Marine Indole Alkaloids

Marine indole alkaloids comprise a large and steadily growing group of secondary metabolites. Their diverse biological activities make many compounds of this class attractive starting points for pharmaceutical development. Several marine-derived indoles were found to possess cytotoxic, antineoplastic, antibacterial and antimicrobial activities, in addition to the action on human enzymes and receptors. The newly isolated indole alkaloids of marine origin since the last comprehensive review in 2003 are reported, and biological aspects will be discussed.


Introduction
Alkaloids represent a large and highly structurally diverse group of secondary metabolites. The presence of nitrogen in their molecular architecture confers biological activity to an exceptionally large fraction of this compound class. Therefore, it comes as no surprise that mammals-including man-have acquired the ability to detect the potentially toxic alkaloids by their bitter taste.
As the origin of life on Earth presumably was the early hydrosphere, the evolution of aquatic life forms has the longest history and a connection may be seen in the enormous chemical complexity of natural marine products.
This review focuses on marine indole alkaloids, discovered since the last comprehensive report by Aygün and Pindur in 2003 [1]. In addition to structures and occurrence, known biological activities of OPEN ACCESS marine indole alkaloids will be discussed. We will make use of Pelletier's general definition of 1983, according to which alkaloids are "cyclic organic compounds containing nitrogen in a negative oxidation state which are of limited distribution among living organisms" [2]. As an additional demarcation against the world of peptides, polypeptidic structures and macrocyclic peptides derived from tryptophan, such as terpeptins [3] and related structures [4], milnamides [5,6], diazonamides [7], lucentamycin B [8], pipestelides [9], kahalalides [10][11][12], jaspamides [13], jasplakinolides [14], etc., will not be discussed here. Indole alkaloids which were isolated from genetically engineered marine derived organisms, from organisms with an artificially altered gene regulation, or which were obtained through genetic engineering of terrestrial organisms using genes of marine organisms will not be discussed in this review [15][16][17][18][19][20][21].
The indole nucleus is one of the most important ring systems for pharmaceutical development and has been termed a "privileged structure" in this respect [22]. It is frequently associated with the action on G-protein coupled receptors, in particular with the modulation of neuronal signal transmission through receptors for serotonin (5-hydroxytryptamine, 5-HT). A large variety of effects on other molecular targets have also been reported, including glycine-gated chloride channel receptors, human protein tyrosine phosphatase-1B, the CXCR4 (C-X-C chemokine receptor type 4) chemokine receptor, Na + /K + -ATPase, nitric oxide synthase, β-secretase, protein kinase C-α, butyrylcholinesterase, and acetylcholinesterase. Furthermore, cytotoxic, antineoplastic, antibacterial, antifungal, antiinsecticidal, and antiplasmodial activities have been detected.
Apart from its capacity to act as a hydrogen bond donor through a free NH function, the high π-electron density and the high HOMO (highest occupied molecular orbital) energy of the planar indole skeleton permit interactions with nucleobases-in particular protonated ones-as well as target proteins, some of which exhibit a high binding specificity for the indole nucleus. The electronic properties together with the relatively low resonance energy of the five-membered ring also determine the chemical behavior of indoles and many of their derivatives. Thus, electrophilic substitutions or oxidative transformations, partly under loss of the aromatic stabilization, are paramount for this compound class, which is also reflected by the structures of many of the compounds discussed in this review.
Regarding related work, an overview of the biosynthesis of indole alkaloids from fungal origin has been published by Xu et al. [23]. Alkaloids from marine algae are discussed by Güven et al. [24] and halogenated indole alkaloids from marine invertebrates have been reviewed by Pauletti et al. [25].

Simple Indole Alkaloids
The simple indole alkaloids are mostly derived from tryptophan or its direct precursor indole, which itself is formed from chorismate through anthranilate and indole-3-glycerol-phosphate in microorganisms and plants. As the ultimate step of the tryptophan biosynthesis is reversible, free indole can also be formed in this catabolic process [26]. Electrophilic substitutions with iodine and especially bromine are frequently encountered in this and other subclasses presented here while the even more common prenylated indoles, with and without halogen substituents, will be discussed in a separate section.
The ascidian Herdmania momus was also a source of nucleosides (132)(133)(134)(135), compound 132 was given the trivial name momusine A ( Figure 31). None of the compounds exhibited antiviral activity against a series of human pathogenic viruses [86].   Didemnidines A (136) and B (137), two indole spermidine alkaloids, were isolated from the New Zealand ascidian Didemnum sp. (Figure 32). Both were found to be inactive as phospholipase A2 and farnesyltransferase enzyme inhibitors and not cytotoxic, but didemnidine B (137) showed mild antiparasitic activity against the malaria parasite Plasmodium falciparum [87].  (138) was isolated from a deep-sea sediment metagenomic clone-derived Escherichia coli fermentation broth and found to have analgetic activity ( Figure 33) [88]. It has a remarkable structural resemblance to the antibiotic chloramphenicol.  Tanjungides A (140) (Z isomer) and B (141) (E isomer), two dibrominated indole enamides, have been isolated from the tunicate Diazona cf. Formosa and were found to have significant cytotoxicity against human tumor cell lines ( Figure 35). In the same publication, the first total synthesis of these compounds is reported employing methyl 1H-indole-3-carboxylate as starting material [90].   Almazolone (145) was isolated from the red alga Haraldiophyllum sp., collected in Dakar (Senegal) as an 88:12 mixture of (Z)/(E) stereoisomers ( Figure 38). Photoisomerization of the (Z) into the (E)-isomer, as well as slow thermal reisomerization of the (E)-isomer, was observed [93].    5-Hydroxyindole alkaloids 5-hydroxyindole-3-glyoxylate methyl ester (150) and (151), together with the bisindole scalaridine A (505, see Figure 83), were isolated from the marine sponge Scalarispongia sp. collected near Dokdo island ( Figure 42). Since 151 was the monoindole analog of hyrtinadine A (496, see Figure 80), it was named hyrtinadine B [97]. Hainanerectamines A-C (152, 153 and X) have been isolated from the Hainan marine sponge Hyrtios erectus, hainanerectamine C (800) belonging to the group of β-carboline alkaloids (see Figure 147). Hainanerectamines B (153) and C (800) display moderate inhibitory effects on the serine/threonine kinase Aurora A (IC50 24.5 and 18.6 μg/mL), which is involved in cell division regulation, but none of the compounds had cytotoxic effects on the tumor cell lines A549 and HT-29 [98].

Prenylated Indoles
Prenylated indole alkaloids represent a large subgroup of the indole alkaloids and provide various potent biological activities. Their wide distribution in terrestrial and marine organisms nicely reflects the high nucleophilicity of the indole core which is an adequate match for the electrophilic reactivity of prenyl-type electrophiles generated from the corresponding pyrophosphates [99]. Biosynthetically, tryptophan is the indole source in most cases [100].

Bis-and Trisindoles
Bis-and trisindole alkaloids are biosynthetically derived from two or three indole building blocks. They show diverse biological activities, as antiviral, antitumor, antibacterial and anti-inflammatory activities and are therefore promising chemical leads for drug development [212,213].

Conclusions
In the twelve year period since the last review on marine indole alkaloids, the numbers of known compounds of this class has increased dramatically. Intense research, mainly driven by teams from the Asian pacific region, has provided the scientific community with new representatives of formerly known structural families but also provided entirely new chemotypes. This gain of structural knowledge is likely to trigger activities in the areas of synthetic organic chemistry, pharmacology and medicinal chemistry as the indole skeleton is the basis of many important drugs and experimental compounds in the biomedical field.