Marine Terpenoids from Polar Latitudes and Their Potential Applications in Biotechnology

Polar marine biota have adapted to thrive under one of the ocean’s most inhospitable scenarios, where extremes of temperature, light photoperiod and ice disturbance, along with ecological interactions, have selected species with a unique suite of secondary metabolites. Organisms of Arctic and Antarctic oceans are prolific sources of natural products, exhibiting wide structural diversity and remarkable bioactivities for human applications. Chemical skeletons belonging to terpene families are the most commonly found compounds, whereas cytotoxic antimicrobial properties, the capacity to prevent infections, are the most widely reported activities from these environments. This review firstly summarizes the regulations on access and benefit sharing requirements for research in polar environments. Then it provides an overview of the natural product arsenal from Antarctic and Arctic marine organisms that displays promising uses for fighting human disease. Microbes, such as bacteria and fungi, and macroorganisms, such as sponges, macroalgae, ascidians, corals, bryozoans, echinoderms and mollusks, are the main focus of this review. The biological origin, the structure of terpenes and terpenoids, derivatives and their biotechnological potential are described. This survey aims to highlight the chemical diversity of marine polar life and the versatility of this group of biomolecules, in an effort to encourage further research in drug discovery.


Foreword
The global market for marine biotechnology is expected to reach US$ $6.4 billion by 2025 [1]. However, in regard to the polar regions, marine biotechnology has lagged and the potential for many sectors is not yet fully realized. These remote and underexploited habitats are promising sources of environmental and biomedical applications and may provide significant opportunities for compound discovery and bioprospecting [2][3][4][5][6].

Marine chemical diversity in Polar Regions
In the Antarctic and Arctic marine environment, a huge reservoir of microbial biodiversity has been recognized as promising for the isolation of new antimicrobial metabolites [85,[156][157][158][159]. Among marine bacteria, Pseudoalteromonas haloplanktis TAC125 is a potential untapped source of biologically active natural products [160]. This cold-adapted bacterium produces valuable bioactive secondary metabolites, such as anti-biofilm metabolites [160], antibiotics such as methylamine, a volatile compound active against Burkholderia cepacia complex strains [81] and anticancer compounds [82]. The biotechnological potential of P. haloplanktis TAC125 is related to its genus Pseudoalteromonas, ubiquitously distributed in almost all marine habitats. The recent reconstruction of the largest Pseudoalteromonas pangenome allowed the identification of Pseudoalteromonas genes for cold adaptation and the production of secondary metabolites, among others [161]. Other Antarctic strains belonging to the same genus have proven useful for cosmetic application, including Antarcticine ®® launched by LIPOTEC as an anti-aging product obtained from extracts of marine Pseudoalteromonas antarctica [162], and SeaCode ®® , a mixture of EPS and other glucidic exopolymers produced by biotechnological fermentation of a Pseudoalteromonas sp. isolated in Antarctic waters [163].
On the macroscopic realm, several new natural products have been isolated from marine polar biota, some yielding encouraging properties for biotech discovery [6]. The Arctic bryozoan Dendrobeania murrayana revealed the presence of the guanidine alkaloid, dendrobeaniamine A, which was inactive in cytotoxicity, antimicrobial, anti-inflammatory and antioxidant assays [115]. The permethylated hexapeptide friomaramide is a potent inhibitor of liver-stage infection by Plasmodium falciparum [164]. Among all marine natural products coming from the polar seas, we will focus in this review on terpenoids and their derivatives (included in Table 1), because they represent one of the most important classes of bioactive molecules commonly found in polar organisms.

Marine Polar Terpenoids
In marine environments, terpenes, terpenoids and their derivatives display an array of diverse chemical structures, with promising biological activities [165][166][167][168]. Terpenes are hydrocarbons that represent a large family of natural compounds, which include primary and secondary metabolites metaphorically biosynthesized from five carbon isoprene units.
Terpenoids, which are sometimes called isoprenoids, are derivatives or modified terpenes. Although sometimes used interchangeably with "terpenes," terpenoids are often polycyclic structures where methyl groups have been moved or removed, and oxygen-containing functional groups have been added. About 60% of known natural products are terpenoids [169].
Modification of the isoprene unit structures leads to a wide structural diversity of derivatives showing diverse bioactivities. Terpenes and terpenoids are often classified by the number of isoprene units added to the parent terpene, and divided into biogenetic subclasses, e.g., monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes and tetraterpenes, containing two, three, four, five, six and seven isoprene units, respectively. The triterpenes include sterols and steroids and their derivatives conjugated to other functional group while the tetraterpenes include carotenoids. There are also compounds that contain terpene fragments, such as prenylated polyketides (meroterpenes, indole alkaloids).
Their biosynthesis was described in 1953, by Leopold Ružička as the C 5 rule or biogenetic isoprene rule, reporting the linking of isoprene units "head to tail" to form chains [170]. There are two metabolic pathways that create terpenoids ( Figure 1): (a) the mevalonic acid or mevalonate pathway (MVA pathway), which also produces cholesterol and occurs in the cytoplasm of most organisms (e.g., bacteria, archaea, fungi, plants, animals), except green algae; and (b) the 2-C-methyl-d-erythritol 4-phosphate/1-deoxy-d-xylulose 5-phosphate pathway (MEP/DOXP pathway), also known as non-mevalonate pathway, takes place in plastids of plants and green algae, in apicomplexan protozoa and in many bacteria [171]. From these two pathways isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP) are derived, which are sequentially elongated by prenyltransferases to geranyl diphosphate (C 10 ), farnesyl diphosphate (C 15 ) and geranylgeranyl diphosphate (C 20 ) (Figure 1). These acyclic intermediates are then transformed by terpenoid synthases into monoterpenes, sesquiterpenes and diterpenes and further modifications produce triterpenes and tetraterpenes [171].
Mar. Drugs 2020, 18, x 17 of 48 and geranylgeranyl diphosphate (C20) (Figure 1). These acyclic intermediates are then transformed by terpenoid synthases into monoterpenes, sesquiterpenes and diterpenes and further modifications produce triterpenes and tetraterpenes [171]. Marine organisms are prolific producers of terpenes and terpenoids. Particularly in cnidarians (corals), mollusks and sponges, these types of compounds are well represented among reported natural products. In ascidians and echinoderms, the proportion of terpene and terpenoid molecules reported to date is lower but they are still relatively common. In total, terpenoids are the most frequently reported natural product class from the Antarctic, displaying a large degree of structural diversity and bioactivity [172]. In the following paragraphs, we will describe some aspects of the biotechnological potential of terpene and terpenoid compounds from polar latitudes.

Monoterpenes and Monoterpenoids
Monoterpenes are comprised of two isoprene units that result from a single condensation between DMAPP and IPP to yield a 10-carbon molecule, which is often further modified ( Figure 1). Polyhalogenated monoterpenes are commonly produced by red algae inhabiting the shallow waters of the polar regions. These metabolites are often found in high abundance and can be either linear or cyclic. Like many natural products found in other phyla, the ecological function of these halogenated secondary metabolites is thought to be multi-faceted. The most commonly assumed role is that of defense, conveying deterrence against herbivory and resistance to detrimental fouling species [173]. These compounds may also be used offensively, possibly providing allelopathic competitive advantages to the producers, while deleteriously affecting potential competitors for space and resources [155,[174][175][176].
Likely owing to their defensive and offensive ecological functions in nature, previous investigations into the therapeutic potential of halogenated metabolites in red seaweeds from other regions have yielded a plethora of relevant biological activities, ranging from antimicrobial to perhaps most notably their antitumor properties [155,[174][175][176][177]. Similarly, a recent chemical investigation of what is generally considered to be an Antarctic subspecies of the red alga Plocamium cartilagineum collected from around Anvers Island along the Western Antarctic Peninsula yielded Marine organisms are prolific producers of terpenes and terpenoids. Particularly in cnidarians (corals), mollusks and sponges, these types of compounds are well represented among reported natural products. In ascidians and echinoderms, the proportion of terpene and terpenoid molecules reported to date is lower but they are still relatively common. In total, terpenoids are the most frequently reported natural product class from the Antarctic, displaying a large degree of structural diversity and bioactivity [172]. In the following paragraphs, we will describe some aspects of the biotechnological potential of terpene and terpenoid compounds from polar latitudes.

Monoterpenes and Monoterpenoids
Monoterpenes are comprised of two isoprene units that result from a single condensation between DMAPP and IPP to yield a 10-carbon molecule, which is often further modified ( Figure 1). Polyhalogenated monoterpenes are commonly produced by red algae inhabiting the shallow waters of the polar regions. These metabolites are often found in high abundance and can be either linear or cyclic. Like many natural products found in other phyla, the ecological function of these halogenated secondary metabolites is thought to be multi-faceted. The most commonly assumed role is that of defense, conveying deterrence against herbivory and resistance to detrimental fouling species [173]. These compounds may also be used offensively, possibly providing allelopathic competitive advantages to the producers, while deleteriously affecting potential competitors for space and resources [155,[174][175][176].
Likely owing to their defensive and offensive ecological functions in nature, previous investigations into the therapeutic potential of halogenated metabolites in red seaweeds from other regions have yielded a plethora of relevant biological activities, ranging from antimicrobial to perhaps most notably their antitumor properties [155,[174][175][176][177]. Similarly, a recent chemical investigation of what is generally considered to be an Antarctic subspecies of the red alga Plocamium cartilagineum collected from around Anvers Island along the Western Antarctic Peninsula yielded several polyhalogenated monoterpenes (1-9) including anverenes A-E ( Figure 2), which displayed cytotoxicity in the low micromolar range (1-13 µM) against a cervical cancer cell line (HeLa) [154].

Sesquiterpenes and Sesquiterpenoids
Sesquiterpenes comprise "one and a half monoterpenes" (sesqui-prefix means one and a half), thus, three isoprene units. They may be acyclic or contain rings, including many unique combinations. As in other terpenes, biochemical modifications such as oxidation or rearrangement produce the related sesquiterpenoids [169,171]. Sesquiterpenes and sesquiterpenoids are an important class of natural products with a wide range of biological activities as semiochemicals, e.g., defensive agents or pheromones, and commonly found in terrestrial organisms (e.g., plants, fungi and insects). Their occurrence in the marine environment is quite remarkable, with several ecological and pharmacological bioactivities described [178]. Therefore, marine sesquiterpenes and derivatives represent important candidates for natural products in drug discovery [166,[179][180][181].
Streptomyces sp. SCO-736, isolated from an Antarctic marine sediment, was found to produce antartin (10) a tricyclic zizaane-type sesquiterpene with an unusual phenyl group ( Figure 3) [79]. Tricyclic sesquiterpenes are an important class of marine natural products characterized by structural diversity often unprecedented when compared to terrestrial metabolites. They often display interesting biological activity, such as antifouling, cytotoxic, antibiotic, antifungal, antiparasitic and anti-inflammatory activities [182]. Antartin displays moderate cytotoxicity against a wide range of cancer cell lines, A549, H1299 and U87 cell lines, by causing cell cycle arrest at the G1 phase [79].

Sesquiterpenes and Sesquiterpenoids
Sesquiterpenes comprise "one and a half monoterpenes" (sesqui-prefix means one and a half), thus, three isoprene units. They may be acyclic or contain rings, including many unique combinations. As in other terpenes, biochemical modifications such as oxidation or rearrangement produce the related sesquiterpenoids [169,171]. Sesquiterpenes and sesquiterpenoids are an important class of natural products with a wide range of biological activities as semiochemicals, e.g., defensive agents or pheromones, and commonly found in terrestrial organisms (e.g., plants, fungi and insects). Their occurrence in the marine environment is quite remarkable, with several ecological and pharmacological bioactivities described [178]. Therefore, marine sesquiterpenes and derivatives represent important candidates for natural products in drug discovery [166,[179][180][181].
Streptomyces sp. SCO-736, isolated from an Antarctic marine sediment, was found to produce antartin (10) a tricyclic zizaane-type sesquiterpene with an unusual phenyl group ( Figure 3) [79]. Tricyclic sesquiterpenes are an important class of marine natural products characterized by structural diversity often unprecedented when compared to terrestrial metabolites. They often display interesting biological activity, such as antifouling, cytotoxic, antibiotic, antifungal, antiparasitic and anti-inflammatory activities [182]. Antartin displays moderate cytotoxicity against a wide range of cancer cell lines, A549, H1299 and U87 cell lines, by causing cell cycle arrest at the G1 phase [79].
Although terpenoid substructures are often mixed with aromatic ring systems of various types (e.g., phenols, quinones, coumarines and flavonoids), they are rarely found in combination with pyrroles; there are only a few cases: pyrrolostatin, isolated from a Brazilian soil Actinobacteria Streptomyces chrestomyceticus EC40 [183], and two pyrrolosesquiterpenes isolated from soil actinomycete Streptomyces sp. Hd7-21 [184]. Although terpenoid substructures are often mixed with aromatic ring systems of various types (e.g., phenols, quinones, coumarines and flavonoids), they are rarely found in combination with pyrroles; there are only a few cases: pyrrolostatin, isolated from a Brazilian soil Actinobacteria Streptomyces chrestomyceticus EC40 [183], and two pyrrolosesquiterpenes isolated from soil actinomycete Streptomyces sp. Hd7-21 [184].
Penicillium sp. S-1-18, a fungus isolated from Antarctic marine sediments, was reported to produce a new sesquiterpene guignarderemophilane F, with no detectable activity, together with six known compounds, among them the sesquiterpenoid xylarenone A (28) ( Figure 5) [93]. Compound 28, previously isolated from the endophytic fungal strain Xylaria sp. NCY2, exhibited moderate antitumor activities against HeLa and HepG2 (human liver carcinoma) cells and displayed growth-inhibitory effects against pathogenic microbes [94].
Chemical examination of an undescribed soft coral collected from the Scotia Arc in the Southern Ocean resulted in the isolation and characterization of two new tricyclic sesquiterpenoids, shagenes A (35) and B (36) (Figure 7). Both compounds displayed significant inhibition against the visceral leishmaniasis, causing a parasite, Leishmania donovani, with no cytotoxicity against the mammalian host [113]. Alcyonium paessleri from South Georgia Island further yielded two new sesquiterpenoids, paesslerins A and B (33 and 34) (Figure 7), with moderate cytotoxicity against human tumor cell lines [105]. The structures shown are revised based on the results of total synthesis of the originally proposed structures [196].
displayed cytotoxicity toward HT-29 (human colon carcinoma) at an IC50 of 10 µg mL −1 [104]. Alcyonium paessleri from South Georgia Island further yielded two new sesquiterpenoids, paesslerins A and B (33 and 34) (Figure 7), with moderate cytotoxicity against human tumor cell lines [105]. The structures shown are revised based on the results of total synthesis of the originally proposed structures [196].
Chemical examination of an undescribed soft coral collected from the Scotia Arc in the Southern Ocean resulted in the isolation and characterization of two new tricyclic sesquiterpenoids, shagenes A (35) and B (36) (Figure 7). Both compounds displayed significant inhibition against the visceral leishmaniasis, causing a parasite, Leishmania donovani, with no cytotoxicity against the mammalian host [113].  (Figure 7). Both compounds displayed significant inhibition against the visceral leishmaniasis, causing a parasite, Leishmania donovani, with no cytotoxicity against the mammalian host [113].
Octocorals or "horny corals" are conspicuous components on Antarctic sea bottoms, which extensively rely on natural products for protection. Eudesmane sesquiterpenes, ainigmaptilones A and B, seem to be taking part of the chemical arsenal of gorgonians Ainigmaptilon antarcticus from the Weddell Sea. Ainigmaptilone A was found to display ecologically relevant activities, in repelling putative sea star predators, and block fouling or microbial infections caused by sympatric bacteria strains and diatoms [197]. Antifouling properties have also been reported in azulenoid sesquiterpenes (i.e., linderazulene, ketolactone 2, and a new brominated C-16 linderazulene derivative) isolated from another Antarctic gorgonian, Acanthogorgia laxa [198]. The nudibranch gastropod, Bathydoris hodgsoni, from the Weddell Sea revealed high concentrations of a new drimane sesquiterpene, hodgsonal, exclusively allocated in the mantle. Hodgsonal has been hypothesized to be de novo synthesized and to play a defensive role, by analogy with drimane sesquiterpenes in other dorid nudibranchs [199,200].
extensively rely on natural products for protection. Eudesmane sesquiterpenes, ainigmaptilones A and B, seem to be taking part of the chemical arsenal of gorgonians Ainigmaptilon antarcticus from the Weddell Sea. Ainigmaptilone A was found to display ecologically relevant activities, in repelling putative sea star predators, and block fouling or microbial infections caused by sympatric bacteria strains and diatoms [197]. Antifouling properties have also been reported in azulenoid sesquiterpenes (i.e., linderazulene, ketolactone 2, and a new brominated C-16 linderazulene derivative) isolated from another Antarctic gorgonian, Acanthogorgia laxa [198]. The nudibranch gastropod, Bathydoris hodgsoni, from the Weddell Sea revealed high concentrations of a new drimane sesquiterpene, hodgsonal, exclusively allocated in the mantle. Hodgsonal has been hypothesized to be de novo synthesized and to play a defensive role, by analogy with drimane sesquiterpenes in other dorid nudibranchs [199,200].
A rare spirocyclic diterpene, named spirograterpene A (37), was isolated from the deep-sea fungus Penicillium granulatum MCCC 3A00475 [92] from Prydz Bay, Antarctica, together with two known biosynthetically-related cyclopianes, conidiogenone I (38) [202] and conidiogenone C (39) (Figure 8) [203]. Spirograterpene A displays an anti-allergic effect on immunoglobulin E (IgE)mediated rat mast RBL-2H3 cells, displaying 18% inhibition compared with the positive control, loratadine, with 35% inhibition at the same concentration of 20 µg/mL [92]. Cyclopianes, belonging to a rarely reported diterpenoid family, are tetracyclic diterpenes characterized by a highly fused and rigid ring system of 6/5/5/5 skeleton. They were first identified in the fungus Penicillium cyclopium in 2002 [204], followed by related compounds, all of which have been obtained only in the Penicillium species [202][203][204][205]. Spirograterpene A (37) is the second example of a diterpene spiro-tetracyclic skeleton with a 5/5/5/5 ring system [92], demonstrating that marine fungi represent a unique source of structurally novel compounds. Among marine invertebrates, cnidarians, and in particular corals, have been found to possess a wide variety of diterpene and diterpenoid products, likely mediating allelochemical interactions Among marine invertebrates, cnidarians, and in particular corals, have been found to possess a wide variety of diterpene and diterpenoid products, likely mediating allelochemical interactions [206]. Cold water polar ecosystems are devoid of scleractinian coral reef formations, such as those in the tropics, but instead harbor rich communities of soft-bodied octocorals that are well-known for their chemical diversity [16,207,208]. The Arctic soft coral Gersemia fruticosa, collected in the Bering sea, revealed the presence of three diterpenes named gersemiols A−C and another eunicellane diterpene, eunicellol A, which were purified together with the known sesquiterpene (+)-α-muurolene. Eunicellol A (40) (Figure 9) was found to exhibit moderate and selective antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) [111].
Five new furanocembranoid diterpenes, keikipukalides A−E (41-45), the known diterpene pukalide aldehyde (46) and the known norditerpenoid ineleganolide (47) (Figure 10) were isolated from the octocoral Plumarella delicatissima collected between 800 and 950 m depth, and demonstrated inhibitory activity against L. donovani [112]. the tropics, but instead harbor rich communities of soft-bodied octocorals that are well-known for their chemical diversity [16,207,208]. The Arctic soft coral Gersemia fruticosa, collected in the Bering sea, revealed the presence of three diterpenes named gersemiols A−C and another eunicellane diterpene, eunicellol A, which were purified together with the known sesquiterpene (+)-αmuurolene. Eunicellol A (40) (Figure 9) was found to exhibit moderate and selective antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) [111].  The feather boa sea pen, Anthoptilum grandiflorum, is a cosmopolitan pennatulacean octocoral. Specimens collected at 662 and 944 m depth north of Burdwood Bank (Scotia Arc) yielded three new briarane diterpenes, bathyptilone A (48) (Figure 11), B and C together with a trinorditerpene, enbepeanone A. Nanomolar cytotoxicity against the neurogenic mammalian cell line Ntera-2 was detected only for bathyptilone A [107]. The feather boa sea pen, Anthoptilum grandiflorum, is a cosmopolitan pennatulacean octocoral. Specimens collected at 662 and 944 m depth north of Burdwood Bank (Scotia Arc) yielded three new briarane diterpenes, bathyptilone A (48) (Figure 11), B and C together with a trinorditerpene, enbepeanone A. Nanomolar cytotoxicity against the neurogenic mammalian cell line Ntera-2 was detected only for bathyptilone A [107].
The feather boa sea pen, Anthoptilum grandiflorum, is a cosmopolitan pennatulacean octocoral. Specimens collected at 662 and 944 m depth north of Burdwood Bank (Scotia Arc) yielded three new briarane diterpenes, bathyptilone A (48) (Figure 11), B and C together with a trinorditerpene, enbepeanone A. Nanomolar cytotoxicity against the neurogenic mammalian cell line Ntera-2 was detected only for bathyptilone A [107]. The gastropod Austrodoris kerguelenensis is considered the most common and conspicuous Antarctic nudibranch, and among the most studied polar species for chemical ecology [13,14,209]. The gastropod Austrodoris kerguelenensis is considered the most common and conspicuous Antarctic nudibranch, and among the most studied polar species for chemical ecology [13,14,209]. Detailed investigation of specimens from the vicinities of Palmer Station (Western Antarctic Peninsula), McMurdo Sound and the Weddell Sea has resulted in the isolation of a suite of tricyclic diterpenoid 2 -monoglyceryl esters (i.e., austrodorin A-B) [210] and diterpenoic acid glycerides [i.e 2 -acetoxyglyceryl (5R,10R,13R)-labda-8-en-15-oate, 3 -acetoxyglyceryl (5R,10R,13R)-labda-8-en-15-oate] [211], which were hypothesized to be produced by the nudibranch cells as opposed to being accumulated from its sponge diet [200]. Out of the variety of diterpene and diterpenoid products known from this mollusk, palmadorins A (49) [211], which were hypothesized to be produced by the nudibranch cells as opposed to being accumulated from its sponge diet [200]. Out of the variety of diterpene and diterpenoid products known from this mollusk, palmadorins A (49)  Sponges are known to be a particularly rich source of defensive diterpenoids, and among polar species, Antarctic Dendrilla sponges, typically reported as D. membranosa (recently revised to D. antarctica), stand out as the most prolific producers of bioactive diterpenes. While the chemical ecology of this sponge has been well-studied, investigations into the bioactive potential of Antarctic Dendrilla sponges was not carried out until 2004, with aplysulphurin (55) isolated from methanolic extracts along with three methyl acetals (56, 58, 60) (Figure 13), which displayed moderate antifungal activity against Candida albicans, and antibiotic activity against S. aureus and Escherichia coli [123]. Sponges are known to be a particularly rich source of defensive diterpenoids, and among polar species, Antarctic Dendrilla sponges, typically reported as D. membranosa (recently revised to D. antarctica), stand out as the most prolific producers of bioactive diterpenes. While the chemical ecology of this sponge has been well-studied, investigations into the bioactive potential of Antarctic Dendrilla sponges was not carried out until 2004, with aplysulphurin (55) isolated from methanolic extracts along with three methyl acetals (56, 58, 60) (Figure 13), which displayed moderate antifungal activity against Candida albicans, and antibiotic activity against S. aureus and Escherichia coli [123]. Termed "membranolides B-D" at the time of original publication, more recent investigations have shown these acetals to be artifacts from the methanolysis of aplysulphurin and have yielded several additional semisynthetic methyl acetal variations of the scaffold, now known collectively as membranoids A-H (56-62) (Figure 13). As a whole, the membranoids show potent bioactivity against the leishmaniasis causing parasite L. donovani, with membranoids B (57), D (59) and G (61) most notably displaying IC 50 values of 0.8 µM, 1.4 µM and 1.9 µM, respectively, against L. donovani infected J774A.1 macrophages, with no discernable cytotoxicity observed towards the healthy variant of human cells [124]. Dendrilla sponges from around Anvers Island, Antarctica, have yielded several further diterpenoid natural products, including darwinolide (63), which was tested against MRSA and was found to be four times more potent against the biofilm (33.2 µM) than the planktonic form of MRSA (132.9 µM). This type of selective toxicity towards biofilms is rare and a promising lead in the search for antibiofilm-specific antibiotics [125]. A recent continuation of that study revealed a library of diterpenoids containing both known (64)(65)(66)(67)(68)(69)(70) (Figure 14) and new (71)(72)(73) natural products along with several additional semisynthetic derivatives (74)(75)(76) (Figure 15). This small but diverse collection of diterpenoids showed remarkable antibiotic properties against a range of infectious disease models. The most prominent bioactivity including membranolide (66) showed >90% eradication of MRSA biofilm at or below concentrations of 25 µg/mL, dendrillin B (71), active against L. donovani infected J774A.1 at macrophages at an IC50 of 3.5 µM, and 76 with 100% inhibition of P. falciparum at 5 µg/mL [126]. 9,11-dihydrogracilin A (64) isolated from Dendrilla sponges collected around the same area, has also recently been shown to display immuno-modulatory and anti-inflammatory properties in human cell lines [127]. Dendrilla sponges from around Anvers Island, Antarctica, have yielded several further diterpenoid natural products, including darwinolide (63), which was tested against MRSA and was found to be four times more potent against the biofilm (33.2 µM) than the planktonic form of MRSA (132.9 µM). This type of selective toxicity towards biofilms is rare and a promising lead in the search for antibiofilm-specific antibiotics [125]. A recent continuation of that study revealed a library of diterpenoids containing both known (64-70) ( Figure 14) and new (71)(72)(73) natural products along with several additional semisynthetic derivatives (74)(75)(76) (Figure 15). This small but diverse collection of diterpenoids showed remarkable antibiotic properties against a range of infectious disease models. The most prominent bioactivity including membranolide (66) showed >90% eradication of MRSA biofilm at or below concentrations of 25 µg/mL, dendrillin B (71), active against L. donovani infected J774A.1 at macrophages at an IC 50 of 3.5 µM, and 76 with 100% inhibition of P. falciparum at 5 µg/mL [126]. 9,11-dihydrogracilin A (64) isolated from Dendrilla sponges collected around the same area, has also recently been shown to display immuno-modulatory and anti-inflammatory properties in human cell lines [127].

Sesterterpenes and Sesterterpenoids
Sesterterpenes are composed of "two and a half monoterpene units" and are typically C 25 , resulting from an initial condensation between DMAPP and isopentenyl IPP pyrophosphate followed by three additional and consecutive condensations of IPP to add to the growing chain. Sesterterpenes are the longest of the terpenes to be formed in this fashion, as subsequently longer terpenes with 30+ carbons are formed by additional condensation of two preformed phosphorylated isoprene precursors [212].
Sesterterpenoids are not as commonly found in the marine polar environment compared to diterpenes or triterpenes, however, sponges of the Suberites genus collected at several spots around Antarctica including King George Island and McMurdo Sound have yielded the polycyclic suberitenones A and B (77, 78) (Figure 16), the latter of which has been shown to inhibit the cholesteryl ester transfer protein (CETP). This CETP protein mediates the transfer of cholesterol ester and triglyceride between high-density lipoproteins (HDL) low-density lipoproteins (LDL) and is a major target for the development of atherosclerotic disease treatments [142].
Dendrilla sponges from around Anvers Island, Antarctica, have yielded several further diterpenoid natural products, including darwinolide (63), which was tested against MRSA and was found to be four times more potent against the biofilm (33.2 µM) than the planktonic form of MRSA (132.9 µM). This type of selective toxicity towards biofilms is rare and a promising lead in the search for antibiofilm-specific antibiotics [125]. A recent continuation of that study revealed a library of diterpenoids containing both known (64)(65)(66)(67)(68)(69)(70) (Figure 14) and new (71)(72)(73) natural products along with several additional semisynthetic derivatives (74)(75)(76) (Figure 15). This small but diverse collection of diterpenoids showed remarkable antibiotic properties against a range of infectious disease models. The most prominent bioactivity including membranolide (66) showed >90% eradication of MRSA biofilm at or below concentrations of 25 µg/mL, dendrillin B (71), active against L. donovani infected J774A.1 at macrophages at an IC50 of 3.5 µM, and 76 with 100% inhibition of P. falciparum at 5 µg/mL [126]. 9,11-dihydrogracilin A (64) isolated from Dendrilla sponges collected around the same area, has also recently been shown to display immuno-modulatory and anti-inflammatory properties in human cell lines [127].

Sesterterpenes and Sesterterpenoids
Sesterterpenes are composed of "two and a half monoterpene units" and are typically C25, resulting from an initial condensation between DMAPP and isopentenyl IPP pyrophosphate followed by three additional and consecutive condensations of IPP to add to the growing chain. Sesterterpenes are the longest of the terpenes to be formed in this fashion, as subsequently longer terpenes with 30+ carbons are formed by additional condensation of two preformed phosphorylated  (74)(75)(76). environment compared to diterpenes or triterpenes, however, sponges of the Suberites genus collected at several spots around Antarctica including King George Island and McMurdo Sound have yielded the polycyclic suberitenones A and B (77, 78) (Figure 16), the latter of which has been shown to inhibit the cholesteryl ester transfer protein (CETP). This CETP protein mediates the transfer of cholesterol ester and triglyceride between high-density lipoproteins (HDL) low-density lipoproteins (LDL) and is a major target for the development of atherosclerotic disease treatments [142].

Triterpenes and Triterpenoids
Triterpenes are formed by six isoprene units, conceptualized as three monoterpene units. Functionalized triterpenes (containing heteroatoms substitutions) should instead be referred to as triterpenoids. Animals, plants and fungi all produce triterpenes and triterpenoids, which exist iñ 200 different skeletons and a great variety of structures (e.g., cholesterol) [213].

Steroids
Animals, plants and fungi all produce triterpenes, among which is squalene, the precursor to all steroids. These contain a core moiety of the triterpene cucurbitane, and in practice are biosynthesized from either lanosterol (animals and fungi) or cycloartenol (plants) via the cyclization of squalene. Steroids are further metabolized from squalene via subsequent demethylation to a tri-nor C 27 skeleton, or further still to even smaller steroids. Steroids have two principal biological functions, being either key components of cell membranes or signaling molecules. Some examples of steroids are vitamin D3, the lipid cholesterol, the sex hormones estradiol and testosterone and the anti-inflammatory drug dexamethasone [214].
The Alcyonacean octocoral Anthomastus bathyproctus Bayer 1993 collected in the South Shetland Islands (Antarctica) afforded seven steroids, all of them displaying a cross-conjugated ketone system in the A ring of the tetracarbocyclic nucleus, while their side chains belong to the cholestane, ergostane and 24-norcholestane types. Compounds 79 to 82 ( Figure 17) showed diverse in vitro cytotoxicity against the human tumor cell lines MDA-MB-231 (breast adenocarcinoma), A-549 (lung carcinoma) and HT-29 (colon adenocarcinoma) [106].
The Alcyonacean octocoral Anthomastus bathyproctus Bayer 1993 collected in the South Shetland Islands (Antarctica) afforded seven steroids, all of them displaying a cross-conjugated ketone system in the A ring of the tetracarbocyclic nucleus, while their side chains belong to the cholestane, ergostane and 24-norcholestane types. Compounds 79 to 82 ( Figure 17) showed diverse in vitro cytotoxicity against the human tumor cell lines MDA-MB-231 (breast adenocarcinoma), A-549 (lung carcinoma) and HT-29 (colon adenocarcinoma) [106].   Six polyoxygenated sterols (90-95) (Figure 19) were isolated from the soft coral Gersemia fruticosa, exhibiting a moderate cytotoxic activity against human erythroleukemia K-562 cells and other leukemia cell lines [109]. Sponges are known to produce a wide variety of bioactive steroids and steroid derivatives, and the species found in polar waters are no exception. A red encrusting sponge within the genus Crella is commonly found on the sheer walls in the shallow waters along the Western Antarctic Peninsula, and a group of specimens collected around Norsel Point near Anvers Island yielded norselic acids A-E (97-101) (Figure 21). Among these oxidized steroids, the most abundant, norselic acid A, showed inhibitory activity against MRSA and vancomycin-resistant Enterococci faecium (VREF) in addition to antifungal activity against C. albicans. All of the norselic acids showed low micromolar activity against the leishmaniasis causing protozoan parasite L. donovani with potencies ranging from 2.0-3.6 µM [122]. Six polyoxygenated sterols (90)(91)(92)(93)(94)(95) (Figure 19) were isolated from the soft coral Gersemia fruticosa, exhibiting a moderate cytotoxic activity against human erythroleukemia K-562 cells and other leukemia cell lines [109].  Gersemia fruticosa was also found to contain further a bioactive 9,11-secosterol steroid, named 24nor-9,11-seco-11-acetoxy-3,6-dihydroxycholest-7,22(E)-dien-9-one (96) (Figure 20). This compound was shown to yield growth inhibition (IC50 below 10 µM) and cytotoxicity against human leukemia K562, human cervical cancer HeLa and Ehrlich ascites tumor cells in vitro [110]. Sponges are known to produce a wide variety of bioactive steroids and steroid derivatives, and the species found in polar waters are no exception. A red encrusting sponge within the genus Crella is commonly found on the sheer walls in the shallow waters along the Western Antarctic Peninsula, and a group of specimens collected around Norsel Point near Anvers Island yielded norselic acids A-E (97-101) (Figure 21). Among these oxidized steroids, the most abundant, norselic acid A, showed inhibitory activity against MRSA and vancomycin-resistant Enterococci faecium (VREF) in addition to antifungal activity against C. albicans. All of the norselic acids showed low micromolar activity against the leishmaniasis causing protozoan parasite L. donovani with potencies ranging from 2.0-3.6 µM [122]. Gersemia fruticosa was also found to contain further a bioactive 9,11-secosterol steroid, named 24nor-9,11-seco-11-acetoxy-3,6-dihydroxycholest-7,22(E)-dien-9-one (96) (Figure 20). This compound was shown to yield growth inhibition (IC50 below 10 µM) and cytotoxicity against human leukemia K562, human cervical cancer HeLa and Ehrlich ascites tumor cells in vitro [110]. Sponges are known to produce a wide variety of bioactive steroids and steroid derivatives, and the species found in polar waters are no exception. A red encrusting sponge within the genus Crella is commonly found on the sheer walls in the shallow waters along the Western Antarctic Peninsula, and a group of specimens collected around Norsel Point near Anvers Island yielded norselic acids A-E (97-101) (Figure 21). Among these oxidized steroids, the most abundant, norselic acid A, showed inhibitory activity against MRSA and vancomycin-resistant Enterococci faecium (VREF) in addition to antifungal activity against C. albicans. All of the norselic acids showed low micromolar activity against the leishmaniasis causing protozoan parasite L. donovani with potencies ranging from 2.0-3.6 µM [122].  Sulphated polyhydroxysteroids, obtained from Antarctic brittle star species, have been providing promising antiviral properties. Ophiuroid Ophiosparte gigas, coming from 70 m depth in the Ross Sea area revealed the presence of cholest-5-ene-2α,3α,4β,21-tetrao1-3,21-disulphate (102), which was remarkably cytotoxic, along with cholest-5-ene-2β,3α, 21-triol-2,21-disulphate (103) with cytoprotective activity against HIV-1 ( Figure 22) [120]. Further disulfated polyhydroxysteroids (104-106) from another Antarctic ophiuroid, Astrotoma agassizii (Figure 22), as well as their synthetic derivatives displayed antiviral activities against one DNA (HSV-2) and two RNA (PV-3, JV) viruses [121]. Despite being most well-known for their role as hormones regulating molting in arthropods, a surprising array of unique ecdysteroids have been found in the Antarctic ascidian Synoicum adareanum, some of which display promising therapeutic activities. Among these are hyousterones A and C (107, 108) ( Figure 23) which displayed IC50 values of 10.7 µM and 3.7 µM, respectively, against the HCT-116 colon cancer cell line, while abeohyousterone (109) (Figure 23) was active at 3.0 µM in the same biological assay, all of which were isolated from tunicates around Anvers Island [149].  Despite being most well-known for their role as hormones regulating molting in arthropods, a surprising array of unique ecdysteroids have been found in the Antarctic ascidian Synoicum adareanum, some of which display promising therapeutic activities. Among these are hyousterones A and C (107, 108) ( Figure 23) which displayed IC 50 values of 10.7 µM and 3.7 µM, respectively, against the HCT-116 colon cancer cell line, while abeohyousterone (109) (Figure 23) was active at 3.0 µM in the same biological assay, all of which were isolated from tunicates around Anvers Island [149].

Tetraterpenes and Tetraterpenoids
Carotenoids Tetraterpenes are terpenes built from eight isoprene units (four monoterpene units). Carotenoids belong to the category of tetraterpenoids. They are natural isoprenoid pigments derived from head-to-tail condensation of two C 15 or C 20 isoprenoid precursors to form a C 30 or C 40 backbone, respectively, which are then modified to obtain different carotenoid structures [215]. They are divided into two main classes: carotenes, which are hydrocarbons, and xanthophylls, oxygenated derivatives of carotenes. Due to the long system of conjugated double bonds, they are able to capture and absorb light in the 400-500 nm range, displaying a peculiar strong coloration [216]. For this feature, carotenoids play a critical role in the photosynthesis process and provide photo-oxidative protection to the cells acting as strong antioxidant compounds. Being chemical quenchers of singlet oxygen, they function as potent scavengers of reactive oxygen species (ROS) [216]. They are essential constituents of photosynthetic organisms (e.g., plants, algae and cyanobacteria), but have been found also in fungi and bacteria [217]. Not synthesized by humans or animals, they are present in their blood and tissues, deriving from dietary sources. Being precursors of retinol (vitamin A), they perform a role of particular significance to human health [216]. Despite being most well-known for their role as hormones regulating molting in arthropods, a surprising array of unique ecdysteroids have been found in the Antarctic ascidian Synoicum adareanum, some of which display promising therapeutic activities. Among these are hyousterones A and C (107, 108) ( Figure 23) which displayed IC50 values of 10.7 µM and 3.7 µM, respectively, against the HCT-116 colon cancer cell line, while abeohyousterone (109) (Figure 23) was active at 3.0 µM in the same biological assay, all of which were isolated from tunicates around Anvers Island [149].

Tetraterpenes and Tetraterpenoids
Carotenoids Tetraterpenes are terpenes built from eight isoprene units (four monoterpene units). Carotenoids belong to the category of tetraterpenoids. They are natural isoprenoid pigments derived from headto-tail condensation of two C15 or C20 isoprenoid precursors to form a C30 or C40 backbone, In fact, carotenoids from marine environments are strong antioxidants used as nutraceutical ingredients in the food industry and cosmeceutical molecules for the photoprotection against UV radiation [218,219].
Although marine animals do not synthesize carotenoids de novo, they contain significant amounts of carotenoids derived from dietary sources. More than 100 carotenoids have been isolated from sponges, cnidarians, mollusks, crustaceans, echinoderms, tunicates and fishes [220].
Marine organisms inhabiting polar environments have developed a variety of adaptive strategies to cope with UV radiation, including light avoidance mechanisms, synthesis of UV-sunscreens, enzymatic and non-enzymatic quenching of ROS and DNA repair mechanisms [2]. The synthesis of carotenoid pigments in the Antarctic marine organisms belongs to the antioxidant defense mechanisms able to counteract ROS damage [2].
Indeed, some pigmented bacteria owe their colors to the presence of carotenoids. The genome mining of Marisediminicola antarctica ZS314T, isolated from intertidal sediments of the cost near the Chinese Antarctic Zhongshan Station in East Antarctica, demonstrated the biosynthetic potential of this orange Actinobacterium in producing carotenoids and their derivatives [221]. Cellulophaga fucicola strain 416 and Zobellia laminarie 465, yellow and orange pigmented bacteria, respectively [98,99], isolated from Antarctic sea sponges, were found to be resistant to UV-B and UV-C radiation, thanks to the expression of carotenoids isolated and chemically identified by ultra-high-performance liquid chromatography with photodiode array and mass spectrometry detectors. Zeaxanthin (110), β-cryptoxanthin (111) and β-carotene (112) were identified in both strains, whereas two isomers of zeaxanthin was identified only in C. fucicola [98] and phytoene (113) only in Z. laminarie (Figure 24) [99]. These pigments displayed a very high antioxidant activity, although they were shown to be phototoxic in murine fibroblast lines [98,99].
The red-orange strain Rhodococcus sp. B7740, isolated from 25 m deep-sea water in the Arctic Ocean, is a promising source of natural carotenoids and isoprenoid quinones, interesting both in amounts and varieties for the application in the food industry [74]. Among them, synechoxanthin (χ,χ-caroten-18,18 -dioic acid) (114), a unique aromatic dicarboxylate carotenoid, recently discovered only in some cyanobacteria [222,223], dehydrogenated menaquinones with eight isoprene units [MK-8 (H 2 )] (115), produced in higher concentration than that reported in other bacteria [224], and isorenieratene (116), an aromatic carotenoid used in smear cheese industry [225], have been identified ( Figure 25). The latter is a promising metabolite in future food and medicine applications for its higher stability than β-carotene and lutein in model gastric conditions and for its high retention rate in the gastrointestinal tract after ingestion [74]. Moreover, it has been demonstrated that isorenieratene, able to prevent UV-induced DNA damage in human skin fibroblasts [226], displays a photoprotective effect against UV-B radiation compared with two macular xanthophylls, lutein and zeaxanthin, in the multilamellar vesicles model and human retina cell model [75]. Additionally, MK-8 (H 2 ), the main menaquinone from Rhodococcus sp. B7740, has a potential application in the field of medicine for its higher antioxidant effect and antiglycation capacity compared with ubiquinone Q10 and MK 4 [76]. The red-orange strain Rhodococcus sp. B7740, isolated from 25 m deep-sea water in the Arctic Ocean, is a promising source of natural carotenoids and isoprenoid quinones, interesting both in amounts and varieties for the application in the food industry [74]. Among them, synechoxanthin (χ,χ-caroten-18,18′-dioic acid) (114), a unique aromatic dicarboxylate carotenoid, recently discovered only in some cyanobacteria [222,223], dehydrogenated menaquinones with eight isoprene units [MK-8(H2)] (115), produced in higher concentration than that reported in other bacteria [224], and isorenieratene (116), an aromatic carotenoid used in smear cheese industry [225], have been identified ( Figure 25). The latter is a promising metabolite in future food and medicine applications for its higher stability than β-carotene and lutein in model gastric conditions and for its high retention rate in the gastrointestinal tract after ingestion [74]. Moreover, it has been demonstrated that isorenieratene, able to prevent UV-induced DNA damage in human skin fibroblasts [226], displays a photoprotective effect against UV-B radiation compared with two macular xanthophylls, lutein and zeaxanthin, in the multilamellar vesicles model and human retina cell model [75]. Additionally, MK-8(H2), the main menaquinone from Rhodococcus sp. B7740, has a potential application in the field of medicine for its higher antioxidant effect and antiglycation capacity compared with ubiquinone Q10 and MK4 [76].

Triterpenoid Conjugates
While steroids come in a variety of forms, they can also be found conjugated to other functional groups. One such example of these remarkable molecules are the sulfated steroid-amino acid conjugates known as polymastiamides A-F, isolated from the cold-water sponge Polymastia boletiformis collected at various locations along the Norwegian coast. Of these compounds, polymastiamide A (117) (Figure 26) has shown activity against plant pathogens Cladosporium cucumerinum and Pythium ultimum as well as human yeast pathogen C. albicans and antibacterial activity against S. aureus [138,139].

Triterpenoid Saponins
Triterpenoid saponins are amphipathic glycosides that have one or more hydrophilic glycoside moieties combined with a lipophilic triterpene or steroid derivative, thus, their chemical class can be identified as triterpenoid glycosides. They are well-known as plant-derived allelochemicals, but they have also been obtained from marine organisms, in particular sea cucumbers, where they have been proposed as chemotaxonomic proxies [227,228]. Several bioactive properties have been reported from these compounds, including anti-feedant (repellents), antimicrobial and ichthyotoxic [229,230]. The term saponin derives from the soapwort plant (genus Saponaria family Caryophyllaceae), the root from which is used as a soap. Additionally, these triterpene conjugates produce a soap-like foam when shaken in aqueous solutions [230]. The amphipathic properties of saponins make them efficient surfactants, due to their capacity to interact with cell membrane components, e.g., cholesterol and phospholipids, and therefore, they are interesting for the development of cosmetics, drugs and nutraceuticals (nutrient absorption enhancers) [231]. Saponins are also readily soluble in water, and have been proposed as adjuvants, to dissolve active principles in the development of vaccines [232].

Triterpene and Triterpenoid Derivatives
Triterpenoid Conjugates While steroids come in a variety of forms, they can also be found conjugated to other functional groups. One such example of these remarkable molecules are the sulfated steroid-amino acid conjugates known as polymastiamides A-F, isolated from the cold-water sponge Polymastia boletiformis collected at various locations along the Norwegian coast. Of these compounds, polymastiamide A (117) (Figure 26) has shown activity against plant pathogens Cladosporium cucumerinum and Pythium ultimum as well as human yeast pathogen C. albicans and antibacterial activity against S. aureus [138,139].

Triterpenoid Saponins
Triterpenoid saponins are amphipathic glycosides that have one or more hydrophilic glycoside moieties combined with a lipophilic triterpene or steroid derivative, thus, their chemical class can be

Triterpene and Triterpenoid Derivatives
Triterpenoid Conjugates While steroids come in a variety of forms, they can also be found conjugated to other functional groups. One such example of these remarkable molecules are the sulfated steroid-amino acid conjugates known as polymastiamides A-F, isolated from the cold-water sponge Polymastia boletiformis collected at various locations along the Norwegian coast. Of these compounds, polymastiamide A (117) (Figure 26) has shown activity against plant pathogens Cladosporium cucumerinum and Pythium ultimum as well as human yeast pathogen C. albicans and antibacterial activity against S. aureus [138,139].

Triterpenoid Saponins
Triterpenoid saponins are amphipathic glycosides that have one or more hydrophilic glycoside moieties combined with a lipophilic triterpene or steroid derivative, thus, their chemical class can be identified as triterpenoid glycosides. They are well-known as plant-derived allelochemicals, but they have also been obtained from marine organisms, in particular sea cucumbers, where they have been proposed as chemotaxonomic proxies [227,228]. Several bioactive properties have been reported from these compounds, including anti-feedant (repellents), antimicrobial and ichthyotoxic [229,230]. The Two trisulfated triterpene glycosides, liouvillosides A (118) and B (119) (Figure 27), both virucidal against herpes simplex virus type 1 (HSV-1), were isolated from the Antarctic cucumarid sea cucumber Staurocucumis liouvillei, collected in South Georgia Islands [118].
The deep sea Arctic holothurian echinoderm Kolga hyalina collected at Amundsen Basin at 4352-4354 m depth was found to contain holothurinoside B (known from temperate holothurid species [233], as well as two novel triterpene holostane nonsulfated pentaosides, kolgaosides A (120) and B (121) (Figure 28), both possessing hemolytic activity against mouse erythrocytes, and mild inhibitory action against Ehrlich ascite carcinoma cells. All these triterpene glycosides are structurally close to achlioniceosides A1-A3 from the Antarctic sea cucumber Rhipidothuria racovitzai Hèrouard, 1901 (=Achlionice violaescupidata [234]), supporting a potential chemotaxonomic value [235]. phospholipids, and therefore, they are interesting for the development of cosmetics, drugs and nutraceuticals (nutrient absorption enhancers) [231]. Saponins are also readily soluble in water, and have been proposed as adjuvants, to dissolve active principles in the development of vaccines [232].

Meroterpenes
Meroterpenes are molecules with a partial terpenoid structure attached to a shikimate-derived aromatic, usually a phenol, and are commonly found in marine ascidians, sponges and to a lesser extent in soft corals [236]. Bioactive meroterpenes featuring sesquiterpene moieties can also be found in organisms inhabiting the harsh polar regions. Tunicates in the genus Aplidium collected in the Ross Sea yielded rossinones A and B (122, 123) (Figure 29), which displayed antiproliferative activity against several cell lines with IC50 values ranging from 0.084 to 30 µM as well as selective antiviral activity against the DNA virus HSV-1 in addition to antibacterial and antifungal activity towards Bacillus subtilis and Trichophyton mentagrophytes [144].
While the majority of compounds reported from polar marine algae are monoterpenes, bioactive diterpenoids in the form of meroterpenes such as menzoquinone (124) (Figure 29) have been isolated from Desmarestia menziesii, a commonly occurring brown algae that plays a major role in structuring the benthic ecosystems along the northern latitudes of the Western Antarctic Peninsula. This

Meroterpenes
Meroterpenes are molecules with a partial terpenoid structure attached to a shikimate-derived aromatic, usually a phenol, and are commonly found in marine ascidians, sponges and to a lesser extent in soft corals [236]. Bioactive meroterpenes featuring sesquiterpene moieties can also be found in organisms inhabiting the harsh polar regions. Tunicates in the genus Aplidium collected in the Ross Sea yielded rossinones A and B (122, 123) (Figure 29), which displayed antiproliferative activity against several cell lines with IC 50 values ranging from 0.084 to 30 µM as well as selective antiviral activity against the DNA virus HSV-1 in addition to antibacterial and antifungal activity towards Bacillus subtilis and Trichophyton mentagrophytes [144].
While the majority of compounds reported from polar marine algae are monoterpenes, bioactive diterpenoids in the form of meroterpenes such as menzoquinone (124) (Figure 29) have been isolated from Desmarestia menziesii, a commonly occurring brown algae that plays a major role in structuring the benthic ecosystems along the northern latitudes of the Western Antarctic Peninsula. This methylated diterpene-quinone bearing a carboxylic acid has shown antimicrobial activity against MRSA and VREF [155].  While the majority of compounds reported from polar marine algae are monoterpenes, bioactive diterpenoids in the form of meroterpenes such as menzoquinone (124) (Figure 29) have been isolated from Desmarestia menziesii, a commonly occurring brown algae that plays a major role in structuring the benthic ecosystems along the northern latitudes of the Western Antarctic Peninsula. This methylated diterpene-quinone bearing a carboxylic acid has shown antimicrobial activity against MRSA and VREF [155].

Perspectives and Conclusions
Bioprospecting is a complex issue as it embraces many fields, such as intellectual property rights, scientific research and exploitation of resources in an eco-friendly ethical manner [237][238][239][240]. Cooperation is needed to develop sustainable, respectful and appropriate access and benefit-sharing mechanisms for marine resources as well as the promotion of the participation by all states in international negotiations for encouraging innovation and greater equity [241][242][243].
Bioactive natural products from the sea are in this particular era are timely to develop drugs to fight against ever more frequent and contagious emerging pathogenic agents. One actual example is a potent antiviral molecule obtained from the ascidian Aplidium albicans, which is under clinical trials on infected humans with Corona Virus, similar to the 2020 pandemic SARS CoV-19 [244].
Marine organisms from the polar regions could greatly contribute to this growing repertoire of promising bioactive compounds. Indeed, extreme environments are important hot spots of microbial, metazoan and symbiotic cluster diversities, where selective forces have promoted the evolution of unique biosynthetic pathways for secondary metabolite production [14]. In the light of the publication record on molecules with pharmacological potential isolated up to date from Arctic and Antarctic marine taxa, terpene and terpenoid derivatives seem to be the most frequently reported [5]. Furthermore, these compound types often yield remarkable antimicrobial properties, including anti-viral and antitumoral activities. Such cytotoxic actions likely respond to detrimental effects driven by terpenoid products on the structure and function of microbial membranes and cell walls [245]. Therefore, natural bioactive terpenes and terpenoids, in these times of increasing incidence of emerging infectious diseases, antibiotic-resistance pathogenesis and cancer, represent a precious glimmer of hope for drug discovery. Bioprospecting of organisms inhabiting the polar environments has already led to the discovery of new bioactive molecules, mainly enzymes with potential commercial use for food, paper and textile industries [4]. It is thus expected that, in the near future, natural products from polar latitudes with an untapped biotechnological potential will also be included in health products to address upcoming epidemics, and disorders related to emerging and resistant infective vectors.