Marine Natural Products from the Yucatan Peninsula

Mexico is one of the three areas of the world with the greatest terrestrial and cultural biological diversity. The diversity of Mexican medicinal flora has been studied for a long time and several bioactive compounds have been isolated. The investigation of marine resources, and particularly the potential of Mexican marine resources, has not been intensively investigated, even though the Yucatan Peninsula occupies 17.4% of the total of the Mexican coast, with great biological diversity in its coasts and the ocean. There are very few studies on the chemistry of natural products from marine organisms that were collected along the coasts of the Yucatan Peninsula and most of them are limited to the evaluation of the biological activity of their organic extracts. The investigations carried out on marine species from the Yucatan Peninsula resulted in the identification of a wide structural variety of natural products that include polyketides, terpenoids, nitrogen compounds, and biopolymers with cytotoxic, antibacterial, antifouling, and neurotoxic activities. This review describes the literature of bioprospecting and the exploration of the natural product diversity of marine organisms from the coasts of the Yucatan Peninsula up to mid-2019.


Introduction
The potential of marine natural products in drug discovery is invaluable due to the extremely rich biodiversity of the marine environment. The marine environment contains a large number of species which are the source of a wide range of structurally diverse bioactive secondary metabolites. Approximately 29,000 marine natural products are known, from which eight compounds have become commercialized drugs. During the last decade, more than 1000 new marine natural products have been annually isolated, but the set of new and unique structures is far from being exhausted [1,2]. The interest in marine organisms has been increasing, since they are capable of producing a great diversity of novel metabolites, such as unusual nucleosides, bioactive terpenes, sterols, cyclic peptides, alkaloids, fatty acids, peroxides, and amino acid derivatives, many of them with high potential for pharmacological applications [3].
The Yucatan Peninsula in Mexico, which comprises the Mexican states of Campeche, Quintana Roo, and Yucatan, is known as a biotic province [4]. Although marine organisms constitute a recognized source of a wide range of structurally diverse natural products, research that is focused on marine natural products from the Yucatan Peninsula is still in infancy, mainly when compared to the numerous studies of those isolated from terrestrial organisms, especially from plants [5].

Steroids
High diversity unusual structures of steroid derivatives with multiple potential biological properties have been isolated from marine organisms. Bohlin

Steroids
High diversity unusual structures of steroid derivatives with multiple potential biological properties have been isolated from marine organisms. Bohlin

Triterpenoid Saponins
Sea cucumbers constitute a rich source of triterpenoid saponins, with some of them exerting pharmacological effects [19]. From the sea cucumber Astichopus multifidus, collected on the Yucatan Peninsula coasts, Mena-Rejón and collaborators reported the isolation and the structural elucidation of three oligoglycoside triterpenes in 2016. Two of them, stichloroside B2 (38) and astichoposide C (39), were known, while the third one, named as astichoposide D (40)  Steroid structures of the A-nor-5α-cholestanes 24-35 isolated from the sponge Teichaxinella morchella (now Axinella corrugata) and the cholesterol derivatives 36 and 37 isolated from the brown algae Padina sanctae-crucis and Turbinaria tricostata.

Triterpenoid Saponins
Sea cucumbers constitute a rich source of triterpenoid saponins, with some of them exerting pharmacological effects [19]. From the sea cucumber Astichopus multifidus, collected on the Yucatan Peninsula coasts, Mena-Rejón and collaborators reported the isolation and the structural elucidation of three oligoglycoside triterpenes in 2016. Two of them, stichloroside B 2 (38) and astichoposide C (39), were known, while the third one, named as astichoposide D (40)

Indole Derivatives
Olguin-Uribe et al. isolated two indoles, indole-3-carbaldehyde (42) and its brominated derivate, 6-bromoindole-3-carbaldehyde (43), in 1997 from two different sources, the tunicate Stomozoa murrayi (currently known as Stomozoa roseola) and the bacterium Acinetobacter sp. associated to its surface [22]. The tunicate was collected at a depth of 3-5 m in Puerto Morelos, Quintana Roo state, very close to the Institute of Marine Sciences and Limnology research station of the National Autonomous University of Mexico (UNAM). These compounds were evaluated in several biological assays. The brominated indole 43 displays antimicrobial activity by inhibiting the growth of four marine bacterial

Indole Derivatives
Olguin-Uribe et al. isolated two indoles, indole-3-carbaldehyde (42) and its brominated derivate, 6-bromoindole-3-carbaldehyde (43), in 1997 from two different sources, the tunicate Stomozoa murrayi (currently known as Stomozoa roseola) and the bacterium Acinetobacter sp. associated to its surface [22]. indole 43 displays antimicrobial activity by inhibiting the growth of four marine bacterial strains SM-S2, SM-Z, Bacillus marinus, and Vibrio campbellii, while its debrominated analog 42 shows no inhibitory activity. On the other hand, both of the compounds exhibit antifouling activity by completely inhibiting the settlement of Balanus amphitrite (now Amphibalanus amphitrite) at the highest concentration tested at 100 µg mL −1 (0.13 and 0.084 µM respectively) and, even, the most active compound 43 can inhibit larval settlement by 80% at 10 µg mL −1 /0.044 µM. Finally, these compounds showed no antipredatory (deterrent) activity against the Serranus cabrilla fish, which were collected in the Mediterranean Sea, or significant antialgal activity against the diatom Nitzchia acicularis (Figure 7).
Mar. Drugs 2020, 18, x FOR PEER REVIEW 8 of 24 strains SM-S2, SM-Z, Bacillus marinus, and Vibrio campbellii, while its debrominated analog 42 shows no inhibitory activity. On the other hand, both of the compounds exhibit antifouling activity by completely inhibiting the settlement of Balanus amphitrite (now Amphibalanus amphitrite) at the highest concentration tested at 100 μg mL −1 (0.13 and 0.084 μM respectively) and, even, the most active compound 43 can inhibit larval settlement by 80% at 10 μg mL −1 /0.044 μM. Finally, these compounds showed no antipredatory (deterrent) activity against the Serranus cabrilla fish, which were collected in the Mediterranean Sea, or significant antialgal activity against the diatom Nitzchia acicularis ( Figure  7). Pech-Puch et al. reported the isolation of another indole, serotonin (44), from the salivary glands of Octopus maya collected in Sisal, Yucatan state in 2016 [23]. The neurotoxic activity previously found in its extract was attributed to that compound (Figure 7).

Nucleosides and Nitrogenous Bases
The importance of the study of nucleosides comes from the fact that the arabino-nucleosides spongothymidine and spongouridine, isolated from a marine sponge, were the first marine natural products that showed their potential as drugs, because they constituted the basis of the development of the first synthetic nucleosides approved as therapeutic drugs: the anticancer cytarabine (ara-C) and the antiviral vidarabine (ara-A) [1].

Nucleosides and Nitrogenous Bases
The importance of the study of nucleosides comes from the fact that the arabino-nucleosides spongothymidine and spongouridine, isolated from a marine sponge, were the first marine natural products that showed their potential as drugs, because they constituted the basis of the development of the first synthetic nucleosides approved as therapeutic drugs: the anticancer cytarabine (ara-C) and the antiviral vidarabine (ara-A) [1].
Three nucleosides, thymidine (45), 2 -desoxyuridine (46), and uridine (47) strains SM-S2, SM-Z, Bacillus marinus, and Vibrio campbellii, while its debrominated analog 42 shows no inhibitory activity. On the other hand, both of the compounds exhibit antifouling activity by completely inhibiting the settlement of Balanus amphitrite (now Amphibalanus amphitrite) at the highest concentration tested at 100 μg mL −1 (0.13 and 0.084 μM respectively) and, even, the most active compound 43 can inhibit larval settlement by 80% at 10 μg mL −1 /0.044 μM. Finally, these compounds showed no antipredatory (deterrent) activity against the Serranus cabrilla fish, which were collected in the Mediterranean Sea, or significant antialgal activity against the diatom Nitzchia acicularis ( Figure  7). Pech-Puch et al. reported the isolation of another indole, serotonin (44), from the salivary glands of Octopus maya collected in Sisal, Yucatan state in 2016 [23]. The neurotoxic activity previously found in its extract was attributed to that compound (Figure 7).

Nucleosides and Nitrogenous Bases
The importance of the study of nucleosides comes from the fact that the arabino-nucleosides spongothymidine and spongouridine, isolated from a marine sponge, were the first marine natural products that showed their potential as drugs, because they constituted the basis of the development of the first synthetic nucleosides approved as therapeutic drugs: the anticancer cytarabine (ara-C) and the antiviral vidarabine (ara-A) [1].

Conotoxins
The venomous fish-hunting cone snails that belong to the Conus genus are composed of a collection of toxin peptides that serve to immobilize prey by targeting different physiological mechanisms in their neuromuscular system. In this way, ω-conotoxin MVIIA, isolated from Conus magus, is commercialized as the synthetic Prialt ® (ziconatide), which constituted the first FDA-approved drug that was directly derived from a marine natural product as a pain control drug [1]. On the basis of this background, the research group lead by Aguilar from the Institute of Neurobiology-UNAM at Queretaro in Mexico, reported the isolation of new conotoxins from three different snails, mainly belonging to the Conus genus, which were collected along the coasts of the Mexican Caribbean.
From the extract of the venom duct of a second mollusk, Conus spurius, Aguilar and collaborators reported the isolation of twelve new conotoxin derivatives 53-64, from two different places: Quintana Roo and Campeche states. Conotoxin sr5a (53), which was reported in 2006, is a hydrophobic peptide belonging to the T-1 conotoxin family with a molecular mass of 1616.60 Da and a pair of disulfide bridges. In a biological test in mice, this conotoxin caused a depressed behavioral activity [29]. One year later, two new α-conotoxins of 18 amino acids, SrIA (54) and SrIB (55), with a molecular mass of 2202.9 and 2158.8 Da, respectively, were reported. Conotoxis 54 and 55 were evaluated as antagonists to nicotinic acetylcholine receptors in order to search for new therapeutic alternatives against brain diseases (schizophrenia, nocturnal frontal lobe epilepsy and Alzheimer's disease). The results suggested not only that these conotoxins can operate as nicotinic acetylcholine receptor inhibitors, but also that they bind to nicotinic acetylcholine receptors with a very high affinity, increasing their intrinsic cholinergic response, and making them excellent model tools for studying toxin-receptor interaction [30]. The fourth new peptide, conotoxin sr11a (56), with a molecular weight of 3650.77 Da, was reported in 2007, being the first I-conotoxin that was isolated from the Western Atlantic. This peptide produces a stiffening of body, limbs, and tail when intracranially injected into mice [31]. Conotoxin sr7a (57), containing 32 amino acids (3330.74 Da) and reported in 2007, displays several in vivo effects, such as hyperactivity in mice and paralysis in freshwater snails (Pomacea paludosa), while it was inactive in intramuscular trials with the limpet Patella opea and the freshwater fish Lebistes reticulatus [32]. In contrast, conorfamide-Sr2 (CNF-Sr2, 58), as reported in 2008, with a molecular mass of 1468.70 Da and without cysteine residues, exhibits paralytic activity in the limpet Patella opea and produces hyperactivity in the freshwater snail Pomacea paludosa and mice [33]. From specimens of Conus spurius, collected in Isla Arena, Campeche state, were isolated and identified by reverse transcription polymerase chain reaction, seven conotoxins. Four of them belong to the T-1 conotoxin family, (18V) sr5a (59), (18T) sr5a (60), "extended" (61), and "hydrophilic" (62), which were reported in 2009 [34], and they are very similar to the conotoxin sr5a (53). The other three, reported in 2010, were the known conotoxin sr11a (56) already reported in 2007 [31] and the new conotoxins, sr11b (63) and sr11c (64) [35] (Figure 9). Finally, Aguilar and collaborators reported in 2009 the isolation of a new peptide, pal9a (65) (3678.84 Da) with 34 amino acids, including six cysteine residues, from a third mollusk, Polystira albida, collected in Campeche state. This is the first P-conotoxin-like turritoxin isolated from a member of the family Turridae from the Western Atlantic [36] (Figure 9).

Mar. Drugs 2020, 18, x FOR PEER REVIEW 10 of 24
Finally, Aguilar and collaborators reported in 2009 the isolation of a new peptide, pal9a (65) (3678.84 Da) with 34 amino acids, including six cysteine residues, from a third mollusk, Polystira albida, collected in Campeche state. This is the first P-conotoxin-like turritoxin isolated from a member of the family Turridae from the Western Atlantic [36] (Figure 9).

Biopolymers
Freile-Pelegrín and collaborators reported the characterization of l-carrageenan (66) in 2018, being obtained from the direct extraction of the red algae Solieria filiformis collected at Telchac in the Yucatan state. This polysaccharide shows high antiviral activity against Herpes simplex virus with an EC 50 value of 6.3 µg mL −1 /0.019 µM [37] (Figure 10).

Biopolymers
Freile-Pelegrín and collaborators reported the characterization of L-carrageenan (66) in 2018, being obtained from the direct extraction of the red algae Solieria filiformis collected at Telchac in the Yucatan state. This polysaccharide shows high antiviral activity against Herpes simplex virus with an EC50 value of 6.3 μg mL −1 /0.019 μM [37] (Figure 10).

Bioprospecting Overview
A total of 95 scientific documents were recorded and analyzed in this review, including 82 articles, four postgraduate dissertation theses, and nine meeting abstract communications. They describe the reports related to research on pharmacological surveys of extracts, chemical composition, and isolation of marine natural products. A total of 145 species of marine organisms are enclosed, belonging to 12 phyla (Tables 1 and 2), being the most representative Rhodophyta (27%), Chlorophyta (22%), Phaeophyta (17%), and Cnidaria (14%) (Figure 11).

Bioprospecting Overview
A total of 95 scientific documents were recorded and analyzed in this review, including 82 articles, four postgraduate dissertation theses, and nine meeting abstract communications. They describe the reports related to research on pharmacological surveys of extracts, chemical composition, and isolation of marine natural products. A total of 145 species of marine organisms are enclosed, belonging to 12 phyla (Tables 1 and 2), being the most representative Rhodophyta (27%), Chlorophyta (22%), Phaeophyta (17%), and Cnidaria (14%) (Figure 11).

Biopolymers
Freile-Pelegrín and collaborators reported the characterization of L-carrageenan (66) in 2018, being obtained from the direct extraction of the red algae Solieria filiformis collected at Telchac in the Yucatan state. This polysaccharide shows high antiviral activity against Herpes simplex virus with an EC50 value of 6.3 μg mL −1 /0.019 μM [37] (Figure 10).

Bioprospecting Overview
A total of 95 scientific documents were recorded and analyzed in this review, including 82 articles, four postgraduate dissertation theses, and nine meeting abstract communications. They describe the reports related to research on pharmacological surveys of extracts, chemical composition, and isolation of marine natural products. A total of 145 species of marine organisms are enclosed, belonging to 12 phyla (Tables 1 and 2), being the most representative Rhodophyta (27%), Chlorophyta (22%), Phaeophyta (17%), and Cnidaria (14%) (Figure 11). Figure 11. Distribution of the reported marine organisms by phylum. Figure 11. Distribution of the reported marine organisms by phylum.
The mollusk Conus spurius and two algae, Halymenia floresia (now H. floresii) and Sargassum fluitans, with nine reports each, were the most reported species. The coral Millepora complanata and eight algae, Halimeda tuna, Penicillus dumetosus, Udotea flabellum, Bryothamnion triquetrum (now Alsidium triquetrum), Ceramium nitens, Eucheuma isiforme (now Eucheumatopsis isiformis), Gracilaria caudata (now Crassiphycus caudatus), Lobophora variegata, and Turbinaria turbinata, with 6-8 reports each, following the list as it is shown in Figure 12. From the territorial distribution point of view, the highest number of reports corresponds to marine organisms that were collected at the coast of the Yucatan state (38%), followed by the coasts of Quintana Roo state (36%) and, finally, the coasts of Campeche state (4%). However, 22% of the reports did not specify the state where the marine organisms were collected ( Figure 13). From the territorial distribution point of view, the highest number of reports corresponds to marine organisms that were collected at the coast of the Yucatan state (38%), followed by the coasts of Quintana Roo state (36%) and, finally, the coasts of Campeche state (4%). However, 22% of the reports did not specify the state where the marine organisms were collected ( Figure 13).     Figure 14 displays the number of reports per year. As far as we know, the first report was published in 1981 and, since then, the number of publications related to the search for natural marine products of the Yucatan Peninsula has been increasing. However, this increase was not constant, being the years 2007, 2013, 2014, and 2016, with seven publications each, when more reports were published.

Conclusions
The present review represents the first comprehensive report of natural products that have been  Table 1). Out of the 66 marine natural products identified, 26 correspond to structures that
As a concluding remark, this review shows the potential of the Yucatan Peninsula as an The biological studies of the isolated compounds are focused on cytotoxic or antiproliferative activities (diterpenes 15, 18, 20, 22, and 23; steroids 36 and 37, and triterpenoids saponins 38 and 39), the antimicrobial, antifouling, antipredatory (deterrent), and antialgal activity (indole derivative 42 and 43), the antiprotozoal activity (glycolipids 7-9), neurotoxic activity (indole derivative 44), behavioral activity in animal models (conotoxins 53, 56-58), and finally in the interesting pharmacological activities against brain diseases of the new conotoxins 54 and 55, and the high antiviral activity of the known biopolymer L-carrageenan (66).
As a concluding remark, this review shows the potential of the Yucatan Peninsula as an interesting source of new marine natural products, not only because of its unique and rich diversity of marine organisms, but also due to the small number of works that have been published so far, which indicates that this area of research has been poorly investigated. For these reasons, the marine biodiversity of the Yucatan Peninsula can be considered as a poor exploited source of new bioactive marine natural products, which could be the base of the development of new drugs.