Chemistry and Biological Activities of the Marine Sponges of the Genera Mycale (Arenochalina), Biemna and Clathria

Over the past seven decades, particularly since the discovery of the first marine-derived nucleosides, spongothymidine and spongouridine, from the Caribbean sponge Cryptotethya crypta in the early 1950s, marine natural products have emerged as unique, renewable and yet under-investigated pools for discovery of new drug leads with distinct structural features, and myriad interesting biological activities. Marine sponges are the most primitive and simplest multicellular animals, with approximately 8900 known described species, although more than 15,000 species are thought to exist worldwide today. These marine organisms potentially represent the richest pipeline for novel drug leads. Mycale (Arenochalina) and Clathria are recognized marine sponge genera belonging to the order Poecilosclerida, whereas Biemna was more recently reclassified, based on molecular genetics, as a new order Biemnida. Together, these sponge genera contribute to the production of physiologically active molecular entities with diverse structural features and a wide range of medicinal and therapeutic potentialities. In this review, we provide a comprehensive insight and up-to-date literature survey over the period of 1976–2018, focusing on the chemistry of the isolated compounds from members of these three genera, as well as their biological and pharmacological activities, whenever available.


Introduction
Current medical risks, including diabetes, chronic pains, hepatitis, hypertension, microbial infection, together with the emergence of multidrug-resistant microbes and different types of carcinoma, have motivated and encouraged scientists to search for new bioactive compounds with novel modes of action [1]. Naturally occurring compounds derived from plants, marine invertebrates and microorganisms have provided important platforms and ideal validated starting materials for drug development and manufacturing [2]. Marine natural products represent a potent, promising and valuable source of supply for new chemical entities possessing unprecedented and novel mechanisms of action [2][3][4][5][6][7]. At present, marine-derived compounds or derivatives thereof have contributed to seven approved drugs for the market: cytarabine (Cytosar-U ® , Depocyst ® , approved by FDA in 1969 for cancer treatment), vidarabine (Vira-A ® , approved by FDA in 1976 as antiviral), ziconotide (Prialt ® , approved by FDA in in 2004 as analgesic for treatment of severe chronic pain), trabectedin (Yondelis ® , ET-743, approved in the EU in 2007 as an anticancer), eribulin mesylate (Halaven ® , approved by FDA in 2010 and by Heath Canada in 2011 for metastatic breast cancer treatment), brentuximab vidotin (Adcetris ® , approved by FDA in 2011 for Hodgkin's lymphoma cells, and in 2017 for cutaneous T-cell lymphoma) and omega-3 acid ethyl esters (Lovaza ® , approved by FDA in 2004 for lowering blood triglyceride levels in adults with severe hypertriglyceridemia) [8,9]. Moreover, twelve marine natural products are being under exploration in different phases of clinical trials [8], and a number of them are in the preclinical pipeline. Despite being the most basal of metazoan animal phyla, marine sponges (Porifera) greatly contribute as prolific suppliers of potentially valuable novel compounds to the clinical pipeline, with almost 47% of all reported bioactive compounds from the marine environment. Several relevant reports have shown that almost 62.5% (i.e., 10 out of 16) of clinically approved medicines, or those in ongoing advanced clinical phases, are derived from marine invertebrates, including marine sponges [10,11]. Marine sponges of the genera Mycale (Arenochalina) (family Mycalidae), Clathria (family Microcionidae), and Biemna (family Desmacellidae) include diverse sponge species belonging to the orders Poecilosclerida and Biemnida. They are rich producers of diverse and physiologically active secondary metabolites [12,13] with a wide range of biological activities, including cytotoxic, antimalarial [14,15], anti-HIV [16], anti-inflammatory [17,18], enzyme inhibitors [19], antifungal and antibacterial properties [20,21]. Some of these compounds are chemotaxonomic markers, particularly for some Poecilosclerida marine sponges of the genera Batzella, Crambe and Monanchora [22]. The World Porifera Database [23] lists 14  fortis, were chemically studied, while eleven species of the genus Clathria, i.e., Clathria hirsuta, C. gombawuiensis, C. cervicornis, C. compressa, C. araiosa, Clathia. sp., C. calla, C. reinwardtii, C. lissosclera, C. basilana, C. strepsitoxa and C. pyramida were chemically investigated (Table 1). Due to our interest in the marine sponges of the order Poecilosclerida [22,[24][25][26], we have reviewed the literature reporting the isolation of secondary metabolites from these three marine sponge genera, covering the period of 1976-2018. This up-to-date review focuses mainly on the chemistry of the isolated metabolites, although their biological and pharmacological properties are also discussed when they are available. Table 1. Summary of the secondary metabolites isolated from the marine sponges belonging to the genera Mycale (Arenochalina), Biemna and Clathria, their source organisms and biological activities.

Chemistry and Biological Activities of the Secondary Metabolites Isolated from the Marine Sponges of the Genera Mycale (Arenochalina), Biemna and Clathria
In this section, we provide insights into the chemical classes and biological activities of the marine sponge-derived secondary metabolites obtained from these three genera. For convenience, the isolated compounds are divided into fourteen major groups, according to their skeleton as well as their biosynthetic origins. Additionally, their biological potentialities are also discussed whenever applicable.
Mar. Drugs 2018, 16, x 5 of 26 ( Figure 3), were isolated from the marine sponge Clathria (Thalysias) araiosa, collected from Vanuatu. These compounds originated from an unusual mode of linear polymerization of tryptamine units involving a C-C bond formation. Compounds 38-41 were evaluated for their antimicrobial activity; however, none of them displayed significant antibacterial activity against S. aureus or anti-HIV activity [34].

Pyridoacridine, Pteridine, Tetrahydroquinolizine and N-methylpyrrolidone Alkaloids
Pyridoacridine alkaloids are a unique group of marine-derived metabolites and are one of the largest marine alkaloid families. Chemically, they feature a common tetracyclic hetero-aromatic parent-11H-pyrido[4,3,2nm] acridine or 4H-pyrido[2,3,4-kl] acridone [35,36]. Among the three marine sponge genera, pyridoacridine alkaloids were exclusively isolated from Biemna species. Biemnadin  [37]. Moreover, labuanine A (46) was isolated, along with three previously described congeners, i.e., 42, 45 and isocystodamine (47) (Figure 4), from the Indonesian sponge B. fortis. All of these compounds induced multipolar neuritogenesis in more than 50% of Neuro 2A murine neuroblastoma cells at concentrations of 0.03-3 µM. Interestingly, 47 not only displayed the strongest neuritogenic activity but also activated an increase of the acetylcholinesterase level [38]. Matsunaga's group [39] described the isolation of N-methylisocystodamine (48) and methoxymethylisocystodamine (49) (Figure 4), together with 47, from the marine sponge Biemna sp., collected at Oshima-Shinsone, Southern Japan. Both 48 and 49 were found to activate the erythroid differentiation of human leukemia K562 cells, with an ED 50 value of 5 nM [39]. Later on, the same group [40] further isolated N-hydroxymethylisocystodamine (50) and neolabuaninen A (51), together with the previously reported congeners ecionines A (52) and B (53), 42, 45 and 47 (Figure 4), from the same sponge. These compounds displayed cytotoxicity and activated differentiation of K562 leukaemia cells into erythrocytes at a concentration of 5 µg/mL. Furthermore, 47 and 50 were the most active in inducing neuronal differentiation when compared to 42, 45 and 51. Interestingly, while 51 and 52 lowered this activity, 42, 47 and 53 showed no notable activity [40]. Another interesting group of marine-derived alkaloids are the pteridines, which represent a widely distributed family of naturally occurring alkaloids. Chemically, pteridine nucleus is composed of a pyrimidine ring fused with a pyrazine ring. Examples of this group are pseudoanchnazines A-C (54-56) (Figure 4), which were isolated from the marine sponge Clathria sp., collected near the coast of Rio Negro, Argentina. Compound 54 showed a moderate inhibition against E. coli at 50 µg/disk [41]. Additionally, Sperry and Crews described isolation of a new tetrahydroquinolizinium ion, clathryimine A (57), which produced a decarboxylated derivative clathryimine B upon heating in CDCl 3 (Figure 4), from the Indo-Pacific marine sponge C. basilana, collected in Indonesia [42]. Radhika et al. [43] reported the isolation of N-methylpyrrolidone (58) (Figure 4) from C. frondifera, collected from the East coast of India.

Monoindole Alkaloids
Wang et al. [44] reported the isolation of eleven brominated indole alkaloids, 59-69 ( Figure 5), from the marine sponge M. fibrexilis. Since monoindole alkaloids were less common for this sponge family, the authors proposed that they could be specific for this species.

Monoindole Alkaloids
Wang et al. [44] reported the isolation of eleven brominated indole alkaloids, 59-69 ( Figure 5), from the marine sponge M. fibrexilis. Since monoindole alkaloids were less common for this sponge family, the authors proposed that they could be specific for this species.

Monoindole Alkaloids
Wang et al. [44] reported the isolation of eleven brominated indole alkaloids, 59-69 ( Figure 5), from the marine sponge M. fibrexilis. Since monoindole alkaloids were less common for this sponge family, the authors proposed that they could be specific for this species.

Bromine-Containing Amides
Three brominated acetylenic amides, clathrynamides A-C (114-116) (Figure 9), were isolated from the Japanese marine sponge Clathria sp., collected from the Sad-misaki coast. Compound 114 displayed potent inhibitory activity against the mitotic cell division of starfish eggs at a very low concentration, with an IC50 value of 6 ng/mL, and cytotoxicity against the human myeloid K-562 cell line with an IC50 value of 0.2 μg/mL. Compounds 115 and 116 were less active than 114 against the mitotic cell division of starfish eggs, with IC50 values of 0.2 and 1 μg/mL, respectively. Based on the

Bromine-Containing Amides
Three brominated acetylenic amides, clathrynamides A-C (114-116) (Figure 9), were isolated from the Japanese marine sponge Clathria sp., collected from the Sad-misaki coast. Compound 114 displayed potent inhibitory activity against the mitotic cell division of starfish eggs at a very low concentration, with an IC 50 value of 6 ng/mL, and cytotoxicity against the human myeloid K-562 cell line with an IC 50

Conclusions and Prospects
This review presents extensive documented data, focusing on chemical diversity and biological activities of the secondary metabolites, isolated from the three marine sponge genera: Mycale (Arenochalina), Biemna and Clathria, demonstrating these marine species as prolific sources of structurally diverse bioactive compounds. Despite their production of tricyclic guanidine-containing alkaloids, these sponges are classified under two different orders: Mycale (Arenochalina)/Clathria (under the order Poecilosclerida) and Biemna (under the order Biemnida), as recent molecular data revealed that Biemna is not related to the Poecilosclerida, and hence a new order Biemnida was given for the genus Biemna. This finding could highlight the important question of using secondary metabolites as taxonomic markers. Another important chemical feature is the uniqueness of the production of pyridoacridine alkaloids by Biemna sponges, which implies the relatedness of Biemna genus to the order Poecilosclerida. The two hundred and forty-four metabolites reported in this review are put together into fourteen major chemical classes, according to their structural characteristics and biosynthetic origin. The vast array of bioactivities exhibited by some of these metabolites make these marine sponge genera some of the most attractive biological targets, worthy of further exploration.