Batzella, Crambe and Monanchora: Highly Prolific Marine Sponge Genera Yielding Compounds with Potential Applications for Cancer and Other Therapeutic Areas

Pyrroloquinoline and guanidine-derived alkaloids present distinct groups of marine secondary metabolites with structural diversity that displayed potentialities in biological research. A considerable number of these molecular architectures had been recorded from marine sponges belonging to different marine genera, including Batzella, Crambe, Monanchora, Clathria, Ptilocaulis and New Caledonian starfishes Fromia monilis and Celerina heffernani. In this review, we aim to comprehensively cover the chemodiversity and the bioactivities landmarks centered around the chemical constituents exclusively isolated from these three marine genera including Batzella, Crambe and Monanchora over the period 1981–2017, paying a special attention to the polycyclic guanidinic compounds and their proposed biomimetic landmarks. It is concluded that these marine sponge genera represent a rich source of novel compounds with potential applications for cancer and other therapeutic areas.


Introduction
As a result of the rise of many current medical challenges, including hepatitis, parasitic infection, lifestyle-induced diseases, such as diabetes, hypertension, many forms of cancer, multi-drug resistance pathogens and other diseases, searching for new bioactive compounds with novel modes of action is necessary. Marine natural products represent potent, promising and sustainable sources for biomedications [1]. Up to present time, eight marine-derived drugs were approved for market pipelines for the treatment of some of these current medical challenges [2,3]. Marine sponges (phylum Porifera), even though they are the most primitive class within the animal kingdom, are considered renewable powerful suppliers for bioactives. The marine genera belonging to the order Poecilosclerida, Batzella (family Chondropsidae), Crambe and Monanchora (family Crambeidae), are rich in the production of highly physiologically active pyrroloquinoline and guanidine-derived alkaloids [4][5][6], with a vast scope of biological potentialities including cytotoxic and antiviral [7][8][9][10][11][12], HIV-1 inhibitors [13,14], enzyme inhibitors [15], receptor antagonist [16], Ca 2+ channel blocker [17], antifungal [18] and antimicrobial [19][20][21]. These interesting compounds are considered taxonomic markers in particular for some Poecilosclerida and Axinellida marine sponge genera [5]. Their complex molecular architectures and potent biological activities have made them for years ideal target molecules for synthetic applications [22][23][24][25][26][27][28]. Beside the production of guanidine-derived architectures, some deep-water species of Batzella produced pyrroloquinoline-derived alkaloids, which raises a chemotaxonomic question about the systematic relatedness of this genus (family Chondropsidae) to other genera like Crambe and Monanchora (family Crambeidae). A chemosystematic exploration has revealed that Batzella sponges containing cyclic guanidine alkaloids are chemically and taxonomically similar, and perhaps synonymous with, Monanchora and Crambe. However, the deep-water Batzella sponges produced pyrroloquinoline alkaloids is taxonomically unrelated to the Batzella previously mentioned. Chemically, it is almost similar to the Zyzzya and Latrunculia marine sponges but their phylogenetic relationship is still undetermined [29]. Systematically, the World Porifera Database accepts nine valid species of Batzella [30], nine valid species in the genus Crambe [31] and fourteen valid species currently in the genus Monanchora [32]. To the best of our knowledge, previous chemical investigations of Batzella was centered on only a single unidentified species from Madagascar [33], for the genus Crambe only one identified species, the type species Crambe crambe from the Mediterranean [34] and finally five identified Monanchora species including Monanchora ungiculata [35], Monanchora dianchora [36], Monanchora pulchra [37], Monanchora arbuscula [38] and Monanchora unguifera [35] in addition to one unidentified species of Monanchora n. sp. [39].

Chemistry and Biology of Natural Products Isolated from Batzella, Crambe and Monanchora
In this review, we provide comprehensive insights on the previous chemical and biological reports for the metabolites of the three marine genera. To facilitate the handling of this survey, the isolated natural compounds are classified by their polycyclic skeleton coupled with their recorded biological potentialities whenever applicable.

Chemistry and Biology of Natural Products Isolated from Batzella, Crambe and Monanchora
In this review, we provide comprehensive insights on the previous chemical and biological reports for the metabolites of the three marine genera. To facilitate the handling of this survey, the isolated natural compounds are classified by their polycyclic skeleton coupled with their recorded biological potentialities whenever applicable.

Bicyclic Guanidine Alkaloids
Eleven bicyclic guanidine metabolites including five bearing crambescin type A (4-8), three bearing crambescin type B (9-11) and further three possessing crambescin type C (12)(13)(14) were recorded from the Mediterranean sponge Crambe crambe. Their structures were established using NMR and careful HRMS/MS data analyses for the complete assignment of the alkyl chain lengths. These compounds demonstrated cytotoxic activity against neuronal cell lines in micromolar range [34,40,41]. Additional homologue crambescin A (15), the only known bicyclic compound reported

Polycyclic Alkaloids Bearing Batzelladine
Batzelladines represent a distinct class of particular guanidine-derived alkaloids that usually contain two main guanidinic moieties. Chemically, they are esters compounds that bear a principle tricyclic ring system named clathriadic acid that acting as an acidic portion bonded to another clathriadic acid molecule or crambescin A bicyclic system as an alcoholic part. Such a unique class of marine alkaloids is assumed to be synthesized biomimetically from different modes of cyclization between a polyketide-derived chain and a putative guanidine precursor affording these structurally complex metabolites [59]. These natural compounds are known for their potent bioactivities [13,14].

Polycyclic Alkaloids Bearing Batzelladine
Batzelladines represent a distinct class of particular guanidine-derived alkaloids that usually contain two main guanidinic moieties. Chemically, they are esters compounds that bear a principle tricyclic ring system named clathriadic acid that acting as an acidic portion bonded to another clathriadic acid molecule or crambescin A bicyclic system as an alcoholic part. Such a unique class of marine alkaloids is assumed to be synthesized biomimetically from different modes of cyclization between a polyketide-derived chain and a putative guanidine precursor affording these structurally complex metabolites [59]. These natural compounds are known for their potent bioactivities [13,14]. A considerable number of bioactive batzelladines were recorded from Batzella sponges. Batzelladines A-E (51-55), five potential inhibitors of HIV gpl20-human CD4 binding were recorded from the Caribbean sponge Batzella sp. [13,14]. Batzelladines F-I (56-59), four inducers of p56lck-CD4 dissociation, were isolated from Batzella sp. collected from Jamaica [60]. Batzelladine J (60) was isolated from the Caribbean Monanchora unguifera [61]. A further six guanidines-including batzelladines K-N (61-64), batzelladine C (53) and dehydrobatzelladine C (65)-were discovered from Jamaican Monanchora unguifera with activities against several cancer cell lines, protozoa, HIV-1 and AIDS [14,62,63]. Batzelladine C (53) displayed anti-HIV-1 activity at an EC 50 of 7.7 µM [63]. Four batzelladines 66-69 containing crambescin A bicyclic system in addition to dihomodehydrobatzelladine (70) were reported from the Caribbean Monanchora arbuscula. These compounds displayed mild antitumor activity with GI 50 (3-7 µM) against three cancer cell lines, lung carcinoma A549, colon carcinoma HT-29 and breast MDA-MB-231, in addition to antimalarial activity against protozoa [64]. Norbatzelladine L (71) was isolated from unidentified species, Monanchora sp. that displayed MNTC (maximum non-toxic concentration) at 2.5 µg mL −1 against HSV-1, with 97% of inhibition in the viral adsorption phase. Furthermore, it displayed cytotoxicity against several human cancer cell lines including leukemia, colorectal, breast, melanoma and glioblastoma [65,66]. Two anti-infective tricyclic members with unique stereochemical features-named merobatzelladines A-B (72-73)-were isolated from Monanchora sp. Merobatzelladines A-B exhibited moderate antimicrobial activity against Vibrio anguillarum with inhibitory zones of 9-10 mm on application of 50 µg of a sample to a paper disk of 6 mm diameter.

Pentacyclic Alkaloids Bearing Crambescidin
Crambescidines are pentacyclic guanidine-derived alkaloids that represent recognizable complex marine metabolites. Chemically, they bear a common core of (5,6,8b)-triazaperhydroacenaphthalene in their molecules (trivially named as vessel) that coupled with a linear ω-hydroxy fatty acid (spermidine or hydroxyspermidine). These compounds vary from one to another in the length of the internal polymethylene chain and the oxidation degree of the two-spiro rings within the pentacyclic core. This group of compounds covers the major secondary metabolites recorded from these three genera. Since the discovery of the parent antiviral and cytotoxic marine metabolite ptilomycalin A (78) by Kashman and co-workers [74] from Ptilocaulis spiculifer (family Axinellidae) and Hemimycale sp. (family Hymedesmiidae) collected from the Red Sea coast in 1989, renewable efforts led to the discovery of further crambescidin analogues. Crambescidin 800 (79), crambescidin 816 (80), crambescidin 830 (81) and crambescidin 844 (82) were recorded from the Mediterranean marine sponge Crambe crambe [75]. These compounds demonstrated antiviral and cytotoxic activity against Herpes simplex virus, type1 (HSV-l) and cytotoxic activity against L1210 murine leukemia cells. Compounds 79, 80 and 82 showed complete inhibition for HSV-l and 98% of L1210 cell growth at concentration of IC50 = 0.1 μM. Furthermore, crambescidin 816 (80) displayed potent Ca 2+ antagonist activity and inhibited the acetylcholine-induced contraction of guinea pig ileum within very low concentrations [17], however, recent novel evidence showed that compound 80 partially blocked CaV and NaV channels in neurons, proposes that this compound might be included in decreasing the neurotransmitter release and synaptic transmission within the central nervous system [76]. Further, recent study proved that crambescidin 816 (80) could be stored into specialized sponge cells where it can be dispersed into the water affording a chemical umbrella surrounding the Crambe crambe sponge [77]. Recently, Botana and co-workers [78] reported important insights about the mechanism of the neurons cytotoxic activity of crambescidin 816 (80) in primary cultures of cortical neurons. These results showed that compound 80 is responsible for the decreasing of neuronal viability and hence provided a dose-dependent increase in cytosolic Ca 2+ level that was also linked to the presence of Ca 2+ in the extracellular media. Crambescidins 78, 79 and 80 were recorded also from Batzella sp. [14]. 13,14,15-isocrambescidin 800 (83) with trans-ring junction within the pentacyclic core and

Pentacyclic Alkaloids Bearing Crambescidin
Crambescidines are pentacyclic guanidine-derived alkaloids that represent recognizable complex marine metabolites. Chemically, they bear a common core of (5,6,8b)-triazaperhydroacenaphthalene in their molecules (trivially named as vessel) that coupled with a linear ω-hydroxy fatty acid (spermidine or hydroxyspermidine). These compounds vary from one to another in the length of the internal polymethylene chain and the oxidation degree of the two-spiro rings within the pentacyclic core. This group of compounds covers the major secondary metabolites recorded from these three genera. Since the discovery of the parent antiviral and cytotoxic marine metabolite ptilomycalin A (78) by Kashman and co-workers [74] from Ptilocaulis spiculifer (family Axinellidae) and Hemimycale sp. (family Hymedesmiidae) collected from the Red Sea coast in 1989, renewable efforts led to the discovery of further crambescidin analogues. Crambescidin 800 (79), crambescidin 816 (80), crambescidin 830 (81) and crambescidin 844 (82) were recorded from the Mediterranean marine sponge Crambe crambe [75]. These compounds demonstrated antiviral and cytotoxic activity against Herpes simplex virus, type1 (HSV-l) and cytotoxic activity against L1210 murine leukemia cells. Compounds 79, 80 and 82 showed complete inhibition for HSV-l and 98% of L1210 cell growth at concentration of IC 50 = 0.1 µM. Furthermore, crambescidin 816 (80) displayed potent Ca 2+ antagonist activity and inhibited the acetylcholine-induced contraction of guinea pig ileum within very low concentrations [17], however, recent novel evidence showed that compound 80 partially blocked CaV and NaV channels in neurons, proposes that this compound might be included in decreasing the neurotransmitter release and synaptic transmission within the central nervous system [76]. Further, recent study proved that crambescidin 816 (80) could be stored into specialized sponge cells where it can be dispersed into the water affording a chemical umbrella surrounding the Crambe crambe sponge [77]. Recently, Botana and co-workers [78] reported important insights about the mechanism of the neurons cytotoxic activity of crambescidin 816 (80) in primary cultures of cortical neurons. These results showed that compound 80 is responsible for the decreasing of neuronal viability and hence provided a dose-dependent increase in cytosolic Ca 2+ level that was also linked to the presence of Ca 2+ in the extracellular media. Crambescidins 78, 79 and 80 were recorded also from Batzella sp. [14]. 13,14,15-isocrambescidin 800 (83) with trans-ring junction within the pentacyclic core and crambidine (84) were discovered from Crambe crambe [17,79]. Surprisingly, compound 83 was found to be a less potent cytotoxic against L1210 cells compared to other crambescidines and there was no observed antiviral activity against HSV-1. This observation could be attributed to the enclosed ionic pocket feature found in 78 and related crambescidins and lacking in 83 [80]. Additional crambescidin analogues with a chlorinated spermidine motif including crambescidin 818 (85), crambescidin 834 (86), crambescidin 673 (87), crambescidin 687 (88) [86]. Further pentacyclic members were described, including crambescidin acid (94) from Monanchora ungiculata [35] and crambescidic acid (95) from Monanchora unguifera [61]. Crambescidin 359 (90) and 16-β-hydroxycrambescidin 359 (96) were obtained from Monanchora unguifera [63]. Ptilomycalin D (97) showed cytotoxicity against cancer cell line P-388 with IC 50 = 0.1 µM in addition to 78 and 95 were reported from Monanchora dianchora [36]. Monanchocidins A-E (98-102) are five unusual pentacyclic guanidine alkaloids with a morpholine modified spermidine motif from Monanchora pulchra. These compounds exhibited potent cytotoxic activities against HL-60 human leukemia cells with IC 50 values of 540, 200, 110, 830 and 650 µM respectively [37]. Monanchocidin A (97) showed anti-migratory activity against several human cancer cell lines where it is able to prevent local expansion and metastatic spread of cancer cells [87]. Moreover, it could be a promising new compound for overcoming resistance to standard therapies in genitourinary malignancies by the induction of autophagy and lysosomal membrane permeabilization [88]. Monanchomycalins A-B (103-104), two pentacyclic with a modified spiro five-membered ring, showed potent cytotoxicity against HL-60 human leukemia cells with the IC 50 values 120 and 140 nM, respectively, were isolated from Monanchora pulchra [89]. Recently, compound 104 was recorded to inhibit of the TRPV1, TRPV2 and TRPV3 channels with EC 50 values 6.02, 2.84 and 3.25 µM, respectively, however it displayed no activity against the TRPA1 receptor [90]. Moreover, monanchomycalin C (105) exhibited cytotoxicity against human breast cancer cell lines MAD-MB-231 with an IC 50 of 8.2 µM, isolated from Monanchora pulchra [91]. Normonanchocidins A-B and D (106-108) were isolated from Monanchora pulchra. Compound 106 and a mixture of 107 and 108 (1:1) displayed cytotoxic activities against human leukemia THP-1 cells with IC 50 values of 2.1 µM and 3.7 µM and against cervix epithelial carcinoma HeLa cells with IC 50 of 3.8 µM and 6.8 µM, respectively [92]. Recently, further three cytotoxic pentacyclic guanidine compounds including crambescidin 786 (109) (111) with this new pentacyclic motif carries some biogenesis impacts and raises some important insights about the variation in the oxidation degree and the mode of cyclization within the pentacyclic core [39]. A further two new hybrid pentacyclic guanidines monanchoxymycalin A-B (112)(113) were obtained from the Far-Eastern marine sponge Monanchora pulchra. They displayed cytotoxic activities against cervical epithelioid carcinoma HeLa cells and breast adenocarcinoma MDA-MB231 cells [93]. Additionally, ptilomycalins E-H (114-117)-with guanidinic modified spermidine-were recorded from the Madagascar marine sponge Monanchora unguiculata. They displayed promising antimalarial activity against Plasmodium falciparum with IC 50 values 0.38, 0.30 and 0.27 µM respectively [94,95] (Figures 7 and 8).

Acyclic Guanidine Alkaloids
Small number of open chain guanidine-derived alkaloids was recorded. Pulchranin A (118), was described as the first marine non-peptide inhibitor of TRPV-1 channels with an EC 50 value 41.2 µM, in addition two other acyclic members pulchranins B-C (119-120) reported from the Far-Eastern marine sponge Monanchora pulchra. Compounds 119 and 120 exhibited moderate inhibition against TRPV1 with EC 50 value 95 and 183 µM respectively and were even less potent against TRPV3 and TRPA1 receptors [96,97]. Moreover, two synthetic derivatives-dihydropulchranin A (121) and hexadecylguanidine (122)-were prepared and studied for their TRPV channel-regulating activities. Compound 121 showed activity as an inhibitor of rTRPV1 and hTRPV3 receptors with EC 50 values of 24.3 and 59.1 µM, respectively, while compound 122 was found not active against those receptors [98]. Additionally, recent studies revealed that pulchranin A (118) exhibited cytotoxic properties and prevented EGF-induced neoplastic transformation in vitro [99]. Further, acyclic analogue unguiculin A (123) with a modified bis-guanidine spermidine motif was isolated from the Madagascar marine sponge Monanchora unguiculata. It displayed antimalarial activity against the parasite Plasmodium falciparum with IC 50 value of 6.04 µM [94,95]. Recently, a further two acyclic bis-guanidine alkaloids-named unguiculins B-C (124-125), beside unguiculin A (123)-were discovered from the French Polynesian Monanchora n. sp. sponge. These compounds displayed potent cytotoxic activity against KB cell lines with IC 50 values 0.19/0.22, 0.08/0.09 and 0.03/0.03 µM respectively. Such activity might be attributed to the two terminal guanidines ends. Moreover, unguiculin C (125), the shorter homologue was found the most active. This could be concluded of how the chain and its length can play an important role as a spacer between two sites of interaction. Moreover, unguiculin B (124) showed further cytotoxicity against HCT-116, HL-60 and MRC-5 cell lines with IC 50 values 3.6/3.6, >10/>10 and 9.6/11.4 µM respectively [100,101] (Figure 9).

Acyclic Guanidine Alkaloids
Small number of open chain guanidine-derived alkaloids was recorded. Pulchranin A (118), was described as the first marine non-peptide inhibitor of TRPV-1 channels with an EC50 value 41.2 μM, in addition two other acyclic members pulchranins B-C (119-120) reported from the Far-Eastern marine sponge Monanchora pulchra. Compounds 119 and 120 exhibited moderate inhibition against TRPV1 with EC50 value 95 and 183 μM respectively and were even less potent against TRPV3 and TRPA1 receptors [96,97]. Moreover, two synthetic derivatives-dihydropulchranin A (121) and hexadecylguanidine (122)-were prepared and studied for their TRPV channel-regulating activities. Compound 121 showed activity as an inhibitor of rTRPV1 and hTRPV3 receptors with EC50 values of 24.3 and 59.1 μM, respectively, while compound 122 was found not active against those receptors [98]. Additionally, recent studies revealed that pulchranin A (118) exhibited cytotoxic properties and prevented EGF-induced neoplastic transformation in vitro [99]. Further, acyclic analogue unguiculin A (123) with a modified bis-guanidine spermidine motif was isolated from the Madagascar marine sponge Monanchora unguiculata. It displayed antimalarial activity against the parasite Plasmodium falciparum with IC50 value of 6.04 μM [94,95]. Recently, a further two acyclic bis-guanidine alkaloids-named unguiculins B-C (124-125), beside unguiculin A (123)-were discovered from the French Polynesian Monanchora n. sp. sponge. These compounds displayed potent cytotoxic activity against KB cell lines with IC50 values 0.19/0.22, 0.08/0.09 and 0.03/0.03 μM respectively. Such activity might be attributed to the two terminal guanidines ends. Moreover, unguiculin C (125), the shorter homologue was found the most active. This could be concluded of how the chain and its length can play an important role as a spacer between two sites of interaction. Moreover, unguiculin B (124) showed further cytotoxicity against HCT-116, HL-60 and MRC-5 cell lines with IC50 values 3.6/3.6, >10/>10 and 9.6/11.4 μM respectively [100,101] (Figure 9).

Biomimetic Landmarks of Polycyclic Guanidinium Motifs
The bio-mechanistic studies along with the structural analyses for the different polycyclic guanidine alkaloids revealed two important insights; the first is chemical; where they are sharing the same biogenesis routs. A second is ecological; where marine sponges that produced such metabolites could be systematically classified under the same order. Generally, the different polycyclic guanidinic moieties could be biomimetically synthesized by way of the double aza Michael strategy, by the addition of free guanidine to α, β unsaturated polyketide chains (Figure 11) [59].

Biomimetic Landmarks of Polycyclic Guanidinium Motifs
The bio-mechanistic studies along with the structural analyses for the different polycyclic guanidine alkaloids revealed two important insights; the first is chemical; where they are sharing the same biogenesis routs. A second is ecological; where marine sponges that produced such metabolites could be systematically classified under the same order. Generally, the different polycyclic guanidinic moieties could be biomimetically synthesized by way of the double aza Michael strategy, by the addition of free guanidine to α, β unsaturated polyketide chains ( Figure 11) [59].

Bicyclic Compounds Possessing Crambescins Type A, B and C
Snider and his team had several contributions towards the biomimetic synthesis of the polycyclic guanidinic motifs. The bicyclic crambescin alkaloids possess three different cyclic moieties-crambescin type A with tetrahydropyrrolo [1,2-c] pyrimidine nucleus, crambescin type B possesses an oxa-6,8-diazaspiro [4.5] motif, while crambescin type C displays a tetrahydropyrimidin fragment. Crambescins type B and C were isolated exclusively from the Mediterranean marine sponge Crambe crambe [34,40,41]. A postulated strategy showed that these three guanidinium cores could be constructed biomimetically through a conjugated Michael addition of guanidine to enone ester. This strategy seems pertinent since it gathers the formation of three different atom arrangements from one unified precursor ( Figure 12) [106].

Bicyclic Compounds Possessing Crambescins Type A, B and C
Snider and his team had several contributions towards the biomimetic synthesis of the polycyclic guanidinic motifs. The bicyclic crambescin alkaloids possess three different cyclic moieties-crambescin type A with tetrahydropyrrolo [1,2-c] pyrimidine nucleus, crambescin type B possesses an oxa-6,8-diazaspiro [4.5] motif, while crambescin type C displays a tetrahydropyrimidin fragment. Crambescins type B and C were isolated exclusively from the Mediterranean marine sponge Crambe crambe [34,40,41]. A postulated strategy showed that these three guanidinium cores could be constructed biomimetically through a conjugated Michael addition of guanidine to enone ester. This strategy seems pertinent since it gathers the formation of three different atom arrangements from one unified precursor ( Figure 12) [106].

Bicyclic Compounds Possessing Crambescins Type A, B and C
Snider and his team had several contributions towards the biomimetic synthesis of the polycyclic guanidinic motifs. The bicyclic crambescin alkaloids possess three different cyclic moieties-crambescin type A with tetrahydropyrrolo [1,2-c] pyrimidine nucleus, crambescin type B possesses an oxa-6,8-diazaspiro [4.5] motif, while crambescin type C displays a tetrahydropyrimidin fragment. Crambescins type B and C were isolated exclusively from the Mediterranean marine sponge Crambe crambe [34,40,41]. A postulated strategy showed that these three guanidinium cores could be constructed biomimetically through a conjugated Michael addition of guanidine to enone ester. This strategy seems pertinent since it gathers the formation of three different atom arrangements from one unified precursor ( Figure 12) [106].   Based on the previous biomimetic approach, Berlinck and co-workers [43] accomplished the biomimetic synthesis of the cytotoxic and anti-parasitic monalidine A (18). 1,3-diketone 153 was introduced for condensation with guanidine free base to afford the corresponding pyrimidine 154 in 25% yield. Subsequently, the key intermediate 152 was cyclized using the Mitsunobu modified protocol to afford 18 as hydrochloride salt in a 67% yield ( Figure 14).

Tricyclic Possessing Ptilocaulin/Batzelladine
(±)-Ptilocaulin (32) was first synthesized biomimetically as a racemic mixture via Michael addition strategy by addition of free guanidine to enone 155 followed by intramolecular enamine formation. (−)-Ptilocaulin (156) was formed as a kinetic product where the guanidine was added to the less hindered top convex face of enone 155, whereas (+)-ptilocaulin (32) was obtained as a thermodynamic adduct as the guanidine was added to the more hindered bottom side of enone 155. This strategy highlights and proves a unique unified biosynthetic route for ptilocaulins and related tricyclic guanidinic analogues ( Figure 15) [107][108][109].  Based on the previous biomimetic approach, Berlinck and co-workers [43] accomplished the biomimetic synthesis of the cytotoxic and anti-parasitic monalidine A (18). 1,3-diketone 153 was introduced for condensation with guanidine free base to afford the corresponding pyrimidine 154 in 25% yield. Subsequently, the key intermediate 152 was cyclized using the Mitsunobu modified protocol to afford 18 as hydrochloride salt in a 67% yield ( Figure 14).  Based on the previous biomimetic approach, Berlinck and co-workers [43] accomplished the biomimetic synthesis of the cytotoxic and anti-parasitic monalidine A (18). 1,3-diketone 153 was introduced for condensation with guanidine free base to afford the corresponding pyrimidine 154 in 25% yield. Subsequently, the key intermediate 152 was cyclized using the Mitsunobu modified protocol to afford 18 as hydrochloride salt in a 67% yield ( Figure 14).

Tricyclic Possessing Ptilocaulin/Batzelladine
(±)-Ptilocaulin (32) was first synthesized biomimetically as a racemic mixture via Michael addition strategy by addition of free guanidine to enone 155 followed by intramolecular enamine formation. (−)-Ptilocaulin (156) was formed as a kinetic product where the guanidine was added to the less hindered top convex face of enone 155, whereas (+)-ptilocaulin (32) was obtained as a thermodynamic adduct as the guanidine was added to the more hindered bottom side of enone 155. This strategy highlights and proves a unique unified biosynthetic route for ptilocaulins and related tricyclic guanidinic analogues ( Figure 15) [107][108][109].

Tricyclic Possessing Ptilocaulin/Batzelladine
(±)-Ptilocaulin (32) was first synthesized biomimetically as a racemic mixture via Michael addition strategy by addition of free guanidine to enone 155 followed by intramolecular enamine formation. (−)-Ptilocaulin (156) was formed as a kinetic product where the guanidine was added to the less hindered top convex face of enone 155, whereas (+)-ptilocaulin (32) was obtained as a thermodynamic adduct as the guanidine was added to the more hindered bottom side of enone 155. This strategy highlights and proves a unique unified biosynthetic route for ptilocaulins and related tricyclic guanidinic analogues (Figure 15) [107][108][109].
formation. (−)-Ptilocaulin (156) was formed as a kinetic product where the guanidine was added to the less hindered top convex face of enone 155, whereas (+)-ptilocaulin (32) was obtained as a thermodynamic adduct as the guanidine was added to the more hindered bottom side of enone 155. This strategy highlights and proves a unique unified biosynthetic route for ptilocaulins and related tricyclic guanidinic analogues ( Figure 15) [107][108][109].  The tricyclic guanidinium framework of batzelladine K (61) was biomimetically synthesized through the addition of free guanidine to a bis-enone 157 affording the pyrrolidine-dione 158, which was subsequently introduced to cyclization followed by iminium ion formation giving rise to the full fused tricyclic guanidinium core. A subsequent reduction afforded 61. A unified synthetic strategy was applied to ptilocaulin (32), isoptilocaulin (33) and batzelladine K (61), which indicated that these classes of tricyclic guanidines are subjected to the same biomimetic gate ( Figure 16) [71,110,111].
Nutrients 2018, 10, 33 16 of 24 The tricyclic guanidinium framework of batzelladine K (61) was biomimetically synthesized through the addition of free guanidine to a bis-enone 157 affording the pyrrolidine-dione 158, which was subsequently introduced to cyclization followed by iminium ion formation giving rise to the full fused tricyclic guanidinium core. A subsequent reduction afforded 61. A unified synthetic strategy was applied to ptilocaulin (32), isoptilocaulin (33) and batzelladine K (61), which indicated that these classes of tricyclic guanidines are subjected to the same biomimetic gate ( Figure 16) [71,110,111].

Pentacyclic Possessing Ptilomycalins, Crambescidins and Monanchomycalins
Numerous total syntheses of the pentacyclic guanidinium core of ptilomycalin A (78), crambescidin 800 (79) and crambescidin 359 (95) were biomimetically achieved [23,112,113]. A biomimetic synthesis of the methyl ester of the pentacyclic nucleus of 78 was conducted through a conjugated condensation of O-methylisourea as protected guanidine strategy with double Michael acceptor bis-enone 159 as α-β unsaturated polyketide framework. Subsequently, desilylation under acidic conditions provided the first seven-membered spiroaminal ring within the intermediate 160.
Later, the second six-membered spiroaminal ring was achieved under basic conditions followed by subsequently aminal formation affording the ptilomycalin A pentacyclic framework 161 (vessel) in one single biomimetic step ( Figure 17).

Pentacyclic Possessing Ptilomycalins, Crambescidins and Monanchomycalins
Numerous total syntheses of the pentacyclic guanidinium core of ptilomycalin A (78), crambescidin 800 (79) and crambescidin 359 (95) were biomimetically achieved [23,112,113]. A biomimetic synthesis of the methyl ester of the pentacyclic nucleus of 78 was conducted through a conjugated condensation of O-methylisourea as protected guanidine strategy with double Michael acceptor bis-enone 159 as α-β unsaturated polyketide framework. Subsequently, desilylation under acidic conditions provided the first seven-membered spiroaminal ring within the intermediate 160.
Later, the second six-membered spiroaminal ring was achieved under basic conditions followed by subsequently aminal formation affording the ptilomycalin A pentacyclic framework 161 (vessel) in one single biomimetic step ( Figure 17). conjugated condensation of O-methylisourea as protected guanidine strategy with double Michael acceptor bis-enone 159 as α-β unsaturated polyketide framework. Subsequently, desilylation under acidic conditions provided the first seven-membered spiroaminal ring within the intermediate 160.
Later, the second six-membered spiroaminal ring was achieved under basic conditions followed by subsequently aminal formation affording the ptilomycalin A pentacyclic framework 161 (vessel) in one single biomimetic step ( Figure 17). Recently, a detailed biomimetic gate was proposed illustrating the biogenesis of different pentacyclic guanidinium cores. The pentacyclic core of monanchomycalin A (103), suggests polyketide-like biogenesis, followed by spermidine-spermidine condensations. Two different precursors were employed, including either nine acetate units as in monanchomycalin B (104) and Recently, a detailed biomimetic gate was proposed illustrating the biogenesis of different pentacyclic guanidinium cores. The pentacyclic core of monanchomycalin A (103), suggests polyketide-like biogenesis, followed by spermidine-spermidine condensations. Two different precursors were employed, including either nine acetate units as in monanchomycalin B (104) and other known pentacyclic members, or ten acetate and one propionate units as in monanchomycalin A (103). To finish the pentacyclic guanidinium polyketide framework (vessel), a cyclization key-step developed by adding guanidine to bis-α, β unsaturated chain followed by imine-enamine tautomerization (transformation (a)). Further conversions including the allylic oxidation (transformation (b)) to afford putative intermediates (III and/or IV) followed by cyclization-elimination (c) and (d) to generate monanchomycalins A-B (103-104) and related pentacyclic analogues. Moreover, the interconversion of the presumptive intermediates III and IV (transformation (e)) through allylic rearrangement like reactions also might be possible ( Figure 18) [89]. other known pentacyclic members, or ten acetate and one propionate units as in monanchomycalin A (103). To finish the pentacyclic guanidinium polyketide framework (vessel), a cyclization key-step developed by adding guanidine to bis-α, β unsaturated chain followed by imine-enamine tautomerization (transformation (a)). Further conversions including the allylic oxidation (transformation (b)) to afford putative intermediates (III and/or IV) followed by cyclization-elimination (c) and (d) to generate monanchomycalins A-B (103-104) and related pentacyclic analogues. Moreover, the interconversion of the presumptive intermediates III and IV (transformation (e)) through allylic rearrangement like reactions also might be possible ( Figure 18) [89]. Recently, Guzii and collaborators [96] proposed biogenetic correlations linking between the acyclic guanidine alkaloid pulchranin A (118) and the pentacyclic crambescidins and monanchomycalins A-B (103)(104). This proposed biogenetic rout could unify the variation in the oxidation degree for the left-hand side spiroaminal rings ( Figure 19). Recently, Guzii and collaborators [96] proposed biogenetic correlations linking between the acyclic guanidine alkaloid pulchranin A (118) and the pentacyclic crambescidins and monanchomycalins Nutrients 2018, 10, 33

of 24
A-B (103)(104). This proposed biogenetic rout could unify the variation in the oxidation degree for the left-hand side spiroaminal rings ( Figure 19). Recently, Guzii and collaborators [96] proposed biogenetic correlations linking between the acyclic guanidine alkaloid pulchranin A (118) and the pentacyclic crambescidins and monanchomycalins A-B (103)(104). This proposed biogenetic rout could unify the variation in the oxidation degree for the left-hand side spiroaminal rings ( Figure 19).

Conclusions
In conclusion, we have presented complete and comprehensive up-to date literature survey exclusively dedicated to the chemistry, biology and insights on the most leading biomimetic syntheses of guanidine derived natural products isolated from marine sponges of three genera Batzella, Crambe and Monanchora. One hundred forty-seven marine natural products were recorded with distinct structural diversities that afforded wide scope of bioactivities. For their chemodiversity, along with their displayed biological potentialities, they still present promising and attractive marine species that are worth attracting the worldwide interest of natural products chemists and pharmacologists.

Conclusions
In conclusion, we have presented complete and comprehensive up-to date literature survey exclusively dedicated to the chemistry, biology and insights on the most leading biomimetic syntheses of guanidine derived natural products isolated from marine sponges of three genera Batzella, Crambe and Monanchora. One hundred forty-seven marine natural products were recorded with distinct structural diversities that afforded wide scope of bioactivities. For their chemodiversity, along with their displayed biological potentialities, they still present promising and attractive marine species that are worth attracting the worldwide interest of natural products chemists and pharmacologists.