{'fraction_non_alphanumeric': 0.04058676871339943, 'fraction_numerical': 0.035165536035252506, 'mean_word_length': 4.9690257830074405, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Secondary Metabolites from Marine Sponges of the Genus Oceanapia: Chemistry and Biological Activities

In this review, we summarized the distribution of the chemically investigated Oceanapia sponges, including the isolation and biological activities of their secondary metabolites, covering the literature from the first report in 1989 to July 2019. There have been 110 compounds reported during this period, including 59 alkaloids, 33 lipids, 14 sterols and 4 miscellaneous compounds. Besides their unique structures, they exhibited promising bioactivities ranging from insecticidal to antibacterial. Their complex structural characteristics and diverse biological properties have attracted a great deal of attention from chemists and pharmaceuticals seeking to perform their applications in the treatment of disease.


Introduction
Marine sponges, living in harsh marine conditions from tropic to polar regions, offer an enormous source of natural products bearing unique structures and significant bioactivities, making them ideal candidates for drug discovery projects [1]. Of them, the animals belonging to the genus Oceanapia (phylum, Porifera; class, Demospongiae; subclass, Heteroscleromorpha; order, Haplosclerida; family, Phloeodictyidae) have proven to be a biochemical warehouse for secondary metabolites, such as alkaloids, lipids, sterols, etc. It is particularly interesting that these compounds exhibited a wide range of biological features ranging from antibacterial and cytotoxic to ichthyotoxic activities [2]. In order to better understand the natural products from this genus, there would be a demand for a review.
Notably, several other generic names (Phloeodictyon Carter, 1882; Rhizochalina Schmidt, 1870; Biminia Wiedenmayer, 1977; Foliolina Schmidt, 1870) are now considered as synonyms for Oceanapia [3]. However, there is no associated reference on secondary metabolites of two genera Biminia and Foliolina listed in SciFinder Scholar. Therefore, this review covers topics on three nominal genera, Oceanapia, Phloeodictyon and Rhizochalina, covering different types of compounds, with a literature survey from 1989 to July 2019. During this period, 110 compounds have been reported, including 59 alkaloids, 33 lipids, 14 sterols and 4 other miscellaneous compounds. More than eight species of Oceanapia sponges have been chemically investigated including Oeanapia sagittaria, Oceanapia fistulosa, Oceanapia bartschi, Phloeodictyon sp., Rhizochalina incrustata, Oceanapia ramsayi, Oceanapia phillipensis, Oceanupia cf. tenuis and Oceanapia sp. The global distribution of the chemically investigated marine Oceanapia sponges according to their species is shown in Figure 1.

Pyridoacridine Alkaloids
Faulkner's group found the sponge Oceanapia sagittaria from Palau contained two pyridoacridine alkaloids dercitamide (1) and sagitol (2) (Figure 2). Of them, 2 was the first pyridoacridine alkaloid from a marine sponge in which the aromatic system had been disrupted. Interestingly, 2 could be obtained by autoxidation of 1. Faulkner et al. suggested that 2 was not an artifact that was supported by CD measurements. [4]. Two years later, Proksch et al. reported three pyridoacridine alkaloids kuanoniamine C (1), kuanoniamine D (3) and N-deacetylkuanoniamine C (4) were afforded by the Micronesian sponge Oceanapia sp. [5]. It may be worthy to point out that the structures of dercitamide and kuanoniamide C were established to be identical by Faulkner and his co-workers [6]. Herein, the same numbering was assigned for these two different nomenclative compounds. Proksch et al. performed many bioassays for these three alkaloids. When incorporated into an artificial diet, compounds 1 and 3 exhibited insecticidal activity toward neonate larvae of the polyphagous pest insect Spodoptera littoralis (LC50 of 156 and 59 ppm, respectively). Both compounds also showed toxicity in the brine shrimp lethality test with LC50 values of 37 and 19 µ g/mL, respectively. Although the N-deacyl derivative 4 did not show any remarkable effect in either of the abovementioned bioassays, it appeared to be active in the cytotoxic biotests against two human cell lines. The IC50 of 4 was 1.2 µ g/mL toward HeLa cells and 2.0 μg/mL toward MONO-MAC 6 cells. In receptor binding assays, compound 3 showed affinity to A1-and A2A-adenosine receptors with Ki values of 2.94 and 13.7 µ M, respectively. Compound 1 was less active than its homologue 3, whereas the N-deacyl derivative 4 showed no affinity toward adenosine receptors. In addition, compounds 1, 3 and 4 exhibited moderate affinity to benzodiazepine binding sites of GABAA receptors [5]. Meanwhile, Proksch et al. explored the distribution of compounds 1 and 3 in the sponge Oceanapia sp., as well as its ecological implications. It was found that the secondary metabolites 1 and 3 showed a sharp increase from the basal root to the capitum. The feeding assays against the spongivorous angelfish Pomacanthus imperator showed that 1 and 3 significantly deterred feeding by natural assemblages of reef fishes at fistule concentrations, confirming their role as defensive agents [7].

Pyridoacridine Alkaloids
Faulkner's group found the sponge Oceanapia sagittaria from Palau contained two pyridoacridine alkaloids dercitamide (1) and sagitol (2) (Figure 2). Of them, 2 was the first pyridoacridine alkaloid from a marine sponge in which the aromatic system had been disrupted. Interestingly, 2 could be obtained by autoxidation of 1. Faulkner et al. suggested that 2 was not an artifact that was supported by CD measurements. [4]. Two years later, Proksch et al. reported three pyridoacridine alkaloids kuanoniamine C (1), kuanoniamine D (3) and N-deacetylkuanoniamine C (4) were afforded by the Micronesian sponge Oceanapia sp. [5]. It may be worthy to point out that the structures of dercitamide and kuanoniamide C were established to be identical by Faulkner and his co-workers [6]. Herein, the same numbering was assigned for these two different nomenclative compounds. Proksch et al. performed many bioassays for these three alkaloids. When incorporated into an artificial diet, compounds 1 and 3 exhibited insecticidal activity toward neonate larvae of the polyphagous pest insect Spodoptera littoralis (LC 50 of 156 and 59 ppm, respectively). Both compounds also showed toxicity in the brine shrimp lethality test with LC 50 values of 37 and 19 µg/mL, respectively. Although the N-deacyl derivative 4 did not show any remarkable effect in either of the abovementioned bioassays, it appeared to be active in the cytotoxic biotests against two human cell lines. The IC 50 of 4 was 1.2 µg/mL toward HeLa cells and 2.0 µg/mL toward MONO-MAC 6 cells. In receptor binding assays, compound 3 showed affinity to A 1 -and A 2A -adenosine receptors with K i values of 2.94 and 13.7 µM, respectively. Compound 1 was less active than its homologue 3, whereas the N-deacyl derivative 4 showed no affinity toward adenosine receptors. In addition, compounds 1, 3 and 4 exhibited moderate affinity to benzodiazepine binding sites of GABA A receptors [5]. Meanwhile, Proksch et al. explored the distribution of compounds 1 and 3 in the sponge Oceanapia sp., as well as its ecological implications. It was found that the secondary metabolites 1 and 3 showed a sharp increase from the basal root to the capitum. The feeding assays against the spongivorous angelfish Pomacanthus imperator showed that 1 and 3 significantly deterred feeding by natural assemblages of reef fishes at fistule concentrations, confirming their role as defensive agents [7]. Kijjoa and his co-workers reported another specimen, O. sagittaria from the Gulf of Thailand, afforded kuanoniamine C (1) and its relative compound kuanoniamine A (5). In this study, compounds 1 and 5 were evaluated for cytotoxic effects against five human tumor cell lines MCF-7 (ER+), MDA-MB-231 (ER-), SF-268, NCI-H460 and UACC-62, and one human non-tumor cell line, MRC-5, by the SRB method. Compound 5 was found to be a potent growth inhibitor of all tumor and the non-tumor cell lines while 1 was less potent but showed high selectivity toward the estrogen-dependent (ER+) breast cancer cell line MCF-7. Furthermore, 5 was shown to be a more potent inhibitor of DNA synthesis than 1. It was also found that 5 caused an extensive reduction in the MCF-7 cells in the G2/M phase as well as an increase in the apoptotic cells [8].
Bioassay-guided fractionation of the MeOH extract of an Australian sponge Oceanapia sp. performed by Carroll's group, using the aspartyl semialdehyde dehydrogenase (ASD) to detect antibacterial activity, led to the discovery of a bright blue compound, petrosamine B (6). It was found 6 was a weak inhibitor of ASD with an IC50 of 306 µ M [9]. In Ibrahim's investigation of the Indonesian sponge Oceanapia sp., sagitol C (7) together with the two abovementioned compounds 1 and 2 were disclosed. The cytotoxic effect of 7 was tested against mouse lymphoma (L5178Y), rat brain (PC12) and human cervix (Hela) cell lines. It exhibited 93%, 88% and 76% growth suppression against the tested cell lines at a concentration of 24.6 μM and 81%, 74% and 37% at a concentration of 12.3 μM with ED50 values of 0.7, 0.9 and 2.3 µ M, respectively [10].

Quinolizidine Alkaloids
A bisquinolizidine alkaloid, petrosin (8), and a series of bis-1-oxaquinolizidine alkaloids, xestospongins A-F (9-16) (Figure 3), were all obtained by Singh and his partners from the ethyl acetate extract of the sponge Oceanapia sp., which was collected from the southern coast of India. The relative stereochemistry of 8 was established by single-crystal X-ray analysis as 1S*,2R*,4R*,9S*,15R*,17R*,22S*,23S*. Compounds 9 and 10 were found to be active against several pathogens such as Cryptococcus neoformans, Aspergillus funigatus, Candida albicans and Aspergillus niger [11]. Kijjoa and his co-workers reported another specimen, O. sagittaria from the Gulf of Thailand, afforded kuanoniamine C (1) and its relative compound kuanoniamine A (5). In this study, compounds 1 and 5 were evaluated for cytotoxic effects against five human tumor cell lines MCF-7 (ER+), MDA-MB-231 (ER-), SF-268, NCI-H460 and UACC-62, and one human non-tumor cell line, MRC-5, by the SRB method. Compound 5 was found to be a potent growth inhibitor of all tumor and the non-tumor cell lines while 1 was less potent but showed high selectivity toward the estrogen-dependent (ER+) breast cancer cell line MCF-7. Furthermore, 5 was shown to be a more potent inhibitor of DNA synthesis than 1. It was also found that 5 caused an extensive reduction in the MCF-7 cells in the G2/M phase as well as an increase in the apoptotic cells [8].
Bioassay-guided fractionation of the MeOH extract of an Australian sponge Oceanapia sp. performed by Carroll's group, using the aspartyl semialdehyde dehydrogenase (ASD) to detect antibacterial activity, led to the discovery of a bright blue compound, petrosamine B (6). It was found 6 was a weak inhibitor of ASD with an IC 50 of 306 µM [9]. In Ibrahim's investigation of the Indonesian sponge Oceanapia sp., sagitol C (7) together with the two abovementioned compounds 1 and 2 were disclosed. The cytotoxic effect of 7 was tested against mouse lymphoma (L5178Y), rat brain (PC12) and human cervix (Hela) cell lines. It exhibited 93%, 88% and 76% growth suppression against the tested cell lines at a concentration of 24.6 µM and 81%, 74% and 37% at a concentration of 12.3 µM with ED 50 values of 0.7, 0.9 and 2.3 µM, respectively [10].

Sesquiterpene Alkaloid
Faulkner's group disclosed the major metabolite of the Philippine sponge Oceanapia sp. was the antimicrobial alkaloid oceanapamine (17) (Figure 4), isolated as trifluoroacetate (TFA) salt. The structure of 17 consisted of a monocyclic sesquiterpene attached to a histamine residue, representing the sole sesquiterpene-alkaloid hybrid from the genus Oceanapia. Compared with related model compounds, the absolute configuration of 17 was assigned as 6R. The TFA salt of 17 was screened rather broadly but only exhibited antimicrobial activity. In the standard disk (6-mm) assay, 17 inhibited Bacillus subtilis and Escherichia coli at 25 µg/disk, Staphyloccocus aureus and C. albicans at 50 µg/disk and Pseudomonas aerivginosa at 100 µg/disk [12]. Mar. Drugs 2022, 20, x FOR PEER REVIEW 4 of 17

Sesquiterpene Alkaloid
Faulkner's group disclosed the major metabolite of the Philippine sponge Oceanapia sp. was the antimicrobial alkaloid oceanapamine (17) (Figure 4), isolated as trifluoroacetate (TFA) salt. The structure of 17 consisted of a monocyclic sesquiterpene attached to a histamine residue, representing the sole sesquiterpene-alkaloid hybrid from the genus Oceanapia. Compared with related model compounds, the absolute configuration of 17 was assigned as 6R. The TFA salt of 17 was screened rather broadly but only exhibited antimicrobial activity. In the standard disk (6-mm) assay, 17 inhibited Bacillus subtilis and Escherichia coli at 25 µ g/disk, Staphyloccocus aureus and C. albicans at 50 μg/disk and Pseudomonas aerivginosa at 100 μg/disk [12].

Sesquiterpene Alkaloid
Faulkner's group disclosed the major metabolite of the Philippine sponge Oceanapia sp. was the antimicrobial alkaloid oceanapamine (17) (Figure 4), isolated as trifluoroacetate (TFA) salt. The structure of 17 consisted of a monocyclic sesquiterpene attached to a histamine residue, representing the sole sesquiterpene-alkaloid hybrid from the genus Oceanapia. Compared with related model compounds, the absolute configuration of 17 was assigned as 6R. The TFA salt of 17 was screened rather broadly but only exhibited antimicrobial activity. In the standard disk (6-mm) assay, 17 inhibited Bacillus subtilis and Escherichia coli at 25 µ g/disk, Staphyloccocus aureus and C. albicans at 50 μg/disk and Pseudomonas aerivginosa at 100 μg/disk [12].

Bromotyrosine Alkaloids
Four bromotyrosine alkaloids 46-49 ( Figure 6) were all isolated from an Australian non-verongid sponge Oceanapia sp. by Bewley's group. Among them, 46 contained an unprecedented imidazolyl-quinolinone substructure attached to a bromotyrosine-derived spiro-isoxazoline. In the bioassay, compounds 46-49 inhibited mycothiol S-conjugate amidase by 50% at 2, 100, 3 and 37 mM, respectively. These four alkaloids represented the Phloeodictines were also found to be components of the sponge Oceanapia [= Phloeodictyon] fistulosa in New Caledonian shallow waters by Mancini et al. They were clarified as a wide structural variety including the known 18-28 and new analogues 29-45 as corresponding mixtures. The complexity of the mixtures, and the very similar behavior of their components, prevented their isolation in pure form. However, crude mixtures and HPLC-enriched fractions were suitable for bioassays and proved to be active against chloroquine-resistant Plasmodium falciparum, with IC 50 values ranging from 0.6 to 6 µM, while cytotoxicity against the human A-549 cell line was low. These biological data might serve to illustrate preliminary structure-activity relationships: 1. The length of the C-6 chain had a greater influence on the bioactivity level than the nature of its terminal portion; 2. methylation of the guanidine moiety lowered the activity. This study showed good prospects for these alkaloids as leads for novel antimalarial agents [16].

Bromotyrosine Alkaloids
Four bromotyrosine alkaloids 46-49 ( Figure 6) were all isolated from an Australian non-verongid sponge Oceanapia sp. by Bewley's group. Among them, 46 contained an unprecedented imidazolyl-quinolinone substructure attached to a bromotyrosine-derived spiro-isoxazoline. In the bioassay, compounds 46-49 inhibited mycothiol S-conjugate amidase by 50% at 2, 100, 3 and 37 mM, respectively. These four alkaloids represented the first examples of natural products that inhibited an enzyme central to a mycothioldependent detoxification pathway found in mycobacteria [17]. first examples of natural products that inhibited an enzyme central to a mycothiol-de pendent detoxification pathway found in mycobacteria [17].
first examples of natural products that inhibited an enzyme central to a mycothiol-de pendent detoxification pathway found in mycobacteria [17].

Nucleotide Alkaloids
In the study of an Australian sponge Oceanapia sp., uranidine (57) (Figure 8) was discovered as one component of the major alkaloids [17]. Very recently, N 6 -isopentenyladenosine (i 6 A, 58), along with N 6 -isopentenyladenosine 5 -monophosphate (i 6 AP, 59), was isolated from a Japanese sponge Oceanapia sp. This was the first report of i 6 A (58) and i 6 AP (59) from a marine sponge. In the cytotoxic biotest, 58 exhibited cytotoxic activity against HeLa cells with an IC 50 value of 2.1 µM. On the other hand, 59 was inactive at a concentration of 50 µM. Further observations demonstrated that the cell cycle was arrested at the G1 phase by 58, which indicated targeting of the Akt/NF-κB pathway [21].
Mar. Drugs 2022, 20, x FOR PEER REVIEW

Nucleotide Alkaloids
In the study of an Australian sponge Oceanapia sp., uranidine (57) (Figure 8) covered as one component of the major alkaloids [17]. Very recently, N 6 -isopenten osine (i 6 A, 58), along with N 6 -isopentenyladenosine 5ʹ-monophosphate (i 6 AP, 59), lated from a Japanese sponge Oceanapia sp. This was the first report of i 6 A (58) a (59) from a marine sponge. In the cytotoxic biotest, 58 exhibited cytotoxic activity HeLa cells with an IC50 value of 2.1 µ M. On the other hand, 59 was inactive at a tration of 50 μM. Further observations demonstrated that the cell cycle was arreste G1 phase by 58, which indicated targeting of the Akt/NF-κB pathway [21].

Lipids
Lipids were the second-largest group of the Oceanapia secondary metabolite could be divided into sphingolipids, ceramides and cerebrosides, dithiocyanates a yacetylenes, according to their structure features.

Sphingolipids
An antimicrobial galactopyranosyl pseudodimeric α,ω-bipolar sphingolipid chalin (60) (Figure 9), was isolated by Makarieva et al. from the sponge Rhizoch crustata near the north-west shore of Madagascar Island [22]. This was the first r sphingolipids in the sponge of the genus Oceanapia. The effects of 60 on cell mem were studied in Ehrlich ascites cells, spleen lymphocytes and erythrocytes, and p lipid liposomes, respectively. At 10-100 mg/mL, this compound altered membra meability. These effects might be related to the cytostatic activity of 60 [23]. Ten yea Molinski and his co-workers determined the absolute stereochemistry of (-)-rhiz (60) as 2R,3R,26R,27R by application of a general CD method based on the super of additive exaction couplings in tetrabenzoyl derivatives of bis-amino alkanols Gaydou et al.'s study of a specimen of Oceanapia ramsayi collected at Itampolo on t coast of Madagascar, rhizochalin (60) was found together with its corresponding a rhizochalinin (61), which were both identified by their corresponding peracetates 61a [25]. A series of cytotoxic bioassays for 60 and 61 against different cell lines in the mechanisms had been carried out. Fedorov et al. reported 60 and 61 were c against JB6 P+ Cl41, HeLa and THP-1 cell lines with IC50 values ranging from 2.8 µ M. A more in-depth study revealed 60 inhibited the EGF-induced transformatio P+ Cl41 cells in a dose-dependent manner [26]. Stonik and Kwak observed 60 an duced apoptosis of HL-60 cells, of which the latter showed a stronger ability. Fur tailed study showed the usual mitochondrial membrane permeability changes decrease in protein levels of procaspases-8, -9 and -3 correlated with their apoptot ity [27]. Choi et al. disclosed 61 induced apoptosis via activation of AMP-activated kinase in HT-29 colon cancer cells [28].

Lipids
Lipids were the second-largest group of the Oceanapia secondary metabolites. They could be divided into sphingolipids, ceramides and cerebrosides, dithiocyanates and polyacetylenes, according to their structure features.

Sphingolipids
An antimicrobial galactopyranosyl pseudodimeric α,ω-bipolar sphingolipid, rhizochalin (60) (Figure 9), was isolated by Makarieva et al. from the sponge Rhizochalina incrustata near the north-west shore of Madagascar Island [22]. This was the first report of sphingolipids in the sponge of the genus Oceanapia. The effects of 60 on cell membranes were studied in Ehrlich ascites cells, spleen lymphocytes and erythrocytes, and phospholipid liposomes, respectively. At 10-100 mg/mL, this compound altered membrane permeability. These effects might be related to the cytostatic activity of 60 [23]. Ten years later, Molinski and his co-workers determined the absolute stereochemistry of (-)-rhizochalin (60) as 2R,3R,26R,27R by application of a general CD method based on the superposition of additive exaction couplings in tetrabenzoyl derivatives of bis-amino alkanols [24]. In Gaydou et al.'s study of a specimen of Oceanapia ramsayi collected at Itampolo on the west coast of Madagascar, rhizochalin (60) was found together with its corresponding aglycone rhizochalinin (61), which were both identified by their corresponding peracetates 60a and 61a [25]. A series of cytotoxic bioassays for 60 and 61 against different cell lines including the mechanisms had been carried out. Fedorov et al. reported 60 and 61 were cytotoxic against JB6 P+ Cl41, HeLa and THP-1 cell lines with IC 50 values ranging from 2.8 to 22.1 µM. A more in-depth study revealed 60 inhibited the EGF-induced transformation of JB6 P+ Cl41 cells in a dose-dependent manner [26]. Stonik and Kwak observed 60 and 61 induced apoptosis of HL-60 cells, of which the latter showed a stronger ability. Further detailed study showed the usual mitochondrial membrane permeability changes and the decrease in protein levels of procaspases-8, -9 and -3 correlated with their apoptotic activity [27]. Choi et al. disclosed 61 induced apoptosis via activation of AMP-activated protein kinase in HT-29 colon cancer cells [28]. Oceanapiside (62), a new bis-α,ω-amino alcohol glycoside from the marine sponge Oceanapia phillipensis collected in southern Australia, was reported by Molinski's group [29]. Soon after, the absolute stereochemistry of 62 was assigned 2S,3R,26R,27R by analysis of CD spectra of its perbenzoate [30]. Compound 62 exhibited significant antifungal activity against the fluconazole-resistant yeast Candida glabrata with an MIC of 10 µ g/mL in broth dilution experiments [29]. In addition, in vitro antifungal activity of a series of α,ω-bifunctionalized amino alcohols derived from 62 against C. glabrata was measured. The dimeric bifunctionalized lipids exhibited activity about 10-fold higher than D-sphingosine, which was a larger factor than expected from the simple additive effects of vicinal amino alcohol groups [31]. It may be worth pointing out that the application of a combined method including micromolarscale Baeyer-Villiger oxidation and LC-MS interpretation by Makarieva et al. led to a revision of the structure of 62, in which the placement of the keto group should be at C-18 rather than C-11 [32]. Oceanalin A (63), a unique hybrid α,ωbifunctionalized sphingoid tetrahydroisoquinoline β-glycoside, was discovered in the sponge Oceanapia sp. collected off the northwest coast of Australia. Its absolute structure 2R,3R was elucidated by chemical correlation with the known rhizochalin 60. Compound 63 exhibited in vitro antifungal activity against C. glabrata with an MIC of 30 µg/mL [33].
Rhizochalin A (64), the fourth representative of two-headed glycosphingolipids, was isolated as its peracetate (64a) from the sponge R. incrustata collected in the Seychelles Oceanapiside (62), a new bis-α,ω-amino alcohol glycoside from the marine sponge Oceanapia phillipensis collected in southern Australia, was reported by Molinski's group [29]. Soon after, the absolute stereochemistry of 62 was assigned 2S,3R,26R,27R by analysis of CD spectra of its perbenzoate [30]. Compound 62 exhibited significant antifungal activity against the fluconazole-resistant yeast Candida glabrata with an MIC of 10 µg/mL in broth dilution experiments [29]. In addition, in vitro antifungal activity of a series of α,ω-bifunctionalized amino alcohols derived from 62 against C. glabrata was measured. The dimeric bifunctionalized lipids exhibited activity about 10-fold higher than D-sphingosine, which was a larger factor than expected from the simple additive effects of vicinal amino alcohol groups [31]. It may be worth pointing out that the application of a combined method including micromolarscale Baeyer-Villiger oxidation and LC-MS interpretation by Makarieva et al. led to a revision of the structure of 62, in which the placement of the keto group should be at C-18 rather than C-11 [32]. Oceanalin A (63), a unique hybrid α,ω-bifunctionalized sphingoid tetrahydroisoquinoline β-glycoside, was discovered in the sponge Oceanapia sp. collected off the northwest coast of Australia. Its absolute structure 2R,3R was elucidated by chemical correlation with the known rhizochalin 60. Compound 63 exhibited in vitro antifungal activity against C. glabrata with an MIC of 30 µg/mL [33].
Rhizochalin A (64), the fourth representative of two-headed glycosphingolipids, was isolated as its peracetate (64a) from the sponge R. incrustata collected in the Seychelles Islands. Based on the chemical correlation, the absolute configuration 2R,3R,26R,27R of 64 was determined to be the same as that of 60. It might be worth pointing out that 64a was the first example of a natural product among known sphingolipids, including the family of two-headed sphingolipids, that contained the rare N-alkyl carbamoyl group [34]. Soon after, rhizochalinin A (65), the aglycone of rhizochalin A (64), was discovered in the former specimen. Compound 65 exhibited antileukemic activity against human leukemia THP-1 cells (IC 50 = 7.5 µM) [35]. Two new, two-headed sphingolipid-like compounds, rhizochalin B (66) and its aglycone rhizochalinin B (67), were obtained as their corresponding peracetates (66a, 67a) from the marine sponge Oceanapia sp. collected near the Scott reef (northwest of Australia). They differed from classical sphingolipids in the α,ω-position of the basic groups, resembling the polar ends of sphingoid bases, and often contained a terminal methyl group instead of the hydroxymethyl group. Notably, the stereochemistry of C-16 in compounds 66 and 67 remained unknown [36].
From the sponge R. incrustata collected in Madagascar, two new representatives of two-headed glycosphingolipids, rhizochalins C (68) and D (69), were discovered. Based on the analysis of 1 H NMR data and CD spectra of their corresponding perbenzoates, the absolute configurations of 68 and 69 were assigned 2R,3R,26R,27R and 2R,3R,27R,28R, respectively. In contrast to the regular 2S,3R-configuration found in normal sphingoid bases, 68 contained the rare 2R,3R threo stereochemistry, while 69 possessed an odd-numbered C-29 hydrocarbon chain instead of C-28 found in canonical members of this series. It was a pity to find that rhizochalins C (68) and D (69) were not active (ED 50 > 150 µM) against the fluconazole-resistant yeast C. glabrata [32]. In 2009, further study on this specimen led to a new antileukemic two-headed sphingolipid rhizochalinin C (70), which was the aglycone of rhizochalin C (68). In the bioassay, 70 exhibited a cytotoxic effect against THP-1 (IC 50 = 6.7 µM) but was inactive against JB6 P+ Cl41 and HeLa cell lines [26]. Four years later, Molinski and his co-worker reported the first total synthesis of rhizochalinin C (70) [37].
Isorhizochalin (71), isolated as its peracetate (71a), was a minor bipolar sphingolipid of stereodivergent biogenesis from the R. incrustata. Similar to 60, its absolute stereochemistry was elucidated as 2S,3R,26R,27R by analysis of the CD spectrum of its perbenzoate. 71 was a C-2 epimer of 60 with an erythro configuration at the glycosylated 2-amino-3-alkanol-αterminus, in contrast to the canonical threo configuration for other representatives of this structural group. In the bioassay, its aglycone, isorhizochalinin (72), showed cytotoxicity against human leukemia HL-60 and THP-1 cells with IC 50 values of 2.90 and 2.20 µM, respectively [38].

Ceramides and Cerebrosides
Chemical investigation on the sponge Oceanapia cf. tenuis collected in Woodin Channel, New Caledonia, led to a series of ceramides, named oceanapins A-F (73-78) (Figure 10), which were unique for branching at both the sphingosine and fatty-acid chains. A pair of Mosher's esters of the silyl ether derived from oceanapin D (76) was prepared, and the subsequent study on their NMR spectra revealed the 2'S,3'R absolute configuration for the source compound 76 [39].
An inseparable mixture of ceramides 79 (Figure 10) containing nonbranched and isobranched C 18 and C 19 -phytosphingosines acylated with nonhydroxylated fatty acids were disclosed in the ethanolic extract of the Australian sponge Oceanapia sp. This was the first report of natural iso-C 19 -phytosphingosine-containing ceramides. Although no bioactivity was reported for these ceramides, the crude ethanolic extract exhibited antimicrobial activities against S. aureus, B. subtilis, E. coli and C. albicans as well as cytotoxic properties against the Erlich murine carcinoma [40]. In another study on the Australian sponge Oceanapia sp., two cerebrosides 80 and 81 containing N-acetylglucosamine were obtained [41]. An inseparable mixture of ceramides 79 ( Figure 10) containing nonbranched and isobranched C18 and C19-phytosphingosines acylated with nonhydroxylated fatty acids were disclosed in the ethanolic extract of the Australian sponge Oceanapia sp. This was the first report of natural iso-C19-phytosphingosine-containing ceramides. Although no bioactivity was reported for these ceramides, the crude ethanolic extract exhibited antimicrobial activities against S. aureus, B. subtilis, E. coli and C. albicans as well as cytotoxic properties against the Erlich murine carcinoma [40]. In another study on the Australian sponge Oceanapia sp., two cerebrosides 80 and 81 containing N-acetylglucosamine were obtained [41].
It was moderately active against four mutants of Saccharomyces cerevisiae and C. albicans but was inactive against Penicillium chrysogenum and Mortierella ramanniana. It also exhibited inhibitory effects against both Gram-positive and Gram-negative bacteria [45].

Synthesis of (± )-Phloeodictine A1 ((± )-21)
The (±)-phloeodictine A1 ((±)-21) was synthesized by a convergent route by Snider et al. as shown in Scheme 1 [15]. Furan-maleic anhydride Diels-Alder adduct 111 was used as the starting material for the 6-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidinium skeleton. Imide 112 was obtained from 111 via a reaction with 3-aminopropanol, which was quantitatively converted to mesylate 113. The reaction of 113 with NaN3 provided azide 114. The Eguchi aza-Wittig reaction of 114 afforded 114b, which was followed by a thermal retro Diels-Alder reaction to liberate 115. The addition of Grignard reagents to 115 produced 116a. Washing a CH2Cl2 solution of 116a with 1 M NaOH solution afforded 116b. In addition, Snider et al. selected a convergent route for iodide 120 containing a protected guanidine on the other end of the chain. The approach was that the reaction of 117 with the appropriate ω-amino-1-alkanol in THF gave 118, then mesylation and successive The (±)-phloeodictine A1 ((±)-21) was synthesized by a convergent route by Snider et al. as shown in Scheme 1 [15]. Furan-maleic anhydride Diels-Alder adduct 111 was used as the starting material for the 6-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidinium skeleton. Imide 112 was obtained from 111 via a reaction with 3-aminopropanol, which was quantitatively converted to mesylate 113. The reaction of 113 with NaN 3 provided azide 114. The Eguchi aza-Wittig reaction of 114 afforded 114b, which was followed by a thermal retro Diels-Alder reaction to liberate 115. The addition of Grignard reagents to 115 produced 116a. Washing a CH 2 Cl 2 solution of 116a with 1 M NaOH solution afforded 116b. In addition, Snider et al. selected a convergent route for iodide 120 containing a protected guanidine on the other end of the chain. The approach was that the reaction of 117 with the appropriate ω-amino-1-alkanol in THF gave 118, then mesylation and successive displacement with iodide afforded 120. Finally, alkylation of 116b with 120 afforded 121, and subsequent deprotection of 121 completed the synthesis of 21. In Crews et al.'s work, indole-3-carboxaldehyde 122 was used as the starting material as outlined in Scheme 2 [19]. First, 122 was esterified to yield its cyanohydrin silylether 123, then the oxidation of 123 via DDQ followed by hydrogenation led to keto-tryptamine synthon 125. Bromination of 125 proceeded in a straightforward fashion, producing the

Synthesis of Rhizochalinin C (70)
Molinski et al. disclosed an optimized procedure for rapid diastereoselective ac to L-threo-sphingoid base synthons, using a remarkable one-pot conversion of unprote D-glucosamine into useful D-serine synthons based on In 0 -mediated allylation. method was successfully applied to rhizochalinin C (70), which was elaborated as sh in Scheme 3 [37].
The allyl-substituted compounds 127a and 128a that were procured from the Ba allylation of D-glucosamine were followed by differential protections of NH2 and groups. 127a was subjected to olefin cross-metathesis with tetradec-13-enyl acetate,

Conclusions and Perspectives
A huge library of secondary metabolites was reported from the sponges of the genus Oceanapia, with up to 110 compounds with unique structures, from 1989 to July 2019. More than eight species of Oceanapia sponges have been chemically investigated, including Oeanapia sagittaria, Oceanapia fistulosa, Oceanapia bartschi, Phloeodictyon sp., Rhizochalina incrustata, Oceanapia ramsayi, Oceanapia phillipensis, Oceanupia cf. tenuis and Oceanapia sp. The chemical structures were classified as alkaloids, lipids, sterols and other miscellaneous. Among them, alkaloids were encountered most frequently. These compounds exhibited diverse biological properties ranging from insecticidal, cytotoxic and antifeedant to antibacterial. Their unique structures and promising bioactivities have attracted a great deal of attention from synthetic chemists for their total synthesis.