Natural Products from the Marine Sponge Subgenus Reniera

Marine sponges are one of the prolific producers of bioactive natural products with therapeutic potential. As an important subgenus of Haliclona, Reniera sponges are mainly distributed in the Mediterranean Sea and Atlantic area, and had been chemically investigated for over four decades. By an extensive literature search, this review first makes a comprehensive summary of all natural products from Reniera sponges and their endozoic microbes, as well as biological properties. Perspectives on strengthening the chemical study of Reniera sponges for new drug-lead discovery are provided in this work.


Introduction
Marine sponges are widely distributed across oceans and represent one of the most diverse groups of primitive multicellular aquatic animals in nature. Numerous chemical investigations have indicated that this marine creature is one of the most attractive sources of precious natural products with the potential of clinical application [1]. As one of the important marine sponges found in the Mediterranean Sea and Atlantic area, Reniera was originally assigned as one genus and later classified to be one subgenus of Haliclona [2]. Morphologically, Reniera sponge has a soft texture and brownish-maroon epidermis, and its body is soft and fragile and looks like a compressed tree with simple digitate branches and spicules of various sizes [3]. Meanwhile, this marine sponge harbors a special arrangement of the flagellated chambers in the incurrent and excurrent canal systems [3]. To the best of our knowledge, the subgenus Reniera consists of at least 16 species, including R. albescens, R. coccinea, R. cratera, R. fallaciosa, R. fascigera, R. fragilis, R. fulva, R japonica, R. lacteal, R. membrana, R. mucosa, R. porosa, R. porrecta, R. reticulata, R. sarai, and R. thomasii [4]. On the basis of an extensive literature search using SciFinder and Dictionary of Natural Products databases covering up to December 2020, this review comprehensively makes an overview of all natural products from Reniera sponges and their endozoic microbes, as well as biological properties.

Other Alkaloids
A search for antimicrobial substance(s) from an unidentified Reniera sponge from Isla Grande (Mexico) led to the isolation of one new isoindole-4,7-dione derivative (35) ( Figure  4) [24], which was chemically synthesized through the cycloaddition of a nonstabilized azomethine ylide and a quinone by Parker and coworkers in 1984 [34]. Chromatography on a column of a cation exchange resin of the n-butanol soluble fraction from the acetone extracts of the sponge R. cratera afforded one simple nitrogenous compound 2-aminoimidazole (36) [35]. One cyclic depsipeptide renieramide (37) was also isolated and characterized from Reniera sp. No. 2115 collected on the Island of Santo (Vanuatu) [2]. Bioassayguided fractionation of the MeOH extract of one marine sponge Haliclona (Reniera) sp.

Other Alkaloids
A search for antimicrobial substance(s) from an unidentified Reniera sponge from Isla Grande (Mexico) led to the isolation of one new isoindole-4,7-dione derivative (35) (Figure 4) [24], which was chemically synthesized through the cycloaddition of a nonstabilized azomethine ylide and a quinone by Parker and coworkers in 1984 [34]. Chro-matography on a column of a cation exchange resin of the n-butanol soluble fraction from the acetone extracts of the sponge R. cratera afforded one simple nitrogenous compound 2-aminoimidazole (36) [35]. One cyclic depsipeptide renieramide (37) was also isolated and characterized from Reniera sp. No. 2115 collected on the Island of Santo (Vanuatu) [2]. Bioassay-guided fractionation of the MeOH extract of one marine sponge Haliclona (Reniera) sp. collected off Ulleung Island (Korea) led to the discovery of a new sphingosine (38) together with two lysophosphatidylcholines (39 and 40), which exhibited moderate cytotoxicity against a panel of five human solid tumor cell lines including A549, SK-OV-3, SK-MEL-2, XF498, and HCT15 [36].

Other Alkaloids
A search for antimicrobial substance(s) from an unidentified Reniera sponge from Isla Grande (Mexico) led to the isolation of one new isoindole-4,7-dione derivative (35) ( Figure  4) [24], which was chemically synthesized through the cycloaddition of a nonstabilized azomethine ylide and a quinone by Parker and coworkers in 1984 [34]. Chromatography on a column of a cation exchange resin of the n-butanol soluble fraction from the acetone extracts of the sponge R. cratera afforded one simple nitrogenous compound 2-aminoimidazole (36) [35]. One cyclic depsipeptide renieramide (37) was also isolated and characterized from Reniera sp. No. 2115 collected on the Island of Santo (Vanuatu) [2]. Bioassayguided fractionation of the MeOH extract of one marine sponge Haliclona (Reniera) sp. collected off Ulleung Island (Korea) led to the discovery of a new sphingosine (38) together with two lysophosphatidylcholines (39 and 40), which exhibited moderate cytotoxicity against a panel of five human solid tumor cell lines including A549, SK-OV-3, SK-MEL-2, XF498, and HCT15 [36].

. Aromatic Polyketides
Polyketides are one of the major groups of Reniera-derived secondary metabolites, such as aromatic and aliphatic polyketides. As many as eighteen aromatic polyketides (51-67) ( Figure 6) had been separated from R. fulva and R. mucosa, which were respectively collected from the Egadi Islands (Italy) and Tarifa Island (Spain) [37,43]. Compounds 52, 53, 56, and 59 possessed in vitro cytotoxicity against P388 mice lymphoma, A549 human lung carcinoma, HT29 human colon carcinoma, and MEL28 human melanoma cell lines with the same ED 50 values of 5 mg/mL [43]. Moreover, compound 59 exhibited a moderate inhibitory effect on DHFR (dihydrofolate reductase) with an ED 50

Aromatic polyketides
Polyketides are one of the major groups of Reniera-derived secondary metabolites, such as aromatic and aliphatic polyketides. As many as eighteen aromatic polyketides (51-67) ( Figure 6) had been separated from R. fulva and R. mucosa, which were respectively collected from the Egadi Islands (Italy) and Tarifa Island (Spain) [37,43]. Compounds 52, 53, 56, and 59 possessed in vitro cytotoxicity against P388 mice lymphoma, A549 human lung carcinoma, HT29 human colon carcinoma, and MEL28 human melanoma cell lines with the same ED50 values of 5 mg/mL [43]. Moreover, compound 59 exhibited a moderate inhibitory effect on DHFR (dihydrofolate reductase) with an ED50 value of 3 mg/mL. At the concentrations from 10 −4 to 10 −8 M, compounds 61 and 63 were shown to be cytotoxic to the NCI-H522 nonsmall lung cancer cell line and CCRF-CEM leukemia cell line, while 54 had more selective cytotoxicity against the latter [37].  Figure 6. Aromatic polyketides derivatives 51-67 from the subgenus Reniera.

Other Polyketide
One new bicyclic eicosanoid named mucosin (74) (Figure 8) was detected in the acetone extracts of R. mucosa samples, which had been collected in different areas including

Other Polyketide
One new bicyclic eicosanoid named mucosin (74) (Figure 8) was detected in the acetone extracts of R. mucosa samples, which had been collected in different areas including Blanes (Spain), Grotte de Jarr (France), Massalubrense, and Procida (Italy) [46]. Interestingly, this metabolite contains an unusual bicyclo [4.3.0] nonane skeleton with equilibrium of normal physiology in mammalian systems.

Other Polyketide
One new bicyclic eicosanoid named mucosin (74) (Figure 8) was detected in the a tone extracts of R. mucosa samples, which had been collected in different areas includi Blanes (Spain), Grotte de Jarr (France), Massalubrense, and Procida (Italy) [46]. Intere ingly, this metabolite contains an unusual bicyclo [4.3.0] nonane skeleton with equilibriu of normal physiology in mammalian systems.

Cerebrosides and Ceramide
Cerebrosides are a group of glycosphingolipids consisting of a glucose or galactose residue attached to a ceramide moiety containing one sphingoid base and an amide-linked long fatty acyl chain. These amphipathic biomolecules are important components of tissues and organs in organisms and possess a broad spectrum of biological functions such as antifungal, antitumor, antiviral, an inhibitory effect on histidine decarboxylase, and cytotoxicity [50]. Chemical analysis of the n-hexane layer of the MeOH extract of the same HO H R Figure 9. Sterols 75-101 from the subgenus Reniera.

Cerebrosides and Ceramide
Cerebrosides are a group of glycosphingolipids consisting of a glucose or galactose residue attached to a ceramide moiety containing one sphingoid base and an amide-linked long fatty acyl chain. These amphipathic biomolecules are important components of tissues and organs in organisms and possess a broad spectrum of biological functions such as antifungal, antitumor, antiviral, an inhibitory effect on histidine decarboxylase, and cytotoxicity [50]. Chemical analysis of the n-hexane layer of the MeOH extract of the same specimen Haliclona (Reniera) sp. J01U-6 collected off the coast of Ulleung Island (Korea) afforded twenty-one new cerebrosides (101-111, 113-122) together with one known analog (112), which possess unprecedented unsaturated or saturated long (C 15 -C 28 ) alkyl chains ( Figure 10) [51,52]. This was the first report on the isolation of isomeric pairs of glucocerebrosides containing saturated C 15 and C 19 acyl chains. Lately, the structural determination of compounds 109-112, 115, 116, 120, and 121 were well established using fast atom bombardment mass spectrometry (FAB-MS) in positive-ion mode by Hong and coworkers [53]. In addition, one ceramide (123) was separated from the same sponge SPV06/12/13 collected off Samalona Island, and its absolute structure was determined by HyperChem computational techniques [49].

Conclusion and Perspectives
The marine sponge subgenus Reniera is one of the most prolific sources of natural products possessing various chemical structures and biological properties, such as cytotoxic poly-APS derivatives, insecticidal and acaricidal sarains A-C (28)(29)(30), and antioxidant zeaxanthin (47). In the recent decade, however, few reports on biological and chemical studies of Reniera sponge had been published. In comparison with those of other marine sponge genera such as Agelas [54] and Phyllospongia [55], chemical investigations of Reniera sponges seem to be less intensive. Therefore, great efforts should be made to carry out global resource surveys and collections of Reniera sponges and chemical studies using hyphenated technology, such as GC-MS and LC-MS-NMR. Furthermore, more attention should be paid on genome mining and the chemical study of symbiotic microorganisms of Reniera sponges as these microbes are potential producers of bioactive secondary metabolites originally derived from their hosts [56][57][58].

Conclusions and Perspectives
The marine sponge subgenus Reniera is one of the most prolific sources of natural products possessing various chemical structures and biological properties, such as cytotoxic poly-APS derivatives, insecticidal and acaricidal sarains A-C (28)(29)(30), and antioxidant zeaxanthin (47). In the recent decade, however, few reports on biological and chemical studies of Reniera sponge had been published. In comparison with those of other marine sponge genera such as Agelas [54] and Phyllospongia [55], chemical investigations of Reniera sponges seem to be less intensive. Therefore, great efforts should be made to carry out global resource surveys and collections of Reniera sponges and chemical studies using hyphenated technology, such as GC-MS and LC-MS-NMR. Furthermore, more attention should be paid on genome mining and the chemical study of symbiotic microorganisms of Reniera sponges as these microbes are potential producers of bioactive secondary metabolites originally derived from their hosts [56][57][58].