Pacifenol is a terpenoid isolated from seaweeds of the marine alga Laurencia claviformis, collected in Easter Island and belonging to the Rhodomelaceae family, whose structure was characterized by chemistry studies and crystallographic analysis in 1971 [32].

The probable precursor of pacifenol, prepacifenol, was originally isolated from the Australian red alga Laurencia filiformis, but later, pacifenol was found naturally in Laurencia tasmanica as well [33]. This halogenated sesquiterpene represented the first example in chemical literature of a natural bioactive obtained from algae containing bromine and chlorine atoms covalently bound [34].

However, these new metabolites, pacifenol and prepacifenol, were found not only in red alga, but also in some marine invertebrates, for example in the digestive system of the mollusk Aplysia californica [35].

An antimicrobial activity of pacifenol derivatives has previously been reported, after testing against some microrganisms, especially against Pseudomonas aeruginosa and Streptococcus enteriditis.

In addition, pacifenol exerts an inhibitory activity on inflammation by decreasing leukotriene B4 (LTB4) and thromboxane B2 (TXB2) production, but also stopping degranulation response [36].

In particular, its anti-inflammatory action, exercised through inhibition of the key enzyme phospholipase A2 and the consequent modulation of the cyclooxigenase pathway, and its anti-allergy effect, could be exploited to contrast the phlogistic processes implicated in the pathogenesis of many inflammatory and allergic diseases.

This terpenoid was isolated from seaweeds of Stypopodium flabelliforme, collected near Easter Island in the South Pacific Ocean [37]. The genus Stypopodium is a tropical group of brown algae, phaeophyceae, with rich components of polycyclic meroditerpenoids, possessing several biological activities [38]. Epitaondiol diacetate showed pharmacological effects in the rat cardiovascular system; a negative inotropic and chronotropic effect was noticed [39], but it also revealed marked anti-inflammatory effects through inhibition of eicosanoids (LTB4 and TXB2) release and modulation of the cyclooxigenase pathway. This happens through inhibition of the key enzyme phospholipase A2, which plays an important role in the release of arachidonic acid and the formation of lipid mediators [40]. Its anti-inflammatory activity is stronger than that of indomethacine [41].

Epitaondiol also showed dose-dependent gastroprotective activity in mice gastric lesions, displaying similar action to lansoprazole [42].

This double effect, both anti-inflammatory and gastroprotective, could be a fascinating treatment strategy without the well known side effects of drugs which are conventionally prescribed for the treatment of inflammatory diseases.

In addition, epitaondiol exhibited antimicrobial effects against gram-positive and gram-negative bacteria, especially against E. faecalis [43], antiviral activity against herpes simplex [44], and antiproliferative properties: human colorectal adenocarcinoma and neuroblastoma cell line showed higher susceptibility [45]. In particular, 2beta-3alpha-epitaondiol possesses sodium channel blocking activity, a cytotoxic active against human lung cancer cells [46].

Instead, the similar molecule called isoepitandiol showed a radical scavenging activity even more powerful than ascorbic acid [47].

Both its powerful anti-inflammatory activity and this strong antioxidant effect deserve further studies, since they may be helpful in targeting the inflammation and oxidative stress that characterize many chronic inflammatory disorders.

This polycyclic meroditerpenoid [48], the complete configuration of which was recently determined [49], was also isolated from the seaweed Stypopodium flabelliforme. It is unstable in air, so that it had to be prepared by acetylation of the organic extract to avoid air oxidation in order to study its characterization and biological activities [50].

Stypotriol displayed antifeedant and anti-inflammatory activity [51]. In particular, it exerts an inhibitory activity on inflammation by interfering with elastase release, by modulating the cyclooxigenase pathway through inhibition of phospholipase A2, and by decreasing the secretion of eicosanoids [40]. This may be useful in inhibiting inflammation and reducing elastase-induced cartilage degradation and articular damage, typical of RA and responsible of pain and loss of joint function.

Similarly to epitaondiol, it showed antibacterial effects against gram-positive and gram-negative bacteria [43], and antiproliferative properties (human colorectal adenocarcinoma and rat basophilic leukemia cell line showed higher susceptibility) and was the most cytotoxic toward cancer cells with a concentration-dependent inhibitory effect, followed by epitaondiol [45].

This natural polyoxygenated steroid with a new side chain, isolated from the marine sponge Petrosia contignata in Papua New Guinea, has been the subject of many investigations, including both biological studies and synthetic work [52].

It belongs to steroid class but it has a particular chemical structure, because of the unusual set of functional groups, the details of which have been already published [53]. Study results have shown its potential value in the treatment of asthma and other inflammatory diseases [27]. In particular, it inhibits the release of histamine from human basophils and lung tissue and attenuates the contractile response to histamine, probably indirectly interacting with cellular signaling systems leading to the inhibition of phospholipase C activity [31], protecting in this way from bronchoconstriction [50].

In addition, contignasterol showed an ability to inhibit platelet aggregation in response to their activating factor PAF, which is a local mediator of thrombotic events, and collagen exposure of vessels, suggesting anti-thrombolytic activity. As a consequence, the pharmacological potential of contignasterol could enable it to be used as a cardiovascular and antiallergic drug, in order to treat hemodynamic disorders involving platelets, hypertension or hypotension, thrombosis, asthma, allergic rhinitis, psoriasis, rashes, osteoarthritis and inflammation in general [54,55].

This pentacyclic polyhidroxylated steroid was isolated in 1992 from the Okinawan marine sponge Xestospongia bergquisita [56].

It is a strong inhibitor of IgE-mediated histamine release from activated mast cells [57], with an inhibitory effect that is much more potent than the antiallergy drug disodium cromoglicate [53].

In particular, Xestobergsterol A dose-dependently inhibited the generation of inositol triphosphate (IP3) and phospholipase C (PLC) activity and inhibits Ca²⁺-mobilization from intracellular Ca²⁺-stores, which are early events in IgE-dependent mediator release [58]. Xestobergsterol has undergone a number of investigations, including synthetic work on its analogues [59].

So, like contignasterol, it could be considered a potential anti-asthma agent with a promising pharmacological potential [27].

Clathriols A and B are novel polyoxygenated steroids isolated from the marine sponge Clathria lissosclera, in New Zealand waters.

They possess the rare and only naturally-occurring 14-beta-stereochemistry, a typical configuration of marine sponges [60]: This makes them structurally and biologically very similar to contignasterol, even if their biological action has turned out to be less powerful than contignasterol and its derivatives in blocking histamine release [27].

Both are not only light anti-allergy molecules, but also moderate anti-inflammatory compounds. In particular, the anti-inflammatory pharmacology of clathriol B was reported in 2000 [61]; however, further studies took place during 2003 [60] and more recently [62,63].

Clathriol B inhibits the production of superoxide from human peripheral blood neutrophils [50], which is known to be implicated in the pathogenesis of inflammatory disorders: in this respect also clathriols should be studied in more depth, since they may also be helpful in alleviating the inflammation and oxidative stress that characterize several chronic degenerative diseases.

This molecule belongs to the prodigiosin family, but here, the side chain is cyclized to form a six-membered ring [64]. Cycloprodigiosin is the red pigment produced by various marine bacteria, including Serratia marcenses, Zooshikella rubidus and Pseudoalteromonas denitrificans, with immunosuppressive properties and apoptotic effects on cancer cells, interacting with p65 and the nuclear factor κB (NF-κB) pathway [65]. In particular, Cycloprodigiosin hydrochloride, produced by Pseudoalteromonas denitrificans, causes cytotoxic effects and apoptotic cell death in various cancerous cell lines, especially with the pro-inflammatory cytokine Tumor Necrosis Factor (TNFα). In fact, it suppresses NF-κB-dependent gene expression, while NF-κB activation is considered to promote survival in cells, inhibiting transcriptional activation [66]. In fact, cycloprodigiosin hydrochloride leads to apoptosis breast [67], liver and colon cancer cells, acting as a H+/Cl− symporter, inducing cytosolic acidification [68]. In addition, it resulted in being useful against promyelocytic leukemia, inducing cell differentiation or apoptosis through up-regulation of Fas ligand, activation of stress-activated protein kinase and caspase [69]. Inhibition of the NF-κB pathway disturbs the immune system, conferring both immunosuppressant and anti-tumor effects [70]. It is also an immunosuppressant agent because of its action as a selective inhibitor of T cell proliferation, like other members of the prodigiosin family [71]. Cycloprodigiosin also stimulates nitric oxide production during hepatic injury, improving cell status by regulating the expression of NF-κB-dependent genes, such as inducible Nitric Oxide Synthase (iNOS) [72], Considering that immunosuppressive drugs such as corticosteroids and mesalazine can prevent the activation of NF-kappaB, both the suppression of NF-κB and increased NO production have been suggested as an anti-inflammatory strategy in inflammatory bowel disease (IBD), so that administration of cycloprodigiosine may limit chronic inflammation [73]. Since NF-κB is known to be a transcription factor regulating inflammatory response genes and implicated in AR, its inhibition could also indicate anti-inflammatory and anti-arthritic properties possessed by cycloprodigiosin [74].

This is an alkaloid isolated from marine sponges, such as Acanthella aurantica and Stylissa massa [75] and investigated for its properties against NF-κB activation, and its inhibitory effect on IL-8, IL-2 and TNF-α production. Hymenialdisine inhibits several proteins regulating cellular cycle and functions, such as glycogen synthase kinase-3beta, cyclin-dependent kinases, and casein kinase 1, by competing with ATP for binding to these kinases [76]. In this way, it also inhibits phosphorylation of the protein tau (which is hyperphosphorylated in Alzheimer’s disease) with promising potential against human neurodegenerative diseases [77], and NF-κB activity, probably by inhibiting both protein kinase C and I-kB phosphorylation [78]: molecules able to interfere with factors involved in the modulation of gene expression, such as NF-κB, can also be considered as potential anti-inflammatory agents. Its anti-inflammatory properties have also been reported, achieved through its ability to decrease IL-8 [79] and IL-1beta production [80].

In addition, hymenialdisine was tested on bovine articular cartilage, also evaluating its inhibitory effect on proteoglycan degradation in a dose-dependent manner [81]. A potential inhibitory effect on proteoglycan degradation should be investigated on human cartilage and articular damage, typical of RA.

Cyclomarins are three cyclic heptapeptides (A, B and C), isolated from the marine bacterium actinomycete, belonging to Streptomyces sp., along the Californian coast.

Marine actinomycetes have been exploited as a source of biologically active secondary metabolites with antibacterial and anticancer properties [92].

Some molecules have also been reported to be anti-inflammatory, such as cyclomarins and salinamides [93].

Cyclomarin A, constituted of three common and four unusual aminoacids, showed potent anti-inflammatory and antiproliferative activities in both in vivo and in vitro assays, managing to inhibit edema and pain similarly to the drug hydrocortisone [94].

This molecule also displayed an ability to kill Mycobacterium tuberculosis by targeting its caseinolytic protease, resulting in a promising component of antitubercular drugs [95].

A moderate anti-inflammatory effect has been reported also in cyclomarin C, whose total synthesis was recently experimented and reported [96].

For this reason both cyclomarin A and C, and their derivatives, can develop as a potential naturally occurring anti-inflammatory therapies.

These five peptides (A, B, C, D and E) were isolated, like cyclomarin, from marine actinomicetes, belonging to Streptomyces sp., isolated from the surface of the jellyfish Cassiopea xamachana, found in Florida waters [93].

Salinamide A and B are the two major bicyclic metabolites, with potent topical anti-inflammatory activity and moderate antibiotic activity against gram-positive bacteria, and could be used in the treatment of tissue inflammation and some infections [97].

Salinamides C, D and E are the minor metabolites, whose structure was established through spectral and chemical techniques: salinamide D has a similar structure but contains a valine residue in place of the isoleucine present in salinamide A; salinamides C and E are represented by monocyclic peptides, which exert a light anti-inflammatory activity [98], being potentially able to combat inflammatory diseases.

These new four metabolites (A, B, C and D) were isolated from the marine sponge Haliclona, found in the waters of Vanuatu. Halipeptins are made up of a peptidic portion, conventional alanine residues and unusual residues, assembled in a 17-membered macrolactone ring [99].

Particular attention has been focused on halipeptin A, because of its potent biological activities. Halipeptin A is a cyclic depsipeptide, whose total synthesis has been successfully carried out [100], together with recent syntheses of halipeptin D and its analogues, in order to take advantage of their biological properties [101].

It was found to possess a strong anti-inflammatory activity, both in vivo and in vitro, even stronger than the classical anti-inflammatory drugs, naproxene and indomethacin [102], resulting in an ability to inhibit edema in mice [99]: this powerful antiphlogistic action is similar to conventional drugs but without their typical side effects, and could be the basis of a beneficial strategy against inflammatory disorders.

These new lipidic compounds, polyacetylenic alcohols, isolated from marine sponges Petrosia [103], were collected from Keomun Island, along the Korean coast [104].

Petrocortyne A showed cytotoxic activity against solid tumor cells and anti-inflammatory activity inhibiting macrophages, decreasing TNF-alpha production and the expression of migration cell factors involved in phlogistic infiltration [105]. As a consequence, it blocks cellular inflammatory processes and immune cell migration to inflamed tissue; this interferes with the immunopathology of acute or chronic inflammatory and autoimmune diseases, such as septic shock, or rheumatoid arthritis, or even multiple sclerosis, where the pro-inflammatory cytokine TNF-α is widely involved [106]. In addition, not only anti-inflammatory, but also pro-aggregative effects of petrocortyne A have been investigated in vitro, establishing that this molecule induces weak intracellular pro-aggregative signals [105,106,107].

Petrocortyne D, E, F, G and H, whose structures were determined through chemical and spectral methods, exhibited moderate cytotoxicity and inhibitory activity against the enzyme phospholipase A2 [104].

This alkaloid has an unusual dimeric structure, firstly elucidated in 1993 [108], which can be considered unique among natural products [109].

It was isolated from Cyanobacteria, is a yellow to brown, lipid-soluble pigment [110], extracted from the terrestrial alga, Nostoc commune vauch [111]. Scytonemin seems to be an inhibitor of polo-like kinase 1 (an enzyme implicated in G2/M transition during the cell cycle) and of platelet-derived growth factor-induced rheumatoid synovial fibroblast.

In addition, T cells treated with scytonemin were induced to apoptosis, so that it could be developed and used for the treatment of hyperproliferative disorders [109]. Besides this antiproliferative and anti-inflammatory activity, Scytonemin also showed considerable antioxidant activity, so that it could be an interesting therapeutic agent [111] against degenerative anti-inflammatory diseases.