1 Introduction

Pharmaceuticals or pharmaceutical products are medicinal drugs—of proven safety, effectiveness and high quality, which are prescribed and intended to rational dosage (www.who.in). In general, most of the pharmacologically active compounds were isolated from microorganisms and plants, drug-resistance and identification of new disease entities have imposed to select both new sources and application areas of drug components (Schwartz et al. 1990).

The beneficial effect of algae-based products on human health has been known since antiquity, their use was, however, limited to folk medicine (Hoppe 1979). Due to the problematic transfer of species from natural habitats to the laboratory-scale cultivation and controversies over the results of algae blooms in aquatic life, the introduction of products to the market was difficult (Garham and Carmichael 1979; Moore 1977; Shimizu 1978). Although the first report on algae medicinal application was ‘Materia Medica’ by Shên-nung in 2700 B.C. (Hoppe 1979), the systematic investigation of algal active compounds—particularly antibiotics, began after World War II (Borowitzka 1995) as lateral direction of studies on unconventional protein sources for increasing human population. Early research verified algae for pharmaceutical activity mainly by in vitro experiments, subjected to public discussion in the late 1960s (Hoppe 1979). In vivo examination, on the other hand, was elaborated in the 1970s at the Roche Research Institute of Marine Pharmacology (Australia) and involved screening of crude extracts, rather than pure compounds, to isolate and identify components with given properties (Baker 1984). At the same time, in vitro screens were advanced and novel designs—assessing enzyme activity variation or cell line behaviour, enabled to develop efficient and low-cost investigation methods. These approaches are commonly used nowadays (Borowitzka 1995; Patterson et al. 1991; Suffness et al.1989). As greater attention was paid to marine source for medicinal application, microalgal biomolecules became products of interest (Borowitzka 1995; Kellam and Walker 1989; Moore et al. 1988; Patterson et al. 1991). At present, algae-based pharmaceuticals belong to small, yet high-value and mid-sized/value markets being appraised for $25–5800 thousand and $2–25 thousand per tonne, respectively (www.biofuelsdigest.com). According to the report of BCC Research from 2011, the global market of the marine-derived drug is expected to increase at compound annual growth rate of 12.5% reaching $8.6 billion by 2016 (BCC Research 2011).

There is a wide range of health disorders—including diseases of the circulatory and digestive systems, goitre and inflammation (Hoppe 1979), against which algae have been traditionally used. Medicinal application of algae depends on biochemical diversity which is affected by a number of factors, including location, season, grazing pressure, salinity, water motion, temperature, light climate (depth, turbidity and UV exposure), biomass density and nutrient availability (Stengel et al. 2011). The main groups of pharmaceutical compounds and their activities are shown (Fig. 1).

Fig. 1
figure 1

Scheme of obtaining pharmaceutical products from algal biomass

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It is a common practice to evaluate the applicability of selected source, based on total biological activity assessed, and pharmaceutical products comprised of pure components rather than a mixture of given properties. Thus, in the current work, review section was divided into seven subsections, each of which described one group of algae-derived compounds.

2 Compounds with Pharmaceutical Potential

2.1 Polysaccharides

Polysaccharides constitute the most widespread group of chemically active compounds found in algae and demonstrating pharmaceutical properties. Antiinflammatory activity of polysaccharides was shown to be a feature dependent on the type of molecule and its biological source. Polysaccharides are able to bind to the surface of leukocytes and decrease inflammation by interference with the migration of white blood cells (Raposo et al. 2015).

Yang et al. (2008) extracted fucoidans from Undaria pinnatifida and observed the anticancer activity of isolated polysaccharides. It was also shown that partial depolymerization of fucoidans in mild conditions significantly improved the anticancer activity of extracted biomolecules (Yang et al. 2008).

The activity of fucoidan from U. pinnatifida towards PC-3 prostate cancer cells was examined by Boo et al. (2013). Extracted polysaccharide induced apoptosis and inhibited the growth of tumour cells through the activation of ERK1/2 MAPK and inactivation of p38MAPK pathways (Boo et al. 2013).

Fucoidan obtained from Cladosiphon novae-caledoniae enhanced activity of chemotherapeutic agents such as cisplatin, tamoxifen and paclitaxel in breast cancer treatment. Its application induced apoptosis and reduced expression of Bcl-xL and Mcl-1 (Zhang et al. 2013).

In another study, fucoidan led to apoptosis induction in MCF-7 tumour cells by the activation of caspase 8 (Yamasaki et al. 2012).

Fucoidans extracted from Laminaria cichorioides and Fucus evanescens were examined for their influence on blood coagulation system. Dose-dependent inhibition of thrombin and Xa factor as a result of different sulfation degree of polysaccharides was observed (Drozd et al. 2006).

Fucoidan was also shown to be a factor able to inhibit binding formation between host cell and virus and hence a great antiviral agent towards HSV, RSV and HIV (Smit 2004).

Fucoidan was also recognized to be effective against allergic response. Polysaccharides isolated from U. pinnatifida caused the reduced concentration of interleukins in bronchoalveolar lavage fluid and suppressed production of IgE in airway hypersensitivity (Maruyama et al. 2005).

The treatment of mouse thymocytes with different concentrations of laminarin extracted from Laminaria japonica led to apoptosis suppression and genes responsible for the production of immune response proteins were activated (Kim et al. 2006a).

Laminarin produced by Laminaria digitata was examined for human colon cancer treatment. It was observed that extracted polysaccharide induced apoptosis of HT-29 cells and activated ErbB2 phosphorylation (Park et al. 2013).

Inhibited proliferation and induced apoptosis after the application of laminarin for prostate cancer PC-3 cells was observed in the study conducted by Zou et al. (2010). Also, increased expression of P27kip1 and PTEN was investigated.

Laminarin showed also beneficial effect against RIF-1 tumour cells. In vitro experiments proved its influence on the prevention of tubule formation. Reduced tumour growth as a result of laminarin application was also observed in the in vivo experiments (Hoffman et al. 1996).

Among algal polysaccharides with pharmacological potential, alginate should also be mentioned. Experiments carried out by Asada et al. (1997), alginate occurring in brown seaweeds inhibited release of hyaluronidase and histamine from mast cells.

Alginate was shown to be able to stimulate Toll-like receptors and activate production of cytokines (Draget and Taylor 2011).

Another possible application of alginate in pharmacology is due to its significant role as a base for the production of controlled-release drug products (Lee and Mooney 2012).

Antiallergic activities of alginic acid were shown to be a result of its suppressive effect on histidine cocarboxylase, interleukin and TNF-α production and reduce systemic anaphylaxis (Jeong et al. 2006).

The pharmacological activity of other polysaccharides from algae was also proved and described in the literature. Porphyran isolated from Porphyratenera was shown to be effective against different allergic responses and reduced contact hypersensitivity reaction by decreasing of IgE in Balb/c mice (Ishikara et al. 2005).

Carrageenans from Gigartina skottsbergii demonstrated potential activity against different strains of HSV (Smit 2004). Similar properties were observed for some agaroids from Gracilaria corticata (Mazumder et al. 2002).

Galactan from red seaweed Cryptonemia crenulata was described as a selective inhibitor of DENV-2 acting through the prevention from virus multiplication during infection (Talarico et al. 2007).

In another study, anticoagulant activity of sulfated galactans isolated from Gellidium crinale and Botryocladia occidentalis was examined. It was observed that proportion of 2,3-di-sulfated α-units in galactan chain is crucial for interaction between protease and coagulation inhibitor (Pereira et al. 2005).

Galactans from Callophyllis variegata were shown to possess antiviral activity against HSV and DENV (Rodriguez et al. 2005).

Matsuhiro et al. (2005) isolated galactans by aqueous extraction of Schizymeniabinderi. Extracted polysaccharides revealed high antiviral activity against HSV types 1 and 2. It was concluded that antiviral activity of galactans was due to the fact that polysaccharides interfere with the initial adsorption of the virus.

2.2 Pigments

Carotenoids, one of the most abundant group of molecules in algae were found to exhibit different biological activities. There is growing interest in their isolation from microalgae mainly due to their potentially beneficial characteristics for pharmacology (Crupi et al. 2013). Carotenoids isolated from algae are famous mainly for antioxidant properties. Currently, an emphasis is put on different groups of carotenoids such as fucoxanthin, astaxanthin, zeaxanthin due to the high potential for the use as pharmaceuticals. It was postulated that the application of algal carotenoids in modern pharmacology can lead to the development of cancer or cardiovascular diseases treatment (Gammone et al. 2015).

The antioxidant properties of fucoxanthin were examined in the in vitro experiments. High radical scavenging activity of isolated marine carotenoids was assumed to be a result of the presence of allenic bonds (Sachindra et al. 2007).

Fucoxanthin was presented as an efficient inhibitor of the cyclin-dependent kinase in the treatment of melanoma cells. Beneficial properties of this pigment were proved in the in vitro and in vivo experiments (Kim et al. 2013).

In another study, the same carotenoid produced by E. bicyclis and Undaria pinnatifida was shown to possess inhibitory activity against PTP1B—negative regulator of the insulin-signaling pathway (Matsuno 2001).

Among many beneficial health effects of fucoxanthin, anti-obesity properties seem to be the best examined (Apostolidis and Lee 2011). Ability of fucoxanthin to decrease glucose levels in blood led to comprehensive studies over its application in diabetes and obesity treatment (Jung et al. 2012). Fucoxanthin from U. pinnatifida was recognized for its inhibitory effect against pancreatic lipase (Matsumoto et al. 2010). In another study, it was demonstrated that the main health care action of fucoxanthin was based on the reduction of cardiovascular risk factors (obesity, cholesterol concentration and hypertension) (D’Orazio et al. 2012).

The antioxidative potential of astaxanthin was shown to be even higher than vitamin E and β-carotene. Pigments found mainly in microalgae such as microalgae Haematococcus pluvialis, Chlorella zofingiensis, and Chlorococcum sp. promotes immune response in liver and kidney diseases. Also, its extraordinary potential in the protection against cancers, diabetes and gastrointestinal diseases was proved (Yuan et al. 2011).

Another algal carotenoid—violaxanthin—was shown to be the major factor detected in dichloromethane extract from Dunaliella tertiolecta, which demonstrated strong antiproliferative activity against two cell lines of human mammary cancer (MCF-7 and LNCaP) (Pasquet et al. 2011). Violaxanthin was also isolated from Chlorella ellipsoidea and examined for its antiinflammatory activity with the use of lipopolysaccharide (LPS)—stimulated RAW 264.7 mouse macrophage cells. As the result of the test, inhibition of NO and prostaglandin E2 was revealed. It was shown that violaxanthin acts mainly on the NF-κB pathway (Soontornchaiboon et al. 2012).

In another study, hepatoprotective properties of the carotenoid-rich extract obtained from Spirulina sp. were examined on rats. Obtained results revealed that carotenoids from microalgae were characterized by the greater antihepatotoxic effect in comparison with synthetic compounds (Murthy et al. 2005).

Inhibitory effects of carotenoids on the increase of ROS levels in gastric cells induced by H2O2 were reported. Furthermore, the application of carotenoids led to the activation of NF-κB and interleukin 8 expressions. It was claimed that supplementation of carotenoids significantly reduced the risk of gastric cancer (Kim et al. 2011). Administration of β-carotene to OVA-immunized mice decreased serum histamine level and hence inhibited an anaphylactic response (Vo et al. 2012).

Another important pigment isolated from microalgae with well-documented pharmaceutical potential is phycoyanin. It is one of the major pigments from Spirulina sp. Its inhibitory activity of allergic responses, such as ear swelling, skin reactions and histamine release from mast cells was documented (Ramirez et al. 2002). Phycoyanin poses also antiinflammatory activity through enhancement of IgA antibody response and suppression of allergivIgE antibody response (Nemoto-Kawamura et al. 2004).

The possible application of phycobilin pigments, such as phycocyanin or phycoerythrin, unique for algae, in photodynamic therapy during cancer treatment was pointed out by Borowitzka (2013).

2.3 Terpenoids

Among organic compounds with high potential for the use in pharmaceuticals and isolated from algae, terpenoids should be also listed.

Methanolic extract from Sargassum micracanthum was shown to be rich in benzoquinone-type compounds and poses great inhibitory activity on lipid peroxidation. Strong antiviral activity against MCMV of the obtained extract was also investigated (Iwashima et al. 2005). Terpenoids extracted from Dictyotapfaffii were presented as potential anti-HIV-1 agents. Conducted experiments showed that Dolabella dienetriol can act as HIV-1 reverse transcriptase enzyme inhibitor (Crime-Santos et al. 2008).

Quinone metabolites isolated from Sargassum sagamianum revealed antibacterial activity against Staphylococcus aureus (Horie et al. 2008). Rhipocephalin, sesquiterpenoid from green algae exhibited high activity in the inhibition of phospholipase A2 from bee venom (Mayer et al. 1993).

Ji et al. (2008) investigated the possibility of the application of triterpenoids isolated from marine algae Laurencia mariannensis in cancer treatment. Obtained results revealed the cytotoxic effect of lauren mariannol and hydroxythyrsiferol against P-388 tumour cells. Triterpenoids extracted from Laurencia viridis displayed cytotoxic activity against murine leukaemia cell lines. Inhibitory activity on protein phosphatase was also determined (Souto et al. 2003).

2.4 Alkaloids

Despite the content of alkaloids in algae is relatively low in comparison with terrestrial plants, they were indicated as factors with high potential for the use in health protection. Alkaloids isolated from marine algae are known for antifungal, antioxidant and antibacterial activity. There are also some reports about the application of alkaloids as pharmaceuticals for effective neuromodulation, growth regulation and neurotransmission (Barbosa et al. 2014; De Souza et al. 2009).

The inhibition of Aβ-induced SH-SY5Y cell damage by racemosins A and B from C. racemosa was evaluated by Liu et al. (2013) in the in vitro experiments.

Alkaloids isolated from Caulerpa taxifolia (Vahl) C. Agardh. displayed inhibitory activity against PTP1B and hPTP1B (Mao et al. 2006).

2.5 Phenolic Compounds

Polyphenols, beside polysaccharides, are one of the most common secondary metabolites produced by algae. Although high content of phenolic compounds in terrestrial plants has been reported, there are fundamental differences in the chemical structure—plant molecules are derivatives of gallic and ellagic acids (Haslam and Cai 1994), whereas most frequently studied polyphenols from algae are composed of polymerized 1,3,5-trihydroxybenzene (phloroglucinol) units. Various algal polyphenols have been isolated, such as: phenolic acids, tannins, flavonoids, catechins, phlorotannins (Kadam et al. 2013); yet, scientific works concerning pharmaceuticals usually focus only on the latter group from marine brown seaweeds, particularly Ecklonia sp. (Singh and Bharate 2006). Beside phloroglucinol, eckol, dieckol, bieckols, phlorofucofuroeckol A and B were suggested, among other phlorotannis, for pharmacological activities (Li et al. 2009; Nagayama et al. 2008; Yoon 2008; Yoon et al. 2008).

Algal phenolic compounds are known for their strong radical scavenging effect, meaning inhibition of H2O2—induced DNA damage in particular (Heo and Jeon 2008). Efficacy of eckol, phlorofucofuroeckol A, dieckol, and 8,8’-bieckol—derived from Ecklonia species, against O2 − and 1,1-diphenyl 1,2-picrylhydrazyl was comparable to L-ascorbic acid and α-tocopherol (Shibata et al. 2008). Moreover, E. cava dieckol was proved to exceptionally mitigate the results of photo-oxidative stress (Heo et al. 2009; Xie et al. 2009). Kim et al. (2006b) showed phlorotannis isolated from E. cava to inhibit matrix metalloproteinase enzymes responsible for chronic inflammation.

Ecklonia-derived phlorotannins were also verified for antimicrobial activity against Campylobacter jejuni, Vibrio parahaemolyticus, Staphylococcus aureus (Eom et al. 2008; Nagayama et al. 2002), while supplementation with phenolic compounds from Ascophyllum nodosum reduced the prevalence of Escherichia coli O157:H7 among feedlot steers (Braden et al. 2004).

Antiviral effect of extracts from brown seaweeds—besides E. cava, such as Dictyota pfaffi, Ishige okamurage, Peyssonelia sp.,—were investigated against human immunodeficiency virus type-1 (HIV-1) and inhibition of HIV-1 reverse transcriptase, HIV-1 integrase and protease were observed (Lee and Jeon 2013).

Currently, a great attention is paid to examine phlorotannins for antidiabetic and anti-obesity activity. The former involves mechanisms shown in Fig. 2, while the latter is correlated with inhibition of pancreatic lipase—a key enzyme for triglyceride absorption in the small intestine (Lowe 1994, 2002).

Fig. 2
figure 2

Mechanisms of phlorotannis antidiabetic activity; GK—hepatic glucokinase, G6Phase—glucose-6-phosphatase, PEPCK—phosphoenolpyruvate carboxykinase, AMPK—5′ adenosine monophosphate-activated protein kinase, Akt—protein kinase B (Lee and Jeon 2013)

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The most recent trend to phlorotannis from Ecklonia maxima and Ishigeo kamurae pharmacological application is to inhibit acetylcholinesterase to protect the neurons from neurodegeneration—especially Alzheimer’s disease—by the enhancement of cholinergic neurotransmission in the brain and, simultaneously, ß-amyloid formationdecrease (Hodges 2006; Kannan et al. 2013; Yoon et al. 2009).Yoon et al. (2008) showed E. maxima extract to affect both acetyl and butylcholinesterase, while the activity of phenolic compounds from Sargassum species were proved against cholinesterase (Choi et al. 2007; Kusumi et al. 1979a, b; Ryu et al. 2003).

3 Peptides and Proteins

Due to intensive studies on the correlation between exposure to oxidative stress and chronic diseases, algal peptides as stress-response compounds have been investigated (Bondu et al. 2015). In vitro examination showed components derived from both micro—Chlorella vulgaris, C. ellipsoidea and Navivulla incerta (Kang et al. 2011, 2012; Ko et al. 2012; Sheih et al. 2009) and macroalgae—Solieria chordalis, Palmaria palmata, Ulva lactuca and Saccharina longicruris, to have activity against radicals, particularly hydroxyl radicals (Fan et al. 2014).

Most peptides showed activation when released from the parent protein molecule by hydrolysis (Fan et al. 2014). At the same time, the use of peptides is limited by their susceptible to degradation in the gastrointestinal tract and chemical modification or encapsulation of biomolecules is required (Shen et al. 2010; Walsh et al. 2004; Wang and Zhang 2013). Regardless of the application issues, algal peptides are also tested for blood pressure control, antiatherosclerotic and anticancer activity.

Cha et al. (2006) verified peptides isolated from Ecklonia cava for affecting hypertensive rats by ACE inhibition. The same mechanism of decreasing blood pressure was observed for microalgal peptides (Ko et al. 2012; Samarakoon et al. 2013). Chlorella and Spirulina-derived peptides were also reported to inhibit the production of adhesion molecules, and thus prevent atherogenesis (Shih et al. 2013; Vo and Kim 2013).

In the work of Zhang and Zhang (2013), anti-tumour peptide from Spirulina platensis with activity against human liver cancer MCF-7 and HepG2 cells is reported. On the other hand, Chlorella sp. components showed cytotoxicity towards both HepG2 cells and gastric cancer (AGS cells), their effectiveness was, however, lower by 80% (Sheih et al. 2010; Wang and Zhang 2013).

4 Fatty Acids

Algae are proved to surpass terrestrial plants in content of essential fatty acids, which, besides being well known dietary supplements of mainly antiatherosclerotic and immune-enhancing effect (Kay 1991; Khotimchenko 1993; Sanchez-Machado et al. 2002), show antiallergic activity by limiting the production and/or the release of allergic response mediator. Polyunsaturated fatty acids—stearidonic acid (C18:4, n-3) and hexadecatetraenoic acid (C16:4, n-3)—from Undaria pinnatifida and Ulva pertusa effectively decreased content of leukotriene B4, leukotriene C4 and 5-hydroxyeicosatetraenoic acid in MC/9 mouse mast cells (Ishihara et al. 1998). Histamine production was efficiently inhibited by treatment of RBL-2H3 cells with both α- and γ-linolenic acid (C18:3, n-3 and n-6, respectively) (Gueck et al. 2003; Kawasaki et al. 1994). Gueck et al. (2003, 2004) verified α- and γ-linolenic acid and docosahexaenoic acid (C22:6, n-3) to affect PGE2 production and histamine release in the canine mastocytoma cell line C2.

5 Conclusions

Algae constitute an abundant source of bioactive compounds, which have a great potential to be used as pharmaceuticals. Currently, the growing interest is put on the application of different algal compounds in the civilization diseases treatment. The market for pharmaceuticals based on compounds of natural origin is growing worldwide. Still untapped reservoir of chemically active compounds and potential in the field of pharmaceuticals imply requirement of increased screening algae for healthcare chemicals. Equally important is development of isolation methods.