Abstract
Living organisms endowed with natural benefits have been used for millions of years in the medical practice. Seaweeds have been widely used around the world for the production of agar and food; however, the pharmaceutical industry has drawn attention to the activities of these natural products. In this chapter, we present some bioactive metabolites of the three phyla of seaweed (green, brown, and red algae) along with their potential for drug development.
Keywords
- Seaweeds
- bioactive compounds
- natural products
- drug development
- bioactivities
1. Introduction
The use of natural resources for medicinal purposes in the treatment and prevention of diseases is one of the oldest practices of mankind. The earliest historical report describing the use of natural derivatives was written and found in Nagpur, India, and is approximately 5000 years old. These records comprise 12 recipes for drug preparation and refer to more than 250 plants [1]. Another historical example is the book written by Emperor Shen Nung circa 2500 BC. This Chinese book describes the use of more than 365 parts of medicinal plants; among these are camphor, the great yellow gentian, ginseng, jimson weed, cinnamon bark, and ephedra [2]. The Ebers Papyrus is one of the oldest and most important medical treatises known in the world. Written in ancient Egypt, it is dated at around 1550 BC and contains more than 700 species of plants and drugs used in therapy, such as pomegranate, castor oil, aloe, senna, garlic, onions, figs, willow, coriander, juniper, and common centaury [3].
The first initiative in the search of natural products of marine origin with pharmacological potential began at a conference in Rhode Island, USA, under the name of “Drugs from the Sea” in 1967. Since this important date, researchers from around the world pledged in search of primary and secondary metabolites of various marine organisms. In 1980, the University of Utah in the USA discovered a toxin derived from cone snail that was able to block a voltage‐gated calcium channel. Based on the initial data, a peptide was synthesized and developed by Elan Corporation. The FDA authorized the sale in 2004 of the first drug derived from a marine natural product under the trade name Prialt for the treatment of chronic pain in spinal cord injuries. In 2007, the second drug derived from marine organisms was developed. The isoquinoline derived from the sea squirt
Seaweed is used extensively for development in the industries of cosmetics, fuel production, agar production, and it also serves as animal and human food. However, due to advances in the isolation and structural elucidation of its primary and secondary metabolites, the pharmaceutical industry is turning its attention toward algae. In this section, we describe the natural products derived from seaweed, which have potential for drug development.
2. Marine seaweeds as a source of new bioactive prototypes
2.1. Green seaweeds as a source of new bioactive prototype
The primary metabolites in green seaweeds are more exploited for the development of drugs than the secondary metabolites. Molecules such as peptides, glycolipids, and sulfated polysaccharides have shown interesting results and are in an advanced phase in the drug test. As an example, the depsipeptide Kahalalide F (KF) isolated from the mollusk
Activity‐directed isolation of the n‐hexane and dichloromethane fractions from the
Also in primary metabolism, green seaweeds produce sulfated polysaccharides, which are said to ulvans. These molecules have shown interesting immunomodulatory and anticoagulant activities. For example, the sulfated polysaccharides of green seaweed
Among the secondary metabolites, green seaweeds synthesize mainly sterols, alkaloids, and prenylated bromohydroquinones. Historically, the ether extract from green seaweed
Alkaloids may be defined as a compound that has nitrogen atom(s) in a cyclic ring. In marine algae, these substances can be classified into: a) Phenylethylamine alkaloids; b) Indole alkaloids; or c) Other alkaloids [24]. In green seaweeds, the indole alkaloids are the main natural products isolated. Caulerpin
In Brazil, caulerpin was used for investigation of their cytotoxicity on Vero cells and antiviral activity against
Steroids are triterpenic compounds having a tetracyclic system; its A, B, and C rings have six carbons while ring D has five carbons. The vast majority of green seaweeds synthesize sterols of 28 and 29 carbons, as an example, with one of the first compounds isolated from
The partition prepared in EtOAc of the green seaweed
Other products found less in green algae also exhibit biological activities described; for example, bromophenols (BPs) found in
2.2. Brown seaweeds as a source of new bioactive prototypes
Among the primary metabolites of brown seaweeds, molecules as glycolipids and sulfated polysaccharides are used in the search for bioactivities to develop new drugs.
The brown seaweed
The brown seaweed
An experiment performed with fucoidans from the
Among the secondary metabolites, brown seaweeds synthesize different types of terpenes and phenolic compounds. Among the diterpenes, the brown seaweeds synthesize secondary metabolites with different carbon frameworks including dolabellane, dolastane, prenylated guaiane diterpenes, and meroditerpenes skeletons of interest in drug development.
The brown seaweed,
The brown seaweed
The extract prepared in dichloromethane/methanol (1:1) of brown seaweed
The brown seaweed
The extract prepared in dichloromethane of brown seaweed
Brown seaweeds also synthesize products such as phlorotannins and sesquiterpenes, which can be used in the development of drugs. The brown seaweed
The brown seaweed
2.3. Red seaweeds as a source of new bioactive prototypes
Among the primary metabolites of red seaweeds, some molecules, such as glycolipids and sulfated polysaccharides, are being used in the search for bioactivities in order to develop new drugs.
Activity‐guided isolation of red seaweed
Antiviral activity has been a major focus in the study of biological activities of polysaccharides of red algae, because its polysaccharides have shown a low cytotoxicity and high efficiency [65]. The sulfated polysaccharides of red seaweeds
Among the secondary metabolism, red seaweeds synthesize substances of different chemical classes such as terpenes, phenols, and acetogenins. Additionally, species of Rhodophyta are skilled in the incorporation of chlorine and bromine atoms.
The monoterpenes are substances with ten carbons formed by two isoprene units, and can be cyclic or aliphatic (acyclic) [68]. Halogenated monoterpenes are found in genres
Sesquiterpenes are natural products with 15 carbons, formed from three isoprene units. The sesquiterpenes are the class of natural products more produced by phylum Rhodophyta, especially by species of
Halogenated sesquiterpenes with bisabolane skeleton are mainly synthesized by species
The chamigrane sesquiterpenes exhibit a
The cuparanes sesquiterpenes are rarely described in red seaweeds. The great majority of isolates is formed by an aromatic ring attached to a ring structure of five carbon atoms and may or may not have double bonds in its interior. In 1996, the synthesis of Cuparene and Cuparenol metabolites has been described from β‐cyclogeraniol [85]. Currently, these substances are marketed, which brings a lot of interest as prototypes with biological activities. Two cuparane sesquiterpenes
The eudesmane sesquiterpenes are formed by two rings of six carbons with the isopropyl group at the carbon 7 and a bromine atom at carbon 1. Eudesmane sesquiterpenes also been isolated from brown seaweeds, for example, from
The laurane sesquiterpenes are similar in chemical structure to cuparanes. These molecules have a phenolic group attached to a cyclopentane through carbon 6, where the vast majority has an addition of bromine to carbon 10 or 12. This metabolite class also shows the first examples of iodinated naturally occurring substances [89]. In 2004, a major study was conducted to evaluate the antibacterial activity of secondary metabolites isolated from the genus
The snideranes form the second largest group of sesquiterpenes described for the algae
The brasilanes sesquiterpenes were isolated only in the species
The diterpenes are composed of 20 carbon atoms, which correspond to four isoprene units. Among the known red seaweeds are more than 20 kinds of diterpene skeletons, with irieane, labdane, and parguerane [96] being the main ones. The first irieane of red seaweeds were isolated in 1975 from the chloroform extract of the genus
The labdane diterpenes are bicyclic, usually with ramification on carbon 9. Historically, brominated diterpene Ent‐13‐epiconcinndiol was found in the specie
The parguerane diterpenes are formed by a tricyclic structure with six carbons in each cycle. All described skeletons have a standard addition of the bromine atom at carbon 15. The vast majority of pargueranes was isolated from red algae, and has a double bond between carbons 9 and 11 with the addition of a hydroxyl group on carbon 16. In a study from Theuri Island, Japan, the isolation of parguerane-type diterpenes was performed and its anticancer activity was tested in P388 and HeLa cells. The monoacetate parguerane diterpene showed the best results with IC50 values of 0.3 and 1.1 µg/mL for HeLa and P388 cells, respectively. The acetoxy group at C2 and bromine at C15 are important for anticancer activity [101].
The triterpenes have 30 carbons in their structure and are derived from six isoprene units [102]. Over 20,000 triterpenoids were isolated and identified in nature, where their structures can be classified into different chemical skeletons, such as squalene, lanostane, dammarane, lupane, oleanane, ursane, and others [103].
The halogenated triterpenoids found in red seaweeds are the type squalene and are known to exhibit excellent anticancer activity. As an example, we can highlight the triterpenoid isolated from red seaweed
The acetogenins are derived from the metabolism of fatty acids. The first acetogenin halogenated C15 of red seaweed was isolated from the methanol extract of seaweed
The BPs are substances formed by one or more benzene rings linked to at least one bromine atom. The first BPs isolated from marine organisms were found in red seaweed
3. Conclusion
Based on the work described in this chapter, it is clear that seaweed is endowed with a variety of structurally and chemically diverse metabolites having a broad spectrum of biological activities. Of all natural products presented, KF peptide from green seaweed appears to be the most promising in the development of a new drug, since it has excellent biological activity and a known synthesis pathway. We also believe that Dolabelladienetriol, a dolabellane diterpene isolated from
References
- 1.
Peter EL, Rumisha SF, Mashoto KO and Malebo HM. Ethno‐medicinal knowledge and plants traditionally used to treat anemia in Tanzania: a cross sectional survey. Journal of Ethnopharmacology. 2014; 154: 767–773. DOI: 10.1016/j.jep.2014.05.002 - 2.
Natnoo SA, Mohammed J. Reference flora—A source of traditional medicine in jammu and kashmir. International Journal of Recent Scientific Research. 2014; 5: 2286–2288. - 3.
Petrovska BB. Historical review of medicinal plants’ usage. Pharmacognosy Reviews. 2012; 6: 1–5. DOI: 10.4103/0973‐7847.95849 - 4.
Molinski TF, Dalisay DS, Lievens SL and Saludes JP. Drug development from marine natural products. Nature Reviews Drug Discovery 2009; 8: 69–85. DOI: 10.1038/nrd2487 - 5.
Hamann MT, Scheuer PJ. Kahalalide F A Bioactive depsipeptide from the sacoglossaa mollusk Elysia rufescens and the green algaBryopsis sp. Journal of the American Chemical Society. 1993; 115: 5825–5826. DOI: 10.1021/ja00066a061 - 6.
Hamann MT, Otto CS, Scheuer PJ. Kahalalides: Bioactive peptides from a marine mollusk Elysia rufescens and its algal dietBryopsis sp. The Journal of Organic Chemistry. 1996; 61: 6594–6600. DOI: 10.1021/jo960877 - 7.
Garcia‐Rocha M, Bonay P, Avila J. The antitumoral compound Kahalalide F acts on cell lysosomes. Cancer Letters. 1996; 99: 43–50. DOI: 10.1016/0304‐3835(95)04036‐6 - 8.
Faircloth GT, Grant W, Smith B, Supko J, Brown A, Geldof A, Jimeno J. Preclinical development of Kahalalide F, a new marine compound selected for clinical studies. Proceedings of the American Association for Cancer Research. 2000; 41: 600. - 9.
López‐Macià A, Jiménez JC, Royo M, Giralt E, Albericio F. Synthesis and structure determination of Kahalalide F. Journal of the American Chemical Society. 2001; 123: 11398–11401. DOI: 10.1021/ja0116728 - 10.
Nuijen B, Bouma M, Talsma H, Manada C, Jimeno JM, Lopez‐Lazaro L, Bult A, Beijnen JH. Development of a lyophilized parenteral pharmaceutical formulation of the investigational polypeptide marine anticancer agent Kahalalide F. Drug Development and Industrial Pharmacy. 2001; 27: 767–780. DOI: 10.1081/DDC‐100107240 - 11.
Brown AP, Morrissey RL, Faircloth GT, Levine BS. Preclinical toxicity studies of kahalalide F, a new anticancer agent: single and multiple dosing regimens in the rat. Cancer Chemotherapy and Pharmacology. 2002; 50: 333–340. DOI: 10.1007/s00280‐002‐0499‐2 - 12.
Rademaker‐Lakhai JM, Horenblas S, Meinhardt W, Stokvis E, Reijke TM, Jimeno JM, Lopez‐Lazaro L, Martin JAL, Beijnen JH, Schellens JHM. Phase I clinical and pharmacokinetic study of Kahalalide F in patients with advanced androgen refractory prostate cancer. Clinical Cancer Research. 2005; 11: 1854–1862. DOI: 10.1158/1078‐0432.CCR‐04‐1534 - 13.
Pardo B, Paz‐Ares L, Tabernero J, Ciruelos E, GarcI¤a M, Salazar R, López A, Blanco M, Nieto A, Jimeno J, Izquierdo MA and Trigo JM. Phase I clinical and pharmacokinetic study of Kahalalide F administered weekly as a 1‐hour infusion to patients with advanced solid tumors. Clinical Cancer Research. 2008; 14: 1116–1123. DOI: 10.1158/1078‐0432.CCR‐07‐4366 - 14.
Miguel‐Lillo B, Valenzuela B, Peris‐Ribera JE, Soto‐Matos A, Pérez‐Ruixo JJ. Population pharmacokinetics of kahalalide F in advanced cancer patients. Cancer Chemotherapy and Pharmacology. 2015; 76: 365–374. DOI: 10.1007/s00280‐015‐2800‐1 - 15.
Fang Z, Jeong SY, Jung HA, Choi JS, Min BS, Woo MH. Capsofulvesins A–C, cholinesterase Inhibitors from Capsosiphon fulvescens . Chemical and Pharmaceutical Bulletin. 2012; 60: 1351–1358. DOI: 10.1248/cpb.c12‐00268 - 16.
Islam MN, Choi SH, Moon HE, Park JJ, Jung HA, Woo MH, Woo HC, Choi JS. The inhibitory activities of the edible green alga Capsosiphon fulvescens on rat lens aldose reductase and advanced glycation end products formation. European Journal of Nutrition. 2014; 53: 233–242. DOI: 10.1007/s00394‐013‐0521‐y - 17.
Kima JK, Chob ML, Karnjanapratumb S, Shinb S, You SG. In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from Enteromorpha prolifera . International Journal of Biological Macromolecules. 2011; 49: 1051–1058. DOI: 10.1016/j.ijbiomac.2011.08.032 - 18.
Arata PX, Quintana I, Canelón DJ, Vera BE, Compagnone RS, Ciancia M. Chemical structure and anticoagulant activity of highly pyruvylatedsulfated galactans from tropical green seaweeds of the order Bryopsidales. Carbohydrate Polymers. 2015; 122: 376–386. DOI: 10.1016/j.carbpol.2014.10.030 - 19.
Högberg HE, Thomson RH, King TJ. The cymopols, a group of prenylated bromohydroquinones from the green calcareous alga Cympolia barbata . Journal of the Chemical Society, Perkin Transactions 1. 1976; 6: 1696–1701. DOI: 10.1039/P19760001696 - 20.
Estrada DM, Martin JD, Perez C. A new brominated monoterpenoid quinol from Cymopolla barbata . Journal of Natural Products. 1987; 50: 735–737. DOI: 10.1021/np50052a028 - 21.
Wall ME, Wani MC, Manikumar G, Taylor H, Hughes TJ, Gaetano K, Gerwick WH, McPhail AT, McPhail DR. Plant Antimutagenic Agents 7. Structure and Antimutagenic Properties of Cymobarbatol and 4‐Isocymbarbatol, New Cymopols from Green Alga ( Cymopolia barbata ). Journal of Natural Products. 1989; 52: 1092–1099. DOI: 10.1021/np50065a028 - 22.
Dorta E, Darias J, Martín AS, Cueto M. New prenylated bromoquinols from the green alga Cymopolia barbata . Journal of Natural Products. 2002; 65: 329–333. DOI: 10.1021/np010418q - 23.
Badal S, Gallimore W, Huang G, Tzeng TR, Delgoda R. Cytotoxic and potent CYP1 inhibitors from the marine algae Cymopolia barbata . Organic and Medicinal Chemistry Letters. 2012; 2: 1–8. DOI: 10.1186/2191‐2858‐2‐21 - 24.
Güven KC, Percot A, Sezik E. Alkaloids in marine algae. Marine Drugs. 2010; 8: 269–284. DOI: 10.3390/md8020269 - 25.
Aguilar‐Santos G. Caulerpin, a new red pigment from green algae of the genus Caulerpa. Journal of the Chemical Society, Perkin Transactions 1. 1970; 6: 842–843. - 26.
Kamal C, Sethuraman MG. Caulerpin—A bis‐Indole alkaloid as a green inhibitor for the corrosion of mild steel in 1 M HCl solution from the marine alga Caulerpa racemosa . Industrial & Engineering Chemistry Research. 2012; 51: 10399–10407. DOI: 10.1021/ie3010379 - 27.
Macedo NRPV, Ribeiro MS, Villaça RC, Ferreira W, Pinto AN, Teixeira VL, Cirne‐Santos C, Paixão ICNP, Giongo V. Caulerpin as a potential antiviral drug herpes simplex virus type 1. Revista Brasileira de Farmacognosia. 2012; 22: 861–867. DOI: 10.1590/S0102‐695X2012005000072 - 28.
Chay CIC, Cansino RG, Pinzón CIE, Torres‐Ochoa RO, Martínez R. Synthesis and anti‐tuberculosis activity of the marine natural product caulerpin and its analogues. Marine drugs. 2014; 12: 1757–1772. DOI: 10.3390/md12041757 - 29.
Rubinstein I, Goad LJ. Sterols of the siphonous marine alga Codium fragile . Phytochemistry.1974; 13: 481–484. DOI: 10.1016/S0031‐9422(00)91238‐X - 30.
Zhang JL, Tian HY, Li J, Jin L, Luo C, Ye WC, Jiang RW. Steroids with inhibitory activity against the prostate cancer cells and chemical diversity of marine alga Tydemania expeditionis . Fitoterapia. 2012; 83: 973–978. DOI: 10.1016/j.fitote.2012.04.019 - 31.
Ali MS, Saleem M, Yamdagni R, Ali MA. Steroid and antibacterial steroidal glycosides from marine green alga Codium iyengarii Borgesen. Natural Product Letters. 2002; 16: 407–413. DOI: 10.1080/10575630290034249 - 32.
Carte BK, Troupe N, Chan JA, Westley JW, Faulkner DJ. Rawsonol, an inhibitor of HMG‐CoA reductase from the tropical green alga Avrainvillea rawsoni . Phytochemistry. 1989; 28: 2917–2919. DOI: 10.1016/0031‐9422(89)80253‐5 - 33.
Plouguerné E, Ioannou E, Georgantea P, Vagias C, Roussis V, Hellio C, Kraffe E, Stiger‐Pouvreau V. Anti‐microfouling activity of lipidic metabolites from the invasive brown alga Sargassum muticum (Yendo) Fensholt. Marine Biotechnology. 2010; 12: 52–61. DOI: 10.1007/s10126‐009‐9199‐9 - 34.
Cantillo‐Ciau Z, Moo‐Puc R, Quijano L, Freile‐Pelegrín Y. The tropical brown alga Lobophora variegata : a source of antiprotozoal compounds. Marine drugs. 2010; 16: 1292–1304. DOI: 10.3390/md8041292 - 35.
Hossain Z, Kurihara H, Hosokawa M, Takahashi K. Growth inhibition and induction of differentiation and apoptosis mediated by sodium butyrate in Caco‐2 cells with algal glycolipids. In Vitro Cellular & Developmental Biology. 2005; 41: 154–159. DOI: 10.1290/0409058.1 - 36.
Mizushina Y, Sugiyama Y, Yoshida H, Hanashima S, Yamazaki T, Kamisuki S, Ohta K, Takemura M, Yamaguchi T, Matsukage A, Yoshida S, Saneyoshi M, Sugawara F, Sakagauchi K. Galactosyldiacylglycerol, a mammalian DNA polymerase alpha‐specific inhibitor from a sea alga, Petalonia bingbamiae . Biological and Pharmaceutical Bulletin. 2001; 24: 982–987. DOI: 10.1248/bpb.24.982 - 37.
Cumashi A, Ushakova NA, Preobrazhenskaya ME, D'Incecco A, Piccoli A, Totani L, Tinari N, Morozevich GE, Berman AE, Bilan MI, Usov AI, Ustyuzhanina NE, Grachev AA, Sanderson CJ, Kelly M, Rabinovich GA, Iacobelli S, Nifantiev NE. A comparative study of the anti‐inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. Glycobiology. 2007; 17: 541–552. DOI: 10.1093/glycob/cwm014 - 38.
Croci DO, Cumashi A, Ushakova NA, Preobrazhenskaya ME, Piccoli A, Totani L, Ustyuzhanina NE, Bilan MI, Usov AI, Grachev AA, Morozevich GE, Berman AE, Sanderson CJ, Kelly M, Di Gregorio P, Rossi C, Tinari N, Iacobelli S, Rabinovich GA, Nifantiev NE. Fucans, but not fucomannoglucuronans, determine the biological activities of sulfated polysaccharides from Laminaria saccharina brown seaweed. PLoS One. 2011; 6: 1–10. DOI: 10.1371/journal.pone.0017283 - 39.
Clinical trials.gov. Phase 1 Dosing Study of BAX 513 in Healthy Volunteers [Internet]. 2010. Available from: https://clinicaltrials.gov/ct2/show/NCT01063101?term=NCT01063101&rank=1 [Accessed: 2015‐12‐14]. - 40.
Barbosa JP, Pereira RC, Abrantes JL, Cirne dos Santos CC, Rebello MA, Frugulhetti IC, Texeira VL. In vitro antiviral diterpenes from the Brazilian brown algaDictyota pfaffii . Planta Medica. 2004; 70: 856–860. DOI: 10.1055/s‐2004‐827235 - 41.
Abrantes JL, Barbosa J, Cavalcanti D, Pereira RC, Frederico Fontes CL, Teixeira VL, Moreno Souza TL, Paixão IC. The effects of the diterpenes isolated from the Brazilian brown algae Dictyota pfaffii andDictyota menstrualis against the herpes simplex type‐1 replicative cycle. Planta Medica. 2010; 76: 339–344. DOI: 10.1055/s‐0029‐1186144 - 42.
Cirne‐Santos CC, Teixeira VL, Castello‐Branco LR, Frugulhetti IC, Bou‐Habib DC. Inhibition of HIV‐1 replication in human primary cells by a dolabellane diterpene isolated from the marine algae Dictyota pfaffii . Planta Medica. 2006; 72: 295–299. DOI: 10.1055/s‐2005‐916209 - 43.
Cirne‐Santos CC, Souza TM, Teixeira VL, Fontes CF, Rebello MA, Castello‐Branco LR, Abreu CM, Tanuri A, Frugulhetti IC, Bou‐Habib DC. The dolabellane diterpene Dolabelladienetriol is a typical noncompetitive inhibitor of HIV‐1 reverse transcriptase enzyme. Antiviral Research. 2008; 77: 64–71. DOI: 10.1016/j.antiviral.2007.08.006 - 44.
Garrido V, Teixeira GAPB, Teixeira VL, Ocampo P, Ferreira WJ, Cavalcanti DN, Campos SMN, Pedruzzi MMB, Olaya P, Santos CCC, Giongo V, Paixão ICP. Evaluation of the acute toxicity of dolabelladienotriol, a potential antiviral from the brown alga Dictyota pfaffii , in BALB/c mice. Brazilian Journal of Pharmacognosy. 2011; 21: 209–215. DOI: 10.1590/S0102‐695X2011005000053 - 45.
Pardo‐Vargas A, de Barcelos Oliveira I, Stephens PR, Cirne‐Santos CC, de Palmer Paixão IC, Ramos FA, Jiménez C, Rodríguez J, Resende JA, Teixeira VL and Castellanos L. Dolabelladienols A‐C, new diterpenes isolated from Brazilian brown alga Dictyota pfaffii . Marine Drugs. 2014; 12: 4247–4259. DOI: 10.3390/md12074247 - 46.
Soares DC, Calegari‐Silva TC, Lopes UG, Teixeira VL, de Palmer Paixão IC, Cirne‐Santos C, Bou‐Habib DC, Saraiva EM. Dolabelladienetriol, a compound from Dictyota pfaffii algae, inhibits the infection byLeishmania amazonensis . PLOS Neglected Tropical Diseases. 2012; 6: e1787. DOI: 10.1371/journal.pntd.0001787 - 47.
Garcia DG, Bianco EM, Santos Mda C, Pereira RC, Faria MV, Teixeira VL, Burth P. Inhibition of mammal Na(+)K(+)‐ATPase by diterpenes extracted from the Brazilian brown alga Dictyota cervicornis . Phytotherapy Research. 2009; 23: 943–947. DOI: 10.1002/ptr.2600 - 48.
Vallim MA, Barbosa JE, Cavalcanti DN, De‐Paula JC, da Silva VAGG, Teixeira VL, Paixão ICNP. In vitro antiviral activity of diterpenes isolated from the Brazilian brown algaCanistrocarpus cervicornis . Journal of Medicinal Plants Research. 2010; 4: 2379–2382. DOI: 10.5897/JMPR10.564 - 49.
de Andrade Moura L, Bianco EM, Pereira RC, Teixeira VL, Fuly AL. Anticoagulation and antiplatelet effects of a dolastane diterpene isolated from the marine brown alga Canistrocarpus cervicornis . Journal of Thrombosis and Thrombolysis. 2011; 31: 235–240. DOI: 10.1007/s11239‐010‐0545‐6 - 50.
Pereira HS, Leão‐Ferreira LR, Moussatché N, Teixeira VL, Cavalcanti DN, Costa LJ, Diaz R, Frugulhetti IC. Antiviral activity of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis against human immunodeficiency virus type 1 (HIV‐1). Antiviral Research. 2004; 64: 69–76. DOI: 2004 Oct;64(1):69–76 - 51.
de Souza Pereira H, Leão‐Ferreira LR, Moussatché N, Teixeira VL, Cavalcanti DN, da Costa LJ, Diaz R, Frugulhetti IC. Effects of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis on HIV‐1 reverse transcriptase. Planta Medica. 2005; 71: 1019–1024. - 52.
Abrantes JL, Barbosa J, Cavalcanti D, Pereira RC, Fontes CFL, Teixeira VL, Souza TML and Paixão IC. The effects of the diterpenes isolated from the Brazilian brown algae Dictyota pfaffii andDictyota menstrualis against the herpes simplex type–1 replicative cycle. Planta Medica. 2010; 76: 339–344. DOI: 10.1055/s-0029-1186144 - 53.
Awad NE, Selim MA, Metawe HM, Matloub AA. Cytotoxic xenicane diterpenes from the brown alga Padina pavonia (L.) Gaill. Phytotherapy Research. 2008; 22: 1610–1613. DOI: 10.1002/ptr.2532 - 54.
Dorta E, Cueto M, Brito I, Darias J. New terpenoids from the brown alga Stypopodium zonale . Journal of Natural Products. 2002; 65: 1727–1730. DOI: 10.1021/np020090g - 55.
Abatisa D, Vagiasa C, Galanakisb D, Norrisc JN, Moreaud D, Roussakisd C, Roussis V. Atomarianones A and B: two cytotoxic meroditerpenes from the brown alga Taonia atomaria . Tetrahedron Letters. 2005; 46: 8525–8529. DOI: 10.1016/j.tetlet.2005.10.007 - 56.
Mendes G, Soares AR, Sigiliano L, Machado F, Kaiser C, Romeiro N, Gestinari L, Santos N, Romanos MT. In vitro anti‐HMPV activity of meroditerpenoids from marine algaStypopodium zonale (dictyotales). Molecules. 2011; 16: 8437–8450. DOI: 10.3390/molecules16108437 - 57.
Okada Y, Ishimaru A, Suzuki R, Okuyama T. A new phloroglucinol derivative from the brown alga Eisenia bicyclis : potential for the effective treatment of diabetic complications. Journal of Natural Products. 2004; 67: 103–105. DOI: 10.1021/np030323j - 58.
Jung HA, Hyun SK, Kim HR, Choi JS. Angiotensin‐converting enzyme I inhibitory activity of phlorotannins from Ecklonia stolonifera . Fisheries Science. 2006; 72: 1292–1299. DOI: 10.1111/j.1444‐2906.2006.01288.x - 59.
Moon HE, Islam N, Ahn BR, Chowdhury SS, Sohn HS, Jung HA and Choi JS. Protein tyrosine phosphatase 1B and α‐glucosidase inhibitory phlorotannins from edible brown algae, Ecklonia stolonifera andEisenia bicyclis . Bioscience, Biotechnology, and Biochemistry. 2011; 75: 1472–1480. DOI: 10.1271/bbb.110137 - 60.
Song F, Xu X, Li S, Wang S, Zhao J, Cao P, Yang Y, Fan X, Shi J, He L, Lü Y. Norsesquiterpenes from the brown alga Dictyopteris divaricata . Journal of Natural Products. 2005; 68: 1309–1313. DOI: 10.1021/np040227y - 61.
Song F, Xu X, Li S, Wang S, Zhao J, Yang Y, Fan X, Shi J, He L. Minor sesquiterpenes with new carbon skeletons from the brown alga Dictyopteris divaricata . Journal of Natural Products. 2006; 69: 1261–1266. DOI: 10.1021/np060076u - 62.
Banskota AH, Stefanova R, Sperker S, Lall SP, Craigie JS, Hafting JT, Critchley AT. Polar lipids from the marine macroalga Palmaria palmata inhibit lipopolysaccharide‐induced nitric oxide production in RAW264.7 macrophage cells. Phytochemistry. 2014; 101: 101–108. DOI: 10.1016/j.phytochem.2014.02.004 - 63.
de Souza LM, Sassaki GL, Romanos MT, Barreto‐Bergter E. Structural characterization and anti‐HSV‐1 and HSV‐2 activity of glycolipids from the marine algae Osmundaria obtusiloba isolated from Southeastern Brazilian coast. Marine Drugs. 2012; 10: 918–931. DOI: 10.3390/md10040918 - 64.
Tsai CJ, Sun Pan B. Identification of sulfoglycolipid bioactivities and characteristic fatty acids of marine macroalgae. Journal of Agricultural and Food Chemistry. 2012; 60: 8404–8410. DOI: 10.1021/jf302241d - 65.
Ghosh T, Chattopadhyay K, Marschall M, Karmakar P, Mandal P, Ray B. Focus on antivirally active sulfated polysaccharides: from structure‐activity analysis to clinical evaluation. Glycobiology. 2009; 19: 2–15. DOI: 10.1093/glycob/cwn092 - 66.
Bouhlal R, Haslin C, Chermann JC, Colliec‐Jouault S, Sinquin C, Simon G, Cerantola S, Riadi H, Bourgougnon N. Antiviral activities of sulfated polysaccharides isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) andBoergeseniella thuyoides (Rhodophyta, Ceramiales). Marine Drugs. 2011; 9: 1187–1209. DOI: 10.3390/md9071187 - 67.
Clinical trials.gov. Carrageenan‐Containing Gel in Reducing the Rate of HPV Infection in Healthy Participants [Internet]. 2015. Available from: https://clinicaltrials.gov/ct2/show/NCT02382419?term=seaweed&rank=11 [Accessed: 2015‐12‐14]. - 68.
Wolwer‐Rieck U, May B, Lankes C, Wust M. Methylerythritol and mevalonate pathway contributions to biosynthesis of mono‐, sesqui‐, and diterpenes in glandular trichomes and leaves of Stevia rebaudiana Bertoni. Journal of Agricultural and Food Chemistry. 2014; 62: 2428–2435. DOI: 10.1021/jf500270s - 69.
Getrey L, Krieg T, Hollmann F, Schrader J, Holtmann D. Enzymatic halogenation of the phenolic monoterpenes thymol and carvacrol with chloroperoxidase. Green Chemistry. 2014; 16: 1104–1108. DOI: 10.1039/C3GC42269K - 70.
Teixeira V. Produtos Naturais de Algas Marinhas Bentônicas. Revista Virtual de Química. 2013; 5: 343–362. DOI: 10.5935/1984‐6835.20130033 - 71.
Rovirosa J, Soler A, Blanc V, León R, San‐Martín A. Bioactive monoterpenes from antarctic Plocamium cartilagineum . Journal of the Chilean Chemical Society. 2013; 58: 2025–2026. DOI: 10.4067/S0717‐97072013000400026 - 72.
Andrianasolo EH, France D, Cornell‐Kennon S and Gerwick WH. DNA methyl transferase inhibiting halogenated monoterpenes from the Madagascar red marine alga Portieria hornemannii . Journal of Natural Products. 2006; 69: 576–579. - 73.
Fuller RW, Cardellina JH II, Jurek J, Scheuer PJ, Alvarado‐Lindner B, McGuire M, Gray GN, Steiner JR, Clardy J, Menez E, et al. Isolation and structure/activity features of halomon‐related antitumor monoterpenes from the red alga Portieria hornemannii . Journal of Medicinal Chemistry. 1994; 37: 4407–4411. DOI: 10.1021/jm00051a019 - 74.
Kladi M, Xenaki H, Vagias C, Papazafiri P, Roussis V. New cytotoxic sesquiterpenes from the red algae Laurencia obtusa andLaurencia microcladia . Tetrahedron. 2006; 62: 182–189. DOI: 10.1002/chin.200621178 - 75.
König GM, Wright AD, Sticher O. A New polyhalogenated monoterpene from the red alga Plocamium cartilagineum . Journal of Natural Products. 1990; 53: 1615–1618. DOI: 10.1021/np50072a041 - 76.
Rodriguez S, Kirby J, Denby CM, Keasling JD. Production and quantification of sesquiterpenes in Saccharomyces cerevisiae , including extraction, detection and quantification of terpene products and key related metabolites. Nature Protocols. 2014; 9 (8): 1980–1996. DOI: 10.1038/nprot.2014.132 - 77.
Davyt D, Fernandez R, Suescun L, Mombru AW, Saldana J, Dominguez L, Fujii MT, Manta E. Bisabolanes from the red alga Laurencia scoparia . Journal of Natural Products. 2006; 69: 1113–1116. DOI: 10.1021/np060235+ - 78.
Ahmad VU, Ali MS. Terpenoids from marine red alga Laurencia pinnatifida . Phytochemistry. 1991; 30: 4172–4174. DOI: 10.1016/0031‐9422(91)83493‐5 - 79.
Davyt D, Fernandez R, Suescun L, Mombrú AW, Saldaña J, Domínguez L, Coll J, Fujii MT, Manta E. New sesquiterpene derivatives from the red alga Laurencia scoparia . Isolation, Structure Determination, and Anthelmintic Activity. Journal of Natural Products. 2001; 64: 1552–1555. DOI: 10.1021/np0102307 - 80.
White DE, Stewart IC, Grubbs RH and Stoltz BM. The catalytic asymmetric total synthesis of elatol. Journal of the American Chemical Society. 2007; 130: 810–811. DOI: 10.1021/ja710294k - 81.
Granado I, Caballero P. Chemical defense in the seaweed Laurencia obtusa (Hudson) Lamouroux. Scientia Marina. 1995; 59: 31–39. - 82.
De Nys R, Leya T, Maximilien R, Afsar A, Nair PSR and Steinberg PD. The need for standardised broad scale bioassay testing: A case study using the red alga Laurencia rigida . Biofouling. 1996; 10: 213–224. DOI: 10.1080/08927019609386281 - 83.
Veiga‐Santos P, Pelizzaro‐Rocha KJ, Santos AO, Ueda‐Nakamura T, Dias Filho BP, Silva SO, Sudatti DB, Bianco EM, Pereira RC, Nakamura CV. In vitro anti‐trypanosomal activity of elatol isolated from red seaweed Laurencia dendroidea . Parasitology. 2010; 137: 1661–1670. DOI: 10.1017/S003118201000034X - 84.
Campos A, Souza CB, Lhullier C, Falkenberg M, Schenkel EP, Ribeiro‐do‐Valle RM, Siqueira JM. Anti‐tumour effects of elatol, a marine derivative compound obtained from red algae Laurencia microcladia . Journal of Pharmacy and Pharmacology. 2012; 64: 1146–1154. DOI: 10.1111/j.2042‐7158.2012.01493.x - 85.
Abad A, Agulló C, Arnó M, Cuñat AC, García MT, Zaragozá RJ. Enantioselective Synthesis of Cuparane Sesquiterpenes. Synthesis of (-)‐Cuparene and (-)‐δ‐Cuparenol. The Journal of Organic Chemistry. 1996; 61: 5916–5919. DOI: 10.1021/jo960463g - 86.
Kladi M, Vagias C, Furnari G, Moreau D, Roussakis C, Roussis V. Cytotoxic cuparene sesquiterpenes from Laurencia microcladia . Tetrahedron Letters. 2005; 46: 5723–5726. DOI: 10.1016/j.tetlet.2005.06.076 - 87.
Ji NY, Wen W, Li XM, Xue QZ, Xiao HL and Wang BG. Brominated Selinane Sesquiterpenes from the Marine Brown Alga Dictyopteris divaricata . Marine Drugs. 2009; 7: 355–360. DOI: 10.3390/md7030355 - 88.
Li XD, Miao FP, Yin XL, Liu JL, Ji NY. Sesquiterpenes from the marine red alga Laurencia composita . Fitoterapia. 2012; 83: 1191–1195. DOI: 10.1016/j.fitote.2012.07.001 - 89.
Kladi M, Vagias C, Papazafiri P, Furnari G, Serio D, Roussis V. New sesquiterpenes from the red alga Laurencia microcladia . Tetrahedron. 2007; 63: 7606–7611. DOI: 10.1016/j.tet.2005.09.113 - 90.
Vairappan CS, Kawamoto T, Miwa H, Suzuki M. Potent antibacterial activity of halogenated compounds against antibiotic‐resistant bacteria. Planta Medica. 2004; 70: 1087–1090. DOI: 10.1055/s‐2004‐832653 - 91.
Kladi M, Xenaki H, Vagias C, Papazafiri P, Roussis V. New cytotoxic sesquiterpenes from the red algae Laurencia obtusa andLaurencia microcladia . Tetrahedron. 2006; 62: 182–189. DOI: 10.1016/j.tet.2005.09.113 - 92.
Rogers CN, De Nys R, Charlton TS, Steinberg PD. Dynamics of Algal Secondary Metabolites in Two Species of Sea Hare. Journal of Chemical Ecology. 2000; 26: 721–744. DOI: 10.1023/A:1005484306931 - 93.
Topcu G, Aydogmus Z, Imre S, Goren AC, Pezzuto JM, Clement JA, Kingston DG. Brominated sesquiterpenes from the red alga Laurencia obtusa . Journal of Natural Products. 2003; 66: 1505–1508. DOI: 10.1021/np030176p - 94.
Iliopoulou D, Vagias C, Galanakis D, Argyropoulos D, Roussis V. Brasilane‐Type Sesquiterpenoids from Laurencia obtusa . Organic Letters. 2002; 4: 3263–3266. DOI: 10.1021/ol026506z - 95.
Aydoğmus Z, Imre S, Ersoy L, Wray V. Halogenated secondary metabolites from Laurencia Obtusa . Natural Product Research. 2004; 18: 43–49. DOI: 10.1080/1057563031000122086 - 96.
Kornprobst JM, Al‐Easa HS. Brominated diterpenes of marine origin. Current Organic Chemistry. 2003; 7: 1181–1229. DOI: 10.2174/1385272033486530 - 97.
Fenical W, Howard B, Gifkins KB, Clardy J. Irieol A and iriediol, dibromoditerpenes of a new skeletal class from Laurencia . Tetrahedron Letters. 1975; 16: 3983–3986. DOI: 10.1016/S0040‐4039(00)91215‐2 - 98.
Vairappan CS, Ishii T, Lee TK, Suzuki M, Zhaoqi Z. Antibacterial activities of a new brominated diterpene from Borneon Laurencia spp. Marine Drugs. 2010; 8: 1743–1749. DOI: 10.3390/md8061743 - 99.
Öztunç A, Imre S, Lotter H, Wagner H. Ent‐13‐epiconcinndiol from the red alga Chondria tenuissima and its absolute configuration. Phytochemistry. 1989; 28: 3403–3404. DOI: 10.1016/0031‐9422(89)80356‐5 - 100.
Suzuki M, Kawamoto T, Vairappan CS, Ishii T, Abe T, Masuda M. Halogenated metabolites from Japanese Laurencia spp. Phytochemistry. 2005; 66: 2787–2793. DOI: 10.1016/j.phytochem.2005.08.008 - 101.
Takeda S, Kurosawa E, Komiyama K, Suzuki T. The Structures of Cytotoxic Diterpenes Containing Bromine from the Marine Red Alga Laurencia obtusa (Hudson) Lamouroux. Bulletin of the Chemical Society of Japan. 1990; 63: 3066–3072. DOI: 10.1246/bcsj.63.3066 - 102.
Connolly JD, Hill RA. Triterpenoids. Natural Product Reports. 2002; 19: 494–513. DOI: 10.1039/B110404G - 103.
Hill RA, Connolly JD. Triterpenoids. Natural Product Reports. 2013; 30: 1028–1065. DOI: 10.1039/C3NP70032A - 104.
Ji NY, Li XM, Xie H, Ding J, Li K, Ding LP, Wang BG. Highly Oxygenated Triterpenoids from the Marine Red Alga Laurencia mariannensis (Rhodomelaceae). Helvetica Chimica Acta. 2008; 91: 1940–1946. DOI: 10.1002/hlca.200890207 - 105.
Hashimoto M, Kan T, Nozaki K, Yanagiya M, Shirahama H, Matsumoto T. Total syntheses of (+)‐thyrsiferol, (+)‐thyrsiferyl 23‐acetate, and (+)‐venustatriol. The Journal of Organic Chemistry. 1990; 55: 5088–5107. DOI: 10.1021/jo00304a022 - 106.
Mahdi F, Falkenberg M, Ioannou E, Roussis V, Zhou YD, Nagle DG. Thyrsiferol Inhibits Mitochondrial Respiration and HIF‐1 Activation. Phytochemistry Letters. 2011; 4: 75–78. DOI: 10.1016/j.phytol.2010.09.003 - 107.
Irie T, Suzuki M, Masamune T. Laurencin, a constituent from laurencia species. Tetrahedron Letters. 1965; 6: 1091–1099. DOI: 10.1016/S0040‐4039(00)90038‐8 - 108.
Gutierrez‐Cepeda A, Fernandez JJ, Gil LV, Lopez‐Rodriguez M, Norte M, Souto ML. Nonterpenoid C15 acetogenins from Laurencia marilzae . Journal of Natural Products. 2011; 74: 441–448. DOI: 10.1021/np100866g - 109.
Kladi M, Vagias C, Papazafiri P, Brogi S, Tafi A, Roussis V. Tetrahydrofuran acetogenins from Laurencia glandulifera . Journal of Natural Products. 2009; 72: 190–193. - 110.
Katsui N, Suzuki Y, Kitamura S, Irie T. 5,6‐dibromoprotocatechualdehyde and 2,3‐dibromo‐4,5‐dihydroxybenzyl methyl ether: New dibromophenols from Rhodomela larix . Tetrahedron. 1967; 23: 1185–1188. DOI: 10.1016/0040‐4020(67)85068‐3 - 111.
Liu M, Hansen PE, Lin X. Bromophenols in Marine Algae and Their Bioactivities. Marine Drugs. 2011; 9: 1273–1292. DOI: 10.3390/md9071273 - 112.
Xu N, Fan X, Yan X, Li X, Niu R, Tseng CK. Antibacterial bromophenols from the marine red alga Rhodomela confervoides . Phytochemistry. 2003; 62: 1221–1224. DOI: 10.1016/S0031‐9422(03)00004‐9 - 113.
Mikami D, Kurihara H, Kim SM, Takahashi K. Red Algal Bromophenols as Glucose 6‐Phosphate Dehydrogenase Inhibitors. Marine Drugs. 2013; 11: 4050–4057. DOI: 10.3390/md11104050