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New and Highly Potent Antitumor Natural Products from Marine-Derived ... 1University of Belgrade, Institute of Multidisciplinary Research - IMSI, Kneza ...
Send Orders for Reprints to [email protected] Current Topics in Medicinal Chemistry, 2013, 13, 2745-2766

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New and Highly Potent Antitumor Natural Products from Marine-Derived Fungi: Covering the Period from 2003 to 2012 Boris Pejin1,*, Katarina K. Jovanovi2, Milo Mojovi3 and Aleksandar G. Savi1,* 1

University of Belgrade, Institute of Multidisciplinary Research - IMSI, Kneza Viseslava 1, 11030 Belgrade, Serbia; Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; 3University of Belgrade, Faculty of Physical Chemistry, Studentski trg 12-16, 11158 Belgrade, Serbia 2

Abstract: This review covers the 2003-2012 literature data published for antitumor natural products from marine-derived fungi. The focus is on new and highly potent cytotoxic compounds, together with details related to the relevant fungal species. It describes 22 promising bioactives, originating mainly from symbiotic fungi. The chemical structures of all highlighted organic molecules are briefly discussed.

Keywords: Antitumor activity, marine-derived fungi, novel leads, secondary metabolites. INTRODUCTION The purpose of this review is to consolidate the research literature published from 2003 to 2012 in the field of antitumor pharmacology of marine-derived fungi. Indeed, the stress is on particularly active new compounds and their intriguing natural resources. Bioprospection has become dynamic scientific field that explores novel possibilities for the implementation of natural products. During more than last 60 years, much of efforts in chemical science have been focused on the metabolites from the sea, the only truly unexplored environment on Earth [1,2]. The chemical and biological diversity of the marine ecosystems represents the extraordinary resource for discovering new leads that can be used in various pharmaceutical purposes, including the treatment of tumors. Estimated number of species inhabiting sea ecosystems is between 1 and 2 millions. Variety of species and environmental conditions significantly different than those in terrestrial ecosystems provided evolutionary pressure for development of unique molecules. These chemicals, generally referred as secondary metabolites, involve polyketides, terpenoids, steroids, alkaloids and peptides, shikimic acid and its derivates, and some other compounds [3]. From the number of novel compounds published each year, it is evident that natural products chemistry of marinederived fungi is rapidly developing, and still has not reached its climax. In most cases, assignments of a given metabolite to a certain category are practically based on structural considerations, and only represent the authors' personal judgment. It is also clear that any approach to classify the enormous structural diversity of these metabolites according to biogenetic categories is somewhat arbitrary, since there are numerous examples of mixed biogenesis, such as PKS – *Address correspondence to this author at the University of Belgrade, Institute of Multidisciplinary Research - IMSI, Kneza Viseslava 1, 11030 Belgrade, Serbia; Tel: +381 11 2078480; Fax: +381 11 3055289; E-mails: [email protected], [email protected] and [email protected] /13 $58.00+.00

NRPS (polyketide synthase – non-ribosomal peptide synthase) hybrids, e.g. responsible for the generation of pseurotin congeners, or the numerous cases of prenylated alkaloids and prenylated polyketides. Polyketides play a dominant role, and if prenylated polyketides and nitrogencontaining polyketides (e.g. alkaloids) are taken into account, their total share will exceed 50% of all new natural products from marine-derived fungi, which is similar to the situation of terrestrial fungi. A clearly emerging picture based on molecular sequence data is that fungal PKS can be grouped into three subtypes, i.e. non-reducing, partiallyreducing and highly reducing, and for the limited number of fungal secondary metabolites for which biogenetic gene clusters have been identified and characterized, this division is also reflected in the relevant structures of the natural products. Among novel compounds from the fungi until mid2010, terpenoids and peptides make 30% (i.e. 15% each), shikimates 2% and lipids 1% [4]. The proper identification and classification of marinederived fungi is critical to the study of natural products. Without proper identification and preservation of fungal isolates, chemical investigations of fungi become difficult if not impossible to reproduce. Although fungi have historically been identified and classified primarily by morphological characteristics, mycologists now employ a number of techniques to help identify fungi and to organize fungal systematics, such as DNA GC (guanine-cytosine) content, RAPD (random amplified polymorphic DNA) fingerprints, RFLP (restriction fragment length polymorphism) analyses. Incorporating chemotaxonomy into fungal natural products research should be also very useful for comparing strains and dereplication of known metabolites [5]. The distribution of marine-derived fungi given in the review of Bugni and Ireland (2004) has been categorized based on the source of the fungus and revealed trends linking fungal sources to biosynthetic diversity. It has been apparent that sponges have yielded the greatest taxonomic diversity. Indeed, fungi obtained from either sponges, algae, or wood © 2013 Bentham Science Publishers

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substrates have accounted for the majority of chemistry described (70%). Interestingly, sponge-derived fungi have accounted for the largest number (33%) of total compounds in the literature and had the overall highest number of new metabolites. Algicolous fungi have been second accounting for 24% of the total number of natural products, but represented a slightly higher percentage (27%) of novel metabolites. Additionally, the ratio of new metabolites to known metabolites have been much higher for algicolous fungi (3.1 : 1) as compared to sponge-derived fungi (1.4 : 1). The dendryphiellins, one of the structures that attract a great deal of attention, came from obligate marine species. Since very few obligate species have been investigated, the marine environment still represents a virtually untapped resource for both fungal and chemical diversity. Relatively little is known about the relationships between fungi and their hosts especially with respect to chemical ecology. Nonetheless, endophyte studies on marine grasses and mangroves clearly show that these habitats represent rich sources for both obligate and facultative fungi. Overall, both endophytic fungi from marine habitats and obligate marine fungi are one of the least studied groups of fungi and therefore offer huge potential for the discovery of novel pharmacologically active compounds [5]. The long lasting dogmatic point of view that salt water represents the environment not suitable for microorganisms, remained the variety of species unexplored for a long time. One difficulty in exploration of marine-derived fungi lies in the fact that many of them are symbiotic which makes the cell culturing and identification of their metabolites highly demanding tasks. Indeed, the fraction of culturable isolates of marine-derived fungal strains is very low, i.e. in the range of 1% or less, with regard to the overall estimated biodiversity, similar to the situation with bacteria [4]. This low culturability may reflect the artificial conditions inherent in most culture media, e.g. the lack of specific nutrient required for growth. Hence, developing cultivation methods is a prerequisite for comprehensive investigation of marine natural products of microbial origin. Different studies in recent years demonstrated that some 'not-yet-cultured' species can be grown by the refinement of classical approaches. Metagenomics enables direct access to the genomes of whole environmental microorganisms by total environmental DNA (eDNA) extraction. It is an effective way to access natural products encoded by the genomes of previously uncultured microbes through introduction of eDNA into a suitable host and screening of these large eDNA libraries for bioactive clones [6]. It is worthy of notice that most metabolites of marinederived fungi are produced by Aspergilli and Penicillia. Although members of each genus are prolific sources of metabolites, they are somewhat ubiquitous and most are not unrivalled species. One explanation for the high number of compounds reported from these two genera is that both Aspergillus and Penicillium spp. are salt tolerant, fast growing species and are easily obtained from many substrates. In addition, many Aspergillus and Penicillium spp. are known to produce extracts with a wide variety of activities. Decreasing the number of ubiquitous species isolated could represent a valid method to increase the probability of producing new chemistry.

Pejin et al.

Extensive exploration of compounds originating from marine-derived fungi has started from the 1990s, with notably increase since 1998 [7]. In 2007, there was a significant increase (38%) in the number of novel natural products from the fungi reported from 2006. If the distribution by phylum for 2006 and 2007 data is compared with the historic average derived for the period 1965-2005, some categories have remained steady. Concerning the category of microorganisms, the noticed rise of 600% in 2007 over the average figure for 1965-2005 is clear reflection of the growing interest in fungi and bacteria of marine origin. On the other hand, steady rises in outputs are also apparent in the more traditional categories of sponges, cnidarians, red algae and echinoderms [8]. The investigation of biological activity of the aforementioned metabolites is mainly focused on the areas of microbiology and oncology. However, other selective activities such as antagonism of platelet activating factor, neuritogenic effect and radical scavenging potential have been examined as well. This review covers 22 new and potent antitumor compounds from marine-derived fungi published from 2003 to 2012. The natural products herein have shown promising activity against broad spectrum of human cancers including leukemia. Since biochemical and genetic mechanisms involved in the development of these cancers differ significantly, the treatment of each type requires specified agents. In ideal case, isolated metabolites should be tested on a large number of tumors, with the aim at resolving the mechanism of action. However, in practice they are often examined to only several cancer cell lines, as the preliminary screening for their cytotoxicity. The importance of finding novel treatments can be easily emphasized by the number of newly diagnosed tumors and deaths in USA for 2013, according to the National Cancer Institute – NCI (Table 1). Lung cancer is the leading cause of cancer-related deaths in men and women worldwide, with over one million deaths per year. Approximately 228.000 new cases is expected, followed by 159.000 deaths [9]. The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC), comprising about 80% of all lung cancers [10]. The great majority of lung cancer has been known to be caused by smoking. However, several epidemiological studies reported increasing proportion in never smokers [11-16]. The most of the colon cancers are adenocarcinomas. Estimated number of novel cases and deaths from colon and rectal cancers are about 143.000 and 51.000, respectively. Heredity plays an important role for development of colon cancer, thus 20-25% of patients with colorectal cancers have the family history of disease [17-19]. Breast cancer affects the tissues of the breast, usually ducts and lobules. Both female and male population are affected, with the estimation of approximately 232.000 female and 2.000 male newly diagnosed patients, respectively. In addition, approximately 40.000 female and 400 male deaths are assumed by the end of 2013. In most cases, breast carcinoma is the epithelial breast cancer. The well studied risk factors include family history, nulliparity, early menarche, advanced age and a personal history of this cancer [20,21].

Promising Marine Substances in Tumor Research

Table 1.

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Estimation of Newly Diagnosed Tumors and Deaths in the United States for 2013, According to the National Cancer Institute.

Cancer

Novel patients

Deaths

Lung

228.190

159.480

Colon

142.820

50.830

Breast

234.580

40.030

Prostate

238.590

29.720

Leukemia

48.610

23.720

Liver

30.640

21.670

Bladder

72.570

15.210

Brain & CNS

23.130

14.080

Ovary

22.240

14.030

Kidney

65.150

13.680

Cervical

12.340

4.030

Prostate cancer usually affects older men; the median age at diagnosis is 72 years. The aforementioned statistics indicates about 239.000 new cases and 30.000 deaths. It should be emphasized that more than 95% of primary prostate cancers are adenocarcinomas. Leukemia is the type of cancer that starts in bloodforming tissue, such as bone marrow. It can occur in any age, but is more frequent in childhood. Approximately 49.000 novel cases and 24.000 deaths are predicted for the year. It is well known that adult acute lymphoblastic leukemia arises from malignant transformation of B- or T-cell progenitor cells [22,23]. Up to 5% of cirrhotic patients develop liver cancer, while 50-80% of patients with the cancer suffer from cirrhosis. More than 30.000 new cases of liver and intrahepatic bile duct and 21.000 deaths are estimated. The incidence of this type of cancer is raising, primarily due to of hepatitis C infection spreading; however, cirrhosis also represents risk factor [24-26]. Majority of the bladder cancers are transitional cell carcinomas, while less frequently are the squamous cell carcinoma and adenocarcinoma. Approximately 73.000 novel cases and about 15.000 deaths have been expected [27]. Brain cancers account 85-90% of all primary CNS cancers. Other, less frequent brain cancers (decreasing order of frequency) include pituitary cancers, schwannomas, CNS lymphomas, oligodendrogliomas, ependymomas, low-grade astrocytomasa and medulloblastomas. Cancers affecting brain and CNS are supposed to be newly diagnosed in about 23.000 patients, causing approximately 14.000 deaths [28,29]. Several malignancies can arise from the ovary. The most common is epithelial carcinoma that causes 50% of all cases

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occurring in women older than 65 years. About 22.000 new cases and 14.000 deaths from ovary carcinoma are predicted for 2013. Herreditary pattern are identified, causing ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers [30,31]. Kidney cancer includes renal cell carcinoma, renal pelvis carcinoma, both affecting the adults and Wilms tumor that affect children under the age of 5. According to the estimates, it should be newly diagnosed in approximately 65.000 patients, followed by 13.500 deaths [32,33]. Fortunately, more than 90% of patients with cervical cancer are diagnosed early, using the Pap test and human papillomavirus (HPV) testing. Mortality rate would be even lower if larger percent of women are tested regularly. The estimations for novel cases and deaths are 12.000 and 4.000, respectively. Mortality significantly increases if capillaries and lymph nodes are affected; indeed, correlation between the tumor size/volume and survival rate has been observed [34-36]. Proposed molecular mechanisms of antitumor activity so far reflect the variety of examined marine natural products. More important, different modes of action strongly open the possibility for their synergistic activity. Phosphoinositidine 3-kinases (PI3Ks) belong to the large family of lipid kinases with major roles in important cellular processes, including cell survival, proliferation and differentiation. Phospholipids, generated by activity of these kinases, participate in activation of the serine/threonine kinase AKT and many other downstream cellular pathways. According to structural characteristics and substrate specificity, PI3Ks are divided into three classes: I, II and III. The class I PI3Ks is the most commonly studied one, because these enzymes are directly activated by cell surface receptors. After it is activated, the synthesis of the phospholipid PI(3,4,5)P3 occurs, which in turn triggers multiple downstream signalling cascades in cell. Phosphatase and tensin homolog (PTEN) is a protein which acts as a tumor suppressor gene and plays a significant role in this complex signal transduction process. PTEN is an antagonist of PI3Ks, working in a way that reduces the cellular pool of PIP3 by converting PI(3,4,5)P3 back to PI(4,5)P2. AKT (protein kinase B, PKB) is a serine/threonine kinase existing in three isoforms in cells: AKT1, AKT2 and AKT3, which are encoded by the PKB, PKB and PKB genes, respectively. Activation of AKT is performed by docking of the N-terminal region of AKT to membrane-bound PI(3,4,5)P3, leading to conformational change of AKT, which is reflected in exposition of two critical amino acid residues for phosphorylation. Indeed, to be fully active both amino acid residues of AKT must be phosphorylated (Fig. 1). Uncontrolled activation of PI3K pathway contributes to all important aspects of tumorigenesis; however, there are inhibitors which target different stages in the signalling pathway [37]. FOXO is the member of O subclass family of forkhead transcription factors in downstream PI3K pathway. The members of its family, namely FOXO1, FOXO3a and FOXO4, are important regulators of cell death. Actually, they promote cell survival and resistance to chemotherapy drugs and radiation therapy. Interestingly, more anticancer drugs such as doxorubicin and paclitaxel have been shown to induce apoptosis through oxidative stress,

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Pejin et al.

Fig. (1). PI3K/AKT pathway (phosphatidylinositol-4,5-bisphosphate – PIP2; phosphatidylinositol-3,4,5-triphosphate – PIP3; phosphoinositide-dependent kinase 1 – PDK1; Bcl-2-associated death promoter protein – BAD; serum and glucocorticoid-inducible kinase – SGK; protein kinase C – PKC; glycogen synthase kinase 3 beta – GSK; mammalian target of rapamycin – mTOR; Ras-related C3 botulinum toxin substrate 1 – Rac1) [37, modified].

which enhances FOXO3a activity by stimulating its nuclear translocation and thus causing overexpression of FOXOresponsive genes such as Bim, p27 and p21 [38]. Vascular endothelial growth factor (VEGF) is a vascular permeability factor secreted by malignant cells and tumorassociated stromal cells as well. During the tumor growth, its cells become hypoxic due to exhaustion of the available oxygen supplies. Secretion of VEGF stimulates growth of blood vessels into hypoxic tumor tissues, supplying the tumor with oxygen and nutrients (Fig. 2). The most established approach today for inhibiting tumor angiogenesis is blocking of the VEGF pathway. Bevacizumab, a humanized anti-

VEGF monoclonal antibody, in combination with 5fluorouracil (5-FU) showed some promising results. Various tyrosine kinase inhibitors (such as sorafenib, sunitinib or pazopanib) were approved together with bevacizumab for clinical use by U.S. Food and Drug Administration (FDA). These targeted therapeutics are used in many forms of cancer: metastatic non-squamous NSCLC, metastatic breast cancer, recurrent glioblastoma multiforme and metastatic renal cell carcinoma [39,40]. Polyamine cations in cells, such as putrescine, spermidine and spermine, play a significant role, controlling the growth and differentiation of animal cells. These molecules

Fig. (2). VEGF pathway (vascular endothelial growth factor – VEGF; placent growth factor – PLGF; neuropilin receptor - NRP) [39,40 modified].

Promising Marine Substances in Tumor Research

participate in regulation of DNA replication, transcription and translation through their binding to cellular polyanionic compounds – DNA, RNA and phospholipids. Indeed, high levels of polyamines are frequently seen in malignant transformed cells. Ornithine decarboxylase (ODC) is the first enzyme in polyamine synthesis and its activity is therefore of crucial importance for tumor progression. MYC oncogene is found to target many enzymes in the polyamine pathway, including ODC and spermidine synthase (SRM). It is well known that polyamines derive from the amino acid arginine, which is converted to ornithine. ODC performs decarboxylation of ornithine, making the third product in a row, putrescine. In subsequent reactions, SRM uses decarboxylated Sadenosylmethionine (dcSAM) as a propyl amine donor, producing spermidine. The compound is capable of converting lysine residue of the eukaryotic translation initiation factor 5A (eIF5A) protein to the novel amino acid hypusine (Fig. 3). Over-expression of MYC oncogene in many cancer types deregulates finely orchestrated polyamine pathway, yielding constitutively high levels of ODC expression and activity [41,42].

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Selected Marine Natural Products of Fungal Origin 2003 1.

Trichodermamide B

2004 1.

Leptosins O and P

2.

Peribysins C and D

2005 1.

3R*,4R*-dihydroxy-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)quinolinone

2006 IB-01212 Zygosporamide 2007 1.

Cephalimysin A

2.

Pericosines A, B and D

3.

Urukthapelstatin A

2008 1.

none [43]

2009 1.

Conidiogenone C

2.

Ustusorane E

2010 1.

Anhydrofusarubin

2.

Cryptosphaerolide

Fig. (3). MYC oncogene in the polyamine pathway (Sadenosylmethionine – SAM; adenosylmethionine decarboxylase – AMD; decarboxylated – dc; eukaryotic translation initiation factor – eIF) [41].

3.

Epoxyphomalin D

4.

Merulin C

5.

Paeciloxocins A

Trichodermamides A and B (Fig. 4), two modified dipeptides, have been isolated from cultures of the marine-derived fungus Trichoderma virens originated from the ascidian Didemnum molle and from the surface of a green alga of the genus Halimeda, both collected in Papua New Guinea. The ascidian-derived culture contained trichodermamide A with traces of trichodermamide B while a greater quantity of trichodermamide B was isolated from the algal-derived strain. The trichodermamides possess a rare cyclic O-alkyloxime functionality incorporated into a six-membered ring. Trichodermamide B displayed significant in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 0.32 g/ml; the chlorohydrin moiety at C4 and C5 might be responsible for its biological activity [45,46]. The total synthesis of the trichodermamides A and B is well described. Starting from affordable, easily available (–)-quinic acid, the enantioselective synthesis of a unique 4H-5,6dihydro-1,2-oxazine ring moiety has been achieved by an intramolecular epoxide ring-opening reaction by an oxime [47].

6.

(2E,4E)-1-(2,6-dihydroxy-3,5-dimethyl-phenyl)hexa-2,4-dien1-one

7.

SZ-685 C

2011 none [44]

Fig. (4). Trichodermamides A and B.

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Leptosins belong to a series of epipolysulfanyldioxopiperazine class of chemical compounds produced mainly by various strains of Leptosphaeria sp. that have been originally isolated from the marine alga Sargassum tortile. These secondary metabolites have similar structures (indole derivatives) and exhibit in vivo cytotoxic activity, to broad spectrum of cell lines. Structurally, leptosins are related to bionectins, isolated from Bionectra byssicola F120, which are known as inhibitors of bacterium growth. Members of leptosin family include A-F, J, K, K1, K2, M, M1, N, O, P, R and S (Figs. 5-8); all of them are tested on cytotoxicity.

Pejin et al.

lymphocytic leukemia cell line and a disease-oriented panel of 39 human cancer cell lines (HCC panel); results collected from various papers are presented in Tables 2 and 3 [48-50]. It has been also found that leptosin M inhibits specifically two protein kinases (PTK and CaMKIII, at a concentration of 10 g/ml by 40-70%) and human topoisomerases II with an IC50 value of 59.1 M. However, the same compound showed no activity against other protein kinases (PKA, PKC and EGFR, at extreme doses such as 100 g/ml) and topoisomerase I (IC50 > 300 M). On the contrary, leptosin F inhibited the activity of both topoisomerases with IC50 values of 10 M and 10-30 M, respectively. Novel identified leptosins O and P exhibited significant cytotoxicity against the murine P-388 leukemia cell line (ED50 values of 1.60 nmol/ml and 0.14 nmol/ml, respectively) [51]. The proposed total enantioselective synthesis of leptosin D starts with the di-(tert-butoxycarbonyl) derivative of the trioxopiperazine natural product gliocladin C, which is readily available by enantioselective chemical synthesis [52]. Cell-adhesion inhibitors, macrosphelides E-I, L and M and peribysins A-G and J, from a strain of Periconia byssoides OUPS-N133, were originally separated from the sea hare Aplysia kurodai. Peribysins A-D are eremophilane sesquiterpenoids of which peribysins C and D represent a new class of furanofuran (Fig. 10).

Fig. (5). Leptosins A-F.

Peribysins C and D were potent inhibitors of the adhesion of HL-60 cells to HUVEC, whereby the latter was the more active compound. Indeed, peribysin D exhibited the inhibitory activity that resulted 332 times more potent than macrosphelide M (one of the most potent cell adhesion inhibitors) and even 380 times more potent than herbimycin A used as standard (Fig. 11, Table 4) [53-59]. Without a doubt, cell-adhesion inhibitors are expected to be useful milestones for prevention of cancer metastasis. It is noteworthy that total synthesis of peribysin E has been recently performed [60]. The alkaloid 3R*,4R*-dihydroxy-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone (1) (Fig. 12) was isolated from Penicillium janczewskii derived from surface water (German Bight, Helgoland Island). Besides this compound, two metabolites with similar structures were isolated from the same organism: 3S*,4R*-dihydroxy-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone (2) and 3-methoxy-4-hydroxy-4-(4-methoxyphenyl)-3,4dihydro-2(1H)-quinolinone. The compound 1 displayed strongly cytotoxic activity to SK-OV-3 cells of human ovarian carcinoma (8.1% viability at a standard concentration of 10 μg/ml, Table 5) [61].

Fig. (6). Leptosin J.

Leptosins A-C, dimeric epidithiodioxopiperazines, have been reported to show more potent antitumor activity than leptosin D, a monomeric epidithiodioxopiperazine. In addition, leptosins K, K1 and K2 exhibited more potent cytotoxic activity than mitomycin C (Fig. 9), tested on the P-388 lymphocytic leukemia cell line. The anticancer potential of leptosins M, M1 and N were examined using the murine P-388

IB-01212, a new cytotoxic cyclodepsipeptide, was isolated from the mycelium extract of Clonostachys pytriodes ESNA-A009. Its chemical structure resembles on thiocoraline (Fig. 13); indeed, IB-01212 is a C2 symmetric octapeptide featuring a six-membered cyclic core, with two residues each of L-N,NMe2Leu, L-Ser, L-NMeLeu and L-NMePhe. It is known that marine organisms have unique biochemical features. Variety of peptide or depsipeptide structure and conformational diversity, lies in the presence of rare residues such as N- or C-alkylated amino acids, ,-dehydro amino acids, D-amino acids and hydroxyl acids. IB-01212 showed potent antitumor activity in test on LNCaP (prostate),

Promising Marine Substances in Tumor Research

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Fig. (7). Leptosins K-N.

Fig. (8). Leptosins O-S.

Fig. (9). Mitomycin C.

SK-BR-3 (breast), HT-29 (colon) and HeLa (cervix) with an GI50 value on the order of 10-8 M [62]. Some synthetic derivates were even more efficient than the original natural product (Table 6) [63-64]. Table 2.

Cytotoxic Activity of Leptosins K, K1 and K2 Against P-388 Cell Line Compound

Leukemia P-388 ED50 (μg/ml)

Leptosin K

0.0038

Leptosin K1

0.0022

Leptosin K2

0.0021

Mitomycin C

0.0400

The D-amino acid analogues 3–5 were less active than synthetic IB-01212, except analogue 2 that was almost as

active as analogue 1 (IB-01212 synthetic natural). This finding demonstrates the importance of the L configuration in each position of the cyclodepsipeptide, and confirms the stereochemical configuration established for IB-01212 in the previous experiments. Analogues 16–21 with a larger macrocycle than the reference compound differed in their activity. Whereas analogues 16 (2 Dab) and 18 (2 Orn) were active against all the cell lines, analogues 17 (Ser, Dab), 19 (Ser, Orn), 20 (2 Lys), and 21 (Ser, Lys) were less active. The lower activity of these four compounds indicates that size is important for activity. The activity of 16 and 18 (also larger cycle sizes) can be interpreted by the presence of the two amide bonds, which counterparts the increase in macrocycle size. This general loss of cytotoxic activity with increased macrocycle size could be explained by a decrease in intramolecular hydrogen bonding of the macrocycle. It may generate a greater degree of freedom in the molecule, which results in more conformations and a decrease in the proportion of the most active conformation. Another possible explanation for the observed activity is an improvement in the

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Table 3.

Pejin et al.

Cytotoxic Activity of Leptosin M Against Broad Spectrum of Human Cancer Cell Lines  Origin of cancer

Breast

Cell line

Log GI50 (M)

HBC-4

-5.55

BSY-1

-5.76

HBC-5

-5.62

MCF-7

-5.29

MDA-MB-231

-5.17

U-251

-5.62

SF-268

-4.96

SF-295

-4.79

SF-539

-5.59

SNB-75

-5.64

SNB-78

-5.59

HCC-2998

-5.36

KM-12

5.21

HT-29

-5.14

HCT-15

-4.75

HCT-116

-5.57

RXF-63IL

-4.80

ACHN

-4.73

NCI-H23

-5.11

NCI-H226

-5.61

NCI-H522

-5.79

NCI-H460

-5.09

A-549

-4.67

DMS-273

-5.55

DMS-114

-5.59

LOX-IMVI

-5.37

OVCAR-3

-5.44

OVCAR-4

-4.77

OVCAR-5

-5.03

OVCAR-8

-5.44

SK-OV-3

-4.61

DU-145

-4.76

PC-3

-4.87

St-4

-4.72

MKN-1

-5.65

MKN-7

-5.45

MKN-28

-5.41

MKN-45

-4.82

MKN-74

-5.76

Central nervous system

Colon

Kidney

Lung

Melanoma

Ovary

Prostate

Stomach

Promising Marine Substances in Tumor Research

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

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Fig. (10). Peribysins A-G.

Fig. (11). Macrosphelide M and herbimycin A.

optimal macrocycle size and its conformation requirements with the receptor binding site. The results indicate that the size and a high degree of symmetry in the molecule are required for biological activity. Finally, analogues 13 and 22 with Cys residues at positions Aaa3 and Aaa7, inspired by the cyclothiodepsipeptide thiocoraline, were also less active than the reference compound. The higher lability of the thioester bonds may cause the decrease in their biological activity. The overall results from these structure-activity relationship (SAR) studies may be used for the design of a new series of cyclodepsipeptides based on the same scaffold. Total solid-phase syntheses of IB-01212 have been performed in parallel via three distinct routes: dimerization of heterodetic fragments, linear synthesis, and convergent synthesis. The convergent strategy gave the best results in terms of product yield and purity and is particularly suitable for the large-scale synthesis of IB-01212 and similar peptides [65]. Zygosporamide is a cyclic depsipeptide isolated from the seawater-based fermentation broth of a marine-derived fungus Zygosporium masonii, strain CNK-458 (Maui, Hawai; the culture of Z. masonii was separated from a cyanobacterium). It is composed of four hydrophobic amino acids (D-Leu, L-Leu and 2 L-Phe/) and one hydrophobic hydroxy acid ((S)-2-hydroxy-4-methylpentanoicacid/O-Leu/) (Fig. 14). This compound was tested for cytotoxicity against 60 cancer cell lines in NCI. Specificity was particularly high against CNS cancer cell line SF-268 and renal cancer cell line RXF-393, with GI50 values of 6.5 nM and less than 5.0 nM, respectively (Table 7). The obtained values are at least

1000 times more selective than most of the 54 tested cancer cell lines considering the median GI50 of 9.1 M. The pattern of cytotoxic activity is unusual and seems to be different from the known molecular mechanisms. The preliminary SAR studies reveals that both the hydrophobic group of DLeu1 and the phenyl group of L-Phe3 or L-Phe5 may be good targets for further rational design. Total synthesis of zygosporamide is performed and includes the macrocyclization at the site of connection D-Leu with L-Phe [66,67]. Table 4.

HL-60/HUVEC Cell-Adhesion Inhibitory Activity of Several Peribysins, Macrosphelide M and Herbimycin A.

Compound

Leukemia HL-60/HUVEC IC50 (μM)

Peribysin A

0.3

Peribysin B

2.7

Peribysin C

2.7

Peribysin D

0.1

Peribysin E

11.5

Peribysin J

11.8

Macrosphelide M

33.2

Herbimycin A

38.0

2754 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Pejin et al.

against the murine P-388 leukemia cell line and the human HL-60 leukemia cell line; the observed IC50 values were 15.0 nM and 9.5 nM, respectively [68,69]. The proposed catalytic enantioselective synthesis of this secondary metabolite takes advantage of a novel tandem photoisomerization/Stetter reaction and provides rapid access to the desired spirofuranone lactam core in good yield and excellent enantioselectivity [70].

Fig. (12). 3R*,4R*-dihydroxy-4-(4- methoxyphenyl)-3,4-dihydro2(1H)-quinolinone (1) and 3S*,4R*-dihydroxy-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone (2). Table 5.

Cytotoxic Activity of Two New Diastereomeric Quinolinones Against the Selected Human Cancer Cell Lines.

Cell line

1*

2*

Breast MDA-MB-231

31.8

52.9

Colon HT-29

32.8

58.8

Kidney CAKI-1

65.1

80.3

Lung A-549

56.8

56.3

Melanoma SK-MEL-2

39.0

55.2

Ovary SK-OV-3

8.1

44.6

Prostate DU-145

48.4

50.6

1 – 3R*,4R*-dihydroxy-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone 2 – 3S*,4R*-dihydroxy-4-(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone * – percent of viability at a standard concentration of 10 μg/ml

Cephalimysin A belongs to a family of natural products containing a unique 1-oxa-7-azaspiro[4.4]non-2-ene-4,6dione core structure. It was isolated from a strain of Aspergillus fumigatus OPUS-T106B-5 originally separated from the marine fish Mugil cephalus (source not given) (Fig. 15). Cephalimysin A exhibited significant cytotoxic activity

Fig. (13). IB-01212 and thiocoraline.

Pericosines A-E (Fig. 16) are carbasugar-type metabolites isolated from a strain of Periconia byssoides originally separated from the sea hare Aplysia kurodai. Pericosines A, B and D were significant growth inhibitor of the murine P388 leukemia cell line (ED50 0.1 μg/cm3, 4.0 μg/cm3 and 3.0 μg/cm3, respectively). Pericosine A also showed remarkable growth inhibition against HBC-5 (breast; log GI50 -5.22) and SNB-75 (CNS, log GI50 -7.27) cell lines. Finally, this compound exhibited significant in vivo tumor-inhibitory activity against P-388 in mice and inhibited protein kinase EGFR (at a concentration of 100 μg/ml by 40-70%) and topoisomerase II (with IC50 value of 100-300 mM) [71]. The first total synthesis of (+)- and (–)-pericosine A has been achieved, enabling the revision and determination of the absolute configuration of this antitumor natural product [72]. Cultured mycelia of Mechercharimyces asporrophorigenens (marine lake sediment, Urukthapel Island, Palau) was the source of urukthapelstatin A (Fig. 17), a cyclic thiopeptide that displayed potent activity against HCC panel, first of all on A-549 cells (lung, IC50 12 nM). A weak correlation coefficient in the COMPARE analysis has indicated that urukthapelstatin A may have a unique mode of action [73,74]. The first total synthesis of this natural product utilizes a convergent synthetic strategy. Interestingly, several intermediates, including the linear and serine cyclized precursors, show a 100-fold decrease in cytotoxicity, with IC50's in the low micromolar range. These data indicate that the rigidity and the consecutive aromatic heterocyclic system are responsible for the biological activity [75]. The diterpene conidiogenone C (Fig. 18) was isolated from Penicillium sp. (sediment, 5080 m, location not given) along with conidiogenol. Several more members of conidiogenone (up to I) were isolated from the culture extracts of Penicillium chrysogenum QEN-24S, an endophytic fungus derived from an unidentified marine red algal species of the

Promising Marine Substances in Tumor Research

Table 6.

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

2755

Cytotoxic Activity of IB-01212 and its Analogues Against the Selected Human Cancer Cell Lines. GI50 (μ) Analogues

Breast SK-BR-3

Colon HT-29

Leukemia K-562

Lung A-549

Melanoma SK-MEL-28

Ovary IGROV

Pancreas PANC-1

Prostate DU-145

1

IB-01212 Synthetic

1.23

0.64

7.69

2.90

1.05

1.27

0.65

2.90

2

2[Me2DLeu4,8]

1.36

0.49

0.41

2.19

1.74

2.18

1.70

1.93

1.47

1.42

1.81

2.91

2.25

3.00

1.97

2.25

3

3,7

2[DSer ] 2,6

4

2[MeDLeu ]

3.69

5.32

4.09

9.68

6.28

6.18

4.31

9.67

5

2[MeDPhe1,5]

1.02

1.21

2.68

2.48

2.04

2.73

1.80

2.35

23.00

10.23

50.26

20.26

10.24

12.4

12.92

10.21

6

2,6

1,5

2[Leu ,Phe ] 1,5

7

2[Phe ]

2.94

3.33

2.41

4.35

2.52

2.94

3.87

2.37

8

2[Leu2,6]

4.89

9.95

6.39

9.95

9.95

5.97

9.95

9.95

2[MeSer ]

0.35

5.90

0.50

1.28

0.38

0.79

0.78

1.58

4,8

9

3,7

10

2[Me3Leu ]

9.40

12.95

9.46

11.40

12.40

9.43

14.40

10.40

11

2[AcMeLeu4,8]

12.75

18.73

17.64

12.45

13.65

15.65

14.09

10.05

12

[AcMeLeu8]

1.27

1.94

2.16

2.84

2.01

2.88

1.94

2.08

13

3



9.83



8.63









7

2[Cys ,Cys ] 3,7

14

2[Dap ]-CH

0.71

0.65

0.54

2.86

0.41

1.01

0.52

2.49

15

[Dap3]



0.24

0.16

0.31

0.17

0.20

0.29

0.16

16

3

0.11

0.55

0.88

0.54

0.32

4.24

0.34

0.51

7

2[Dab ,Dab ] 3

17

[Dab ]

2.38

2.87

1.79

2.87

1.20

2.87

2.87

2.87

18

2[Orn3,Orn7]

2.76

0.65

0.63

2.11

0.84

2.76

1.50

2.39

1.89

1.00

1.84

2.66

1.07

1.81

2.11

2.07

3

19

[Orn ]

20

3

2[Lys ,Lys ]







2.52



2.52





21

[Lys3]

1.95

1.29

1.25

2.61

1.10

2.79

2.03

2.77

22

3

1.93

1.61

1.05

2.86

1.14

2.86

1.93

2.86

7

7

2[Dap ,Cys ]

genus Laurencia. This compound has shown potent cytotoxic effect to HL-60 (leukemia; IC50 0.038 M) and BEL7402 (liver; IC50 0.970 M) cell lines [76,77].

Fig. (14). Zygosporamide.

Ustusoranes A-F (Fig. 19) are the benzofuran derivatives isolated from Aspergillus ustus (rhizosphere soil of the mangrove Bruguiera gymnorrhiza; Wenchang, Hainan Province, China). Their structure is related to pseudodeflectusin, the compound isolated from the same organism. Ustusorane E displayed strong growth inhibition of HL-60 cells (leukemia) with an IC50 value of 0.13 M, ustusolates C and E exhibited moderate growth inhibition of A-549 (lung) and HL-60 (leukemia) cells, while ustusolate A showed weak growth inhibition of the aforementioned cell lines [78]. A successful synthesis of ustusorane C is expected to inspire the synthetic process of the related compounds [79]. Fusaranthraquinone, fusarnaphthoquinones A-C and fusarone were obtained from Fusarium spp. (sea fan Annella sp., Koh Hin Ran Pet, Suratthani Province, Thailand) along with austrocortirubin, a metabolite of Australian Cortinarius toadstools (C. basirubescens and C. persplendidus) [80] and a known Fusarium metabolite, the naphtoquinone anhydrofusarubin (Fig. 20). Austrocortirubin was selectively toxic to MCF-7 cells (breast) while anhydrofusarubin displayed potent and selective cytotoxicity (most probably due to its

2756 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Table 7.

Pejin et al.

Cytotoxic Activity of Zygosporamide Against Broad Spectrum of Human Cancer Cell Lines.

Origin of cancer

Panel/Cell line

Log GI50 (M)

MCF-7

Origin of cancer

Panel/Cell line

Log GI50 (M)

-4.39

A-549

-5.13

NCI/ADR-RES

-4.42

EKVX

-5.04

HOP-62

-5.00

MDA-MB-23

-5.07 HOP-92

-5.06

NCI-H226

-4.84

Breast cancer

CNS cancer

Lung cancer

HS-587T

-4.89

MDA-MB-435

-4.87

NCI-H23

-4.80

BT-549

-5.02

NCI-H322M

-4.60

SF-268

-8.19

NCI-H460

-4.30

SF-295

-4.81

NCI-H522

-4.93

SF-539

-4.82

LOX-IMVI

-4.75

SNB-19

-6.22

MALME-3M

-4.89

U-251

-4.61

M-14

-5.00

COLO-205

-5.17

SK-MEL-2

-4.91

HCC-2998

-4.93

SK-MEL-5

-5.06

HCT-116

-4.94

UACC-257

-5.12

HCT-15

-4.73

UACC-62

-5.07

KM-12

-4.81

IGROV-1

-4.84

SW-620

-4.81

OVCAR-3

-5.00

CCRF-CEM

-4.91

OVCAR-4

-4.88

Melanoma

Colon cancer

Ovarian cancer Leukemia

K-562

-4.91

OVCAR-5

-4.88

MOLT-4

-5.18

OVCAR-8

-5.08

RPMI-8226

-5.09

SK-OV-3

-4.99

SR

-5.00

PC-3

-5.04

DU-145

-4.93

786-0

-4.81

A-498

-4.99

ACHN

-4.74

CAKI-1

-4.97

RXF-393

-8.30

SN-12C

-4.96

TK-10

-4.64

UO-31

-4.89

Prostate cancer

Renal cancer

hydropyran unit) against both KB (ubiquitus keratin HeLa) and MCF-7 cells (breast) (IC50 2.0 μM and 0.9 μM, respectively). Anhydrofusarubin also showed cytotoxic effects on human cancer cell lines HCT-8 (colon), MDA-MB-435 (melanoma) and SF-295 (brain); the corresponding IC50 val-

ues were 9.85 μg/ml, 6.23 μg/ml and 6.32 μg/ml, respectively. Bearing in mind that its molecular mechanism of action is still unknown, the mode of action of partially similar compound bostrycin is quite briefly discussed. This compound can induce apoptosis of breast cancer cells through

Promising Marine Substances in Tumor Research

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Fig. (15). Cephalimysin A.

Fig. (16). Pericosines A-E.

Fig. (17). Urukthapelstatin A.

Fig. (18). Conidiogenone C and conidiogenol.

Fig. (19). Ustusoranes A-F and pseudodeflectusin.

2757

2758 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Pejin et al.

Fig. (20). Fusarnaphthoquinones A-C, fusaranthraquinone, fusarone, austrocortirubin, anhydrofusarubin and bostrycin.

the AKT/FOXO pathway and inhibit proliferation of human lung carcinoma A-549 cells via downregulation of the P13K/AKT pathway [81,82]. Very recently, starting from 2,4,5-trimethoxybenzaldehyde, anhydrofusarubin has been synthesized in 12 steps in an overall yield of 5.3% [83]. Cryptosphaerolide (Fig. 21) is an ester-substituted sesquiterpenoid related to the eremophilane class, isolated from Cryptosphaeria sp. (unidentified ascidian, Bahamas). It is an inhibitor of the protein Mcl-1 (a cancer drug target implicated in apoptosis) in the Mcl-1/Bak fluorescence resonance energy transfer assay (FRET) with an IC50 value of 11.40 μM. Cryptosphaerolide is also significantly cytotoxic against HCT-116 cells (colon, IC50 4.50 μM) [84,85]. It was showed that the crude lipid extract of Phoma sp. had potent cytotoxyc activity to several cell lines. Chemical investigation of a marine-derived fungus Phoma sp. (which was obtained from the marine sponge Ectyplasia perox, collected from the Caribbean Sea, Dominica) led to the discovery of epoxyphomalins A and B, prenylated polyketides, belonging to a small family of sesquiterpenes. Further stud-

ies have revealed epoxyphomalins C-E, the compounds that can be also recognized as the members of the family (Fig. 22). Indeed, these natural products, structurally related to cyclohexenones, are formed by diverse analogues of macrophorin, tauranin, peyssonol A and hyatellaquinone. Only the epoxyphomalins and macrophorins, however, are composed of a decalin ring system linked to an epoxydon moiety, and as such are unique chemical entities. Epoxydon and its congeners are well-studied compounds, typically isolated from fungi of the genera Penicillium, Phoma, Panus, Apiospora and Phyllosticta. Epoxyphomalin A was found to be more active than epoxyphomalin B in a panel of 36 human tumor cell lines (14 lines were solid tumors); the relevant mean IC50 values were 0.11 μg/ml and 1.25 μg/ml, respectively (Table 8). More recently, epoxyphomalins C-E (Fig. 20) were isolated by fermentation of Papaconiothyrum sp. (sponge Ectyplasia perox, Lauro Club Reef, Dominicana, Caribean). Among them, epoxyphomalin D was particularly efficient in cytotoxic activity against PC3M cells (prostate; IC50 0.72 μM) and BXF 1218L cells (bladder; IC50 1.43 μM) [86].

Promising Marine Substances in Tumor Research

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

2759

ined cell lines. Cytotoxic activity of merulin C was tested against human breast ductal carcinoma BT-474 and colon adenocarcinoma SW-620 cell lines; the corresponding IC50 values were 1.57 μg/ml and 4.11 μg/ml, respectively.

Fig. (21). Cryptosphaerolide.

Fig. (22). Epoxyphomalins A-E.

Merulins are members of class of endoperoxides that could be further classified as nor-chamigrane (merulin A) or charmigrane (merulins B and C). They were isolated from endophytic fungus Xylocarpus granatum XG8D (mangrove leaves; Thailand). The strand XG8D was classified as a member of family Meruliaceae (order Polyporales, subclass Incertae sedis, class Agaricomycetes, phylum Basidiomycota). Its structure is related to talaperoxides A-D, the compounds isolated from Talaromyces flavus (Heinan, China) (Fig. 23). Although the chemical structure of merulins is very similar, biological effect differs significantly. Merulins B and D show moderate cytotoxic activity, while merulin C presents a potent antitumor compound. In comparison, related talaperoxides B and D are moderately cytotoxic to the exam-

Proposed mechanism of action of merulin C activity is based on the anti-angiogenesis. Angiogenesis, the formation of new blood vessels, is a necessary process for development, reproduction and reparation of injuries. In pathological conditions, angiogenesis is responsible for various diseases including diabetic retinopathy, age-related macular degradation as well as solid tumor development. Therefore, the angiogenesis can be an important target for cancer treatment. This compound was able to suppress the endothelial cell proliferation and migration using two different molecular pathways: PI3K/AKT and extracellular signal-regulated kinase ERK1/2 are responsible for VEGF stimulus of endothelial cells. Treatment of HUVEC with merulin C suppressed the phosphorylation of ERK1/2 in both a dose- and time-dependent manner, but did not affect the expression of phosphorylated AKT. The antiangiogenic property of merulin C is believed to be mediated by the ERK1/2 signaling pathway. This compound causes a strong suppressive effect on the phosphorylation of ERK1/2, and that is in correlation with a previous report in which inhibitors of the ERK1/2 signaling pathway suppress endothelial cell proliferation. It also has a weak inhibitory effect on cell migration constituent which is consistent with its lack of effect on the phosphorylation of AKT, the substanitial step for endothelial cell migration. Present results indicate that merulin C possesses antiangiogenic activity, mainly due to suppressing endothelial cell proliferation and migration; in addition, its inhibitory effect is mediated by regulation of the ERK1/2 signaling pathway. Finally, at a low concentration, the compound inhibits neovessel formation in both ex vivo and in vivo assays [87-90]. The semisynthetic optimization of the merulin class of endoperoxide natural products has been recently developed [91]. Paeciloxocins A and B, (2-(1-hydroxy-3-methylbutyl) and 2-(1-acetoxy-3-methylbutyl)-11-hydroxy-9-methyl1-methoxy-5H,7H-dibenzo[b,g]-1,5-dioxocin-5-ones) (Fig. 24), are two new aromatic metabolites isolated from the mangrove fungus Paecilomyces sp. collected from the Taiwan Strait. Both paeciloxocin A and paeciloxocin B exhibited cytotoxicity against the HepG2 cell line (liver); the corresponding IC50 values were 1 μg/ml and 65 μg/ml, respectively [92,93]. The monomeric C-methylated hexaketide (2E,4E)-1(2,6-dihydroxy-3,5-dimethyl-phenyl)hexa-2,4-dien-1-one (Fig. 25), a marine secondary metabolite with strong activity to HeLa (cervical cancer; IC50 11.20 μg/ml) and SW-620 cells (colon; 74% inhibition at tested concentration 10 μg/ml), has been reported from Penicillium sp. (sediment, unspecified location) [94]. The anthraquinone SZ-685C (Fig. 26) was isolated from the mangrove endophytic fungus Halorosellinia sp. (South China Sea). It suppressed the proliferation of six cancer cell lines derived from human breast cancer, prostate cancer, glioma and hepatoma (IC50 values ranged from 3.0 to 9.6 μM) and the growth of breast cancer xenografts in mice. Actually, SZ-685C was most active against breast MDA-MB435 cells (IC50 3.0 μM) and hepatoma Hep-3B cells

2760 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Table 8.

Pejin et al.

Cytotoxic Activity of Epoxyphomalins A and B Against Broad Spectrum of Human Cancer Cell Lines. Origin of cancer

Cell line

Epoxyphomalin A IC50 (μg/ml)

Epoxyphomalin B IC50 (μg/ml)

BXF 1218L

0.017

0.606

BXF T24

0.374

0.402

MAXF 401NL

0.010

0.501

MAXF MCF-7

0.116

0.398

CXF HCT-116

0.329

2.245

CXF HCT-29

0.198

0.593

CNXF 498NL

0.022

0.904

CNXF SF268

0.354

0.338

HNXF 536L

0.247

0.326

RXF 1781L

0.469

2.656

RXF 393NL

0.080

1.098

RXF 486L

0.034

3.657

RXF 944L

0.316

0.380

LXF 1121L

0.381

1.584

LXF 289L

0.426

3.604

LXF 526L

0.430

10.000

LXF 529L

0.079

9.501

LXF 629L

0.038

1.920

LXF H-460

0.307

10.513

MEXF 276L

0.047

3.764

MEXF 394NL

0.278

0.338

MEXF 462NL

0.058

2.443

MEXF 514L

0.383

1.425

MEXF 520L

0.316

1.920

PXF 1752L

0.033

0.251

OVXF 1619L

0.258

0.278

OVXF 899L

0.080

2.623

OVXF OVCAR-3

0.017

0.910

PAXF 1657L

0.027

1.481

PAXF PANC-1

0.330

0.523

PRXF 22RV1

0.034

0.589

PRXF DU-145

0.745

1.813

PRXF LNCAP

0.937

0.774

PRXF PC-3M

0.017

0.546

Stomach

GXF 251L

0.034

11.420

Uterus

UXF 1138L

0.031

1.811

0.114

1.249

Bladder

Breast

Colon

Glioblastoma Head and neck

Kidney

Lung

Melanoma

Mesothelioma

Ovary

Pancreas

Prostate

Mean

Promising Marine Substances in Tumor Research

(IC50 3.2 μM). This compound had a direct apoptosisinducing effect through both the extrinsic and intrinsic apoptotic pathways, as shown by activation of caspase-8 and 9 as well as effector caspase-3 and poly (ADP-ribose) polymerase. Phosphorylation of AKT and its downstream effectors, forkhead box protein O1 and forkhead box protein O3a, was down-regulated in SZ-685C-treated cancer cells. Furthermore, the pro-apoptotic protein Bim was up-regulated by SZ-685C treatment consistent with FOXO dephosphorylation. It could induce apoptosis through the AKT/FOXO pathway, which consequently leads to the observed anticancer effect both in vitro and in vivo. Taken all together, the experimental data suggest that SZ-685C is a potentially promising AKT inhibitor and drug candidate [95,96].

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

2761

Fig. (26). SZ-685C.

CONCLUSION In this review, the potent antitumor activity of 22 natural products have been discussed. Among the years covered, 2010 is the most fruitful one with five novel bioactive compounds in a total. The most of cited articles are from the Journal of Natural Products. The geographical data clearly stand out that the region of East-Asia and Pacific is of particular importance as the source of marine-derived fungi worthy to be studied. Interestingly, the output in covered natural products is associated with only a few countries, with notable contribution by authors from Asia [97]. Chemical diversity of compounds shown cannot be taken as trivial one. Indeed, terpenoids, alkaloids and peptides are well represented. The carbasugar pericosines A, B and D (polyhydroxylated cyclohexenes) and paeciloxocin A (a depsidone type molecule) also contribute to this observation. One of advances of marine environment in comparison to terrestrial one lies in physical and chemical properties of water. As the result, utilization of covalently bound halogen atoms, especially chlorine and bromine is common. However, only three natural products reported herein (trichodermamide B, pericosine A and pericosine D) contain chlorine in their structures.

Fig. (23). Merulins A-D and related talaperoxides A-D.

Fig. (24). Paeciloxocins A and B.

Fig. (25). (2E,4E)-1-(2,6-dihydroxy-3,5-dimethyl-phenyl)hexa-2,4dien-1-one.

In general, peptides make poor drugs since they are difficult to administer, are rapidly cleared from the body and can potentially cause an immune response. As a result, there is often a reluctance to consider peptide drugs as potential medicines. On the other hand, cyclic peptides have proven to be effective in minimizing most of the unfavourable factors. Three cyclic peptide molecules (namely, IB-01212, urukthapelstatin A and zygosporamide) and one modified dipeptide (trichodermamide B) indicate the potential significance of this compound class in search for new antitumor drugs. It should be noticed that ten of highlighted bioactives may offer some potential in the treatment of leukemia. Indeed, leptosin P and pericosine A have shown to be particularly active against P-388 cells, while conidiogenone C, peribysin D and ustusorane E are potent inhibitors of the adhesion of HL-60 cells to HUVEC. Additionally, cephalimysin A exhibits high activity toward both cell lines (P-388 and HL-60), indicating the significance of its structure in the search for novel anti-leukemia drugs. Among four active compounds on colon cancer cell lines, trichodermamide B and IB-01212 stand out for the observed effect against HCT-116 and HT-29 cell lines, respectively. Additionally, all natural products with activity against breast cancer cells (merulin C, pericosine A, IB-01212 and SZ-685C), may be considered as promising chemicals in development of improved medicaments with higher therapeutic index. Notable activity of conidiogenone C and paeciloxocin A

2762 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

toward liver cancer cells confirms the antitumor potential of marine-derived fungi. Two compounds each have shown to be active toward cervical cancer /IB-01212 and (2E,4E)1-(2,6-dihydroxy-3,5-dimethyl-phenyl)hexa-2,4-dien-1-one/, prostrate cancer (IB-01212 and epoxyphomalin D) and CNS cancer (pericosine A and zygosporamide). Finally, one compound each exhibits significant activity against lung (urukthapelstatin A), ovarian /3R*,4R*-dihydroxy-4(4-methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone/ and renal (zygosporamide) cancer cell lines. As it can be noticed, much of the research work done so far has been devoted to leukemia, followed by the lack of records on pancreatic cancer, gastric cancer, laryngeal cancer and melanoma. Taking into account the incidence in lung cancer mortality, novel investigations with such principal directions are particularly welcomed. When decide which disease to target, pharmaceutical companies have to consider economic factors as well as the medical ones. As a result, research projects tend to be biased towards 'first world' diseases since this is the market best able to afford new drugs [98]. Therefore, a great deal of research has been currently carrying out on cancer. Without a doubt, the sea has much to offer in the field of cancer pharmacy and medicine. However, none of marine organisms including fungi produce final drugs themselves, but make bioactive compounds tightly linked with adaptations to their ecosystem. In most cases these compounds are secondary metabolites with unique chemical structures and promising biological activities [99-101]. Generally, the value of natural products as a source of drug leads has been well documented, with the majority of small-molecule pharmaceuticals across the disease spectrum being of natural product origin, or natural product derived/inspired. Of the estimated 153.000 known natural products, ~ 22.000 are of marine origin. An analysis of the 'drug-likeness' of the marine natural products data based on the 'rule of five' described by Lipinski suggests that the Actinobacteria and Ascomycota have a greater proportion that meet these criteria in comparison with the other marine phyla examined [102]. However, currently very few marine natural products have been or are being developed into marketable drugs, and this may be attributed in part to the fact that marine natural products have a much shorter history than their terrestrial counterparts. In 2006 at the domain level 95% were Eukaryota in origin [103]. It is noteworthy that just three phyla, Porifera, Cnidaria and Chromophyta, constituted ~60% of the species examined at the time. The phyla that have attracted the most attention are predominantly sessile benthic organisms. Members of these phyla are often conspicuous due to size, abundance or colour. Size and abundance are important when the amount of sample needed for analysis is high, and colour is an advantage at the time of collection. However, during the next 2007 year marine microorganisms have become hot topic in the field. The data based on the geographic descriptors in MarinLit establish the regions where there has been significant growth between 1965 and 2007. These are the Caribbean, the China Sea, the Indian Ocean, Japan and the Western Pacific; the emergence of the China Sea as a significant source of new compounds has been particularly obvious [104,105]. Such a trend seems to be continued for the period covered herein.

Pejin et al.

In the last 30 years only four marine medicines have been approved, but three of them are used in the treatment of cancer: yondelis (the tunicate Ecteinascidia turbinata; PharmaMar), halaven (the sponge Halichondria okadai; Eisai) and adcetris (the mollusc Dolabella auricularia). Yondelis has been authorized in 73 countries of which 39 are outside the European Economic Area. Its successful story has begun with the extracts of a Caribbean tunicate reported to have antitumor effect in 1969 and lead to the first market approval in 2007. There is no doubt that all mentioned drugs demonstrate great potential of the sea and marine biodiversity. The fact that none of the existing marine drugs originates from microbial world support the concept of microorganisms as the ultimate source of biologically active compounds from the sea. Fungi from marine habitats are a prolific source of new chemical diversity, and so far have provided more than 1000 new natural products, some of them with clinically relevant pharmacological activity. In addition, it should be mentioned that over 30 compounds derived from marine microbes, such as didemnin B (Aplidine™) and thiocoraline which are currently in preclinical or clinical studies for the treatment of different types of cancers, promise a lot [6]. Probably the most important representative is the diketopiperazine halimide, initially discovered by Bill Fenical’s group in the 1990s, which acts as a tubulin depolymerising agent. This molecule has served as a lead structure for the closely related synthetic analogue plinabulin (NPI-2358) and undergone phase II clinical trials in patients with advanced NSCLC. Other important classes of metabolites of marinederived fungi include the phomactins, the peribysins and the tryprostatins [4]. A crucial stage in the process of discovery and development of new drugs is their design in which the aim is to improve the activity and properties of the lead compound. There are various strategies which can be used to improve the interactions between a drug and its target: variation of substituents, extension of the structure, chain extensions/contractions, ring expansions/contractions, ring variations, ring fusions, isosteres, simplification and rigidification of the structure. Such improvements should increase activity and may also reduce side-effects if the improved interactions lead to increased selectivity between different targets. Simplification is a strategy which is commonly used on the often complex lead compounds arising from natural sources. Once the essential group of such a drug have been identified by SAR studies, then it is usually possible to discard the nonessential parts of the structure without losing activity. The advantages with simpler structures are that they are much easier, quicker, and cheaper to synthesize in the laboratory. Usually the complex lead compounds obtained from natural sources are impractical to synthesize and have to be extracted from the source material [98]. Although the problem with the biomass seems to be overcomed more easily in the case of micro- than macroorganisms, it is still a very challenging task. On the other hand, computers have a special place in modern medicinal chemistry and are important both in drug discovery and development [106]. Rapid advances in computer hardware and software have meant that many of the operations which were once the exclusive province of the expert can now be carried out on ordinary laboratory com-

Promising Marine Substances in Tumor Research

puters with little specialist expertise in the molecular or quantum mechanics involved. Molecular modelling studies can be useful in drug design even if the structure of the target molecule is unknown. The pharmacophore summarizes the important functional groups which are required for activity and their relative positions in space with respect to each other. Different compounds interacting with the same target can be compared and the important pharmacophore identified, allowing the design of novel structures containing the same pharmacophore. Compound databanks can be searched for those pharmacophores to identify novel lead compounds [98]. Exactly in such a way we should look to the future: natural products of marine-derived fungi are expected to inspire medicinal chemists in their search for better antitumor agents than existing ones, bearing in mind that simplification and computer-aided design may be particularly useful tools. As it has been previously stated, the reported biological testing so far is dominated by various tests for antimicrobial and anticancer activities [107]. The vast majority of drugs used in medicine are targetted on proteins and nucleic acids, so it is likely to be the case with novel antitumor substances isolated from marine microorganisms including the fungi as well. Indeed, until relatively recently carbohydrates were not seen as useful targets for drugs. However, this may change in the future since carbohydrates are now known for important roles in various cellular processes such as cell recognition, regulation and growth. It has been observed that cancer is associated with changes in the structure of cell surface carbohydrates. Therefore, understanding how these compounds are involved in cell recognition and regulation may well allow the design of novel drugs to treat cancer. Although the number of drugs which interact with lipids is relatively small, this drug target may also be of significance for marine pharmacology in the years to come [98]. At the same time future research of natural products from the sea is expected to develop the relevant synthetic processes, which will lead to the production of analogue compounds, some of them being even more efficient in comparison to the initial chemical structures. In a word, Neptune chemists are believed to make a revolution in medicinal chemistry with a very bright future, first of all, for the well-being of cancer patients.

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 21

Dap

=

Diammonium phosphate

ED50

=

Median effective dose

GI50

=

HUVEC =

ACKNOWLEDGEMENTS This study was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Projects No. 172053, 173017, 173040, III 41005 and III 41026). B.P. gratefully acknowledges two fellowships of the Italian Ministry of Foreign Affairs and one fellowship of the European Commission (the project HPC-Europa2) which provided him the opportunity to acquire new knowledge and skills in the field of marine natural product chemistry. ABBREVIATIONS CNS

=

Central nervous system

Dab

=

3,3'-diaminobenzidine

The concentration required to achieve 50% growth inhibition Human-umbilical-vein endothelial cells

IC50

=

The half maximal inhibitory concentration

Orn

=

L-ornithinediium

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Received: July 13, 2013

Revised: August 16, 2013

Accepted: August 20, 2013

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