isolated from Cladiella pachyclados (collected from Hurghada at the Egyptian Red Sea

coast by scuba at depths of 5m) (Hassan et al. 2010; Blunt et al. 2012). Pachycladin A

demonstrated potent activity in an in vitro model of prostate cancer cells PC-3 migration and

invasion. The eunicellins also target microtubules (Cortes et al. 2012).

With the development of numerous specialised software packages, the investigation of

structure-activity relationship (SAR) has become common method for preliminary

determination of chemical properties. Among the most widely examined parameters are

octanol–water partition coefficient (logP, clogP and AlogP), polar surface area (PSA and tPSA)

and the molecular refractivity (MR and AMR). In general, correlation between experiments and

SAR studies is high, but some differences may emerge. Despite all other natural products at

focus herein, acylspermidines A–C failed on Lipinski rule, due to their large MW and high logP

values; the applied software DruLiTo (Drug Likeness Tool) is the frequently used software for

drug design studies (Kerns & Di 2008; Bickerton et al. 2012).

Figure 5. Cembranoids A–D.

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Figure 6. Pachycladins A–E.

Figure 7. Geographical distribution of the cnidarian samples reported herein.

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3. Conclusion

Antitumour activity of 12 novel natural products isolated from 7 marine cnidarian species has

been discussed in this article. The geographical data clearly point out the Far East as one of

particularly important region for the researchers in the field (Figure 7). It is also worth noting that

majority of the research work done so far covered colon and cervical tumours. None of the

marine organisms including the cnidarians produce final drugs all by themselves. On the

contrary, they make bioactive compounds tightly linked with adaptations to their ecosystems.

In any case, these natural products do have potential to inspire chemists and biochemists (using

simplification and computer-aided design) in the search for the better antitumour agents than

existing ones (Pejin et al. 2013; Pejin, Mojovic et al. 2013).

Acknowledgements

This study was supported by the Ministry of Education, Science and Technological Development of theRepublic of Serbia (grant nos 172053 and III 41005). B.P. gratefully acknowledges two fellowships of theItalian Ministry of Foreign Affairs, two fellowships of the European Commission (the projects Basileus andHPC-Europa2, respectively) and two fellowships of the United Nations which provided him the opportunityto acquire new knowledge and skills in the field of natural product chemistry. The same author is alsothankful to the Science Popularisation Society Novi Sad (chaired by Prof. Ruza Halasi, Ph.D. in Chemistry)for its particularly kind help and support.

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