Alkaloids in Marine Algae

This paper presents the alkaloids found in green, brown and red marine algae. Algal chemistry has interested many researchers in order to develop new drugs, as algae include compounds with functional groups which are characteristic from this particular source. Among these compounds, alkaloids present special interest because of their pharmacological activities. Alkaloid chemistry has been widely studied in terrestrial plants, but the number of studies in algae is insignificant. In this review, a detailed account of macro algae alkaloids with their structure and pharmacological activities is presented. The alkaloids found in marine algae may be divided into three groups: 1. Phenylethylamine alkaloids, 2. Indole and halogenated indole alkaloids, 3. Other alkaloids.


Introduction
The term alkaloid was first proposed by Meissner in 1819 to characterize these "alkali-like" compounds found in plants [1,2], but it was not precisely defined [3]. With time, the definition has changed [4] to: a compound that has nitrogen atom(s) in a cyclic ring. Numerous biological amines OPEN ACCESS and halogenated cyclic nitrogen-containing substances are included in the term alkaloid. The latter is specific from marine organisms and marine algae. They could not be found in terrestrial plants.
Some alkaloids isolated from marine algae correspond to contaminants, such as the indole derivative communesin isolated from a Penicillium sp. found on the green alga Enteromorpha intestinalis [5] and leptosins from Leptosphaeria on Sargassum tortillae [6]. These alkaloids were improperly attributed to algae and were not included in this paper.
After the isolation of alkaloids, pure active compounds were used in therapy instead of plant extracts. Isolation of active compounds from plants began in 18th century. Morphine was the first alkaloid extracted from a terrestrial plant in 1805 as reported by Kappelmayer [7] and hordenine was the first alkaloid isolated from a marine algae in 1969 [8,9]. Today approximately two thousand alkaloids are known. They occur abundantly in terrestrial plants and rarely in marine algae.
In this chapter alkaloids in marine algae were classified in three groups as follows: 1. Phenylethylamine alkaloids.

Phenylethylamine (PEA)
PEA (β/2-phenylethylamine, phenethylamine) is an aromatic amine made up of a benzene ring to which an ethylamine side chain is attached (Figure 1a). The PEA alkaloid group includes important alkaloids. It is a precursor of many natural and synthetic compounds. Several substituted PEAs are pharmacologically active compounds found in plants and animals. This group includes simple phenylamine (tyramine, hordenine) and catecholamine (dopamine). The latter was found in animals and terrestrial plants [10]. The structure of PEA allows substitutions on the aromatic ring, the α and β carbons and terminal amino group. The published papers concern amine compounds in marine algae [11,12], and in the plant kingdom including algae [13].
Pharmacological activity: PEA in the human brain acts as a neuromodulator and a neurotransmitter. PEA has been shown to relieve depression in 60% of depressed patients. It has been proposed that a PEA deficit may be the cause of a common form of depressive illness [16]. Substituted PEAs are pharmacologically active compounds as hormones, stimulants, hallucinogens, entactogenes, anorectics, bronchodilators and antidepressants [17]. Source: N-acetylphenylethylamine was first isolated from the red algae Phyllophora crispa and Gelidium crinale [18].
Pharmacological activity: N-ACPEA induced also rotations ipsilateral to the side of the brain lesion as PEA but its activity was 90% less active than β-PEA [16]. Figure 1c) TYR is a monoamine derivative of the amino acid tyrosine. Source: TYR occurs widely in plants, fungi and animal but is rare in algae. It was detected in the brown alga Laminaria saccharina, and red algae Chondrus crispus and Polysiphonia urceolata [19] and in the microalgae Scenedesmus acutus [14].

Tyramine (TYR, 4-hydroxyphenylethylamine;
Pharmacological activity: TYR is a pharmacologically important compound. It stimulates the central nervous system, causes vasoconstriction, increases heart rate and blood pressure and is also responsible for migraines. N-Acetyltyramine (N-ACTYR; Figure 1d) Acetyl derivative of tyramine Source: It was found in the marine algae Phyllophora crispa and Gelidium crinale [18] and is produced by many microorganisms [14] and terrestrial plants [20].
Pharmacological activity: N-ACTYR is a neuropeptide and an important amine for chemical and pharmacological purposes. The presence of urinary N-ACTYR in neuroblastoma patients was demonstrated [21].
Pharmacological activity: The roles of amine compounds in marine algae are not clear [28]. HORD is diuretic and affects the central nervous system. In the past, HORD was used for the treatment of diarrhea and dysentery [29]. It has a positive inotropic effect upon the heart, increases systolic and diastolic blood pressure, peripheral blood volume and inhibits gut movement [30]. All effects are short and only observable with high doses.

Dopamine (DOP, 3,4-dihydroxyphenethylamine; Figure 1f)
DOP is a catecholamine carrying two hydroxyl groups in the position 3 and 4 of the phenyl ring. It is produced in the organism by decarboxylation of dihydroxyphenylalanine.
Source: DOP was found in animals and several terrestrial plants [9] and only one reference mentions its presence in the green alga Monostroma fuscum [31].
Pharmacological activity: It is a hormone and a neurotransmitter. DOP is a sympathomimetic compound. It was used to treat cardiovascular and kidney disorders [32].
The content of CLP (I) in Caulerpa sp. are 15% for C. lentilifera, 5% for C. rasemosa, 2% for C.microphysa and 8% for C. sertulorides [51]. C. taxifolia has bloomed explosively in the Mediterranean Sea and has become a major ecological problem [52].
Pharmacological activity: There are different opinions on the toxicity of CLP (I). Symptoms were observed after the ingestion of Caulerpa genus [33]. It shows low toxicity [43]. C. racemosa extracts showed some cytotoxicity, but CLP (I) isolated from these extracts did not show any activity [53]. CLP (I) exhibited a moderate in-vitro antitumor activity against crown gall tumor [54]. CLP (I) showed moderate antibacterial activity against 8 species of bacteria isolated from algal surface [51]. CLP (I) containing alga Laurencia majuscula showed antifungal activity [55]. CLP (I) has been shown to be a plant growth regulator [55][56][57]. CLP (I) showed no peroxidase activity [58].

Fragilamide (FRG)
FRG was extracted from the red alga Martensia fragilis. It is a labile amine and it rapidly autooxidized in solution. FRG is a 3-substituted indole and corresponds to a N-methylhomoisoleucyl unit and a p-hydroxybenzyl group connected to the indole unit C-3. The amide NH was connected to a cis disubstituted carbon-carbon double bond [64] (Figure 4).

Almazolone (ALM)
ALM was isolated from the red alga Haraldiophyllum sp. collected in Dakar (Senegal). ALM is a disubstituted oxazolindole derivate. It has two steroisomers, which correspond to synthesized E and Z isomers [69] (Figure 8).

Halogenated Indole Alkaloids (HLI)
HLI alkaloids were isolated only in marine organisms and algae but not in terrestrial plants. Many HLI alkaloids were isolated from red algae and only one from a green alga. These alkaloids contain an indole group substituted by bromine and chlorine atoms. Sulfur-containing bromoalkaloids were also extracted from red algae.
Pharmacological activity: Antibacterial activities of halogenated alkaloids were examined on terrestrial and some marine bacteria.

Polyhalogenated indoles
Many polyhalogenated indoles were identified in Rhodophyllis membranacea collected from the Kaikoura coast (New Zealand). The fractions obtained from the extract of R. membranacea contain polychlorinated and polybrominated alkaloids [75] (Figure 12).

Conclusions
Marine algal alkaloids have been reviewed in this paper. Structurally the alkaloids isolated from marine algae mostly belong to the phenylethylamine and indole groups. Biological activities of these alkaloids were not wholly investigated. Alkaloids of marine algae are relatively rare, when compared with terrestrial plant alkaloids. Research on marine drugs has largely focused on finding drugs for cancer treatment. Nowadays, no alkaloids obtained from marine algae are used in medicine.