## 3 Stigonematales as a Source of Bioactive Metabolites  
Although metabolites typically classified as \"cyanotoxins\" are not generally linked to this family, there have notably been documented instances of members of the order producing known toxins. For example, a freshwater isolate of _Fischerella_ was found [11] to produce the widely distributed hepatotoxin, microcystin-LR (MC-LR). Similarly, MC-LA was identified from a collection of a terrestrial species of _Hapalosiphon_[12]. And more recently, _Fischerella_ isolated from a freshwater system in Australia was found [13] to produce several microcystin variants (_i.e._, MC-LR, MC-LA, MC-LF, MC-FR and demethyl-MC-LR). In addition, the neurotoxic amino acid, \(\beta\)-methylamino-L-alanine (BMAA), was recently identified from an epiphytic stigonematalean species [14]. It was also previously found that a freshwater isolate of the species, _Umezakia natans_, apparently produced the hepatotoxic alkaloid, cylindrospermopsin; however, subsequent taxonomic analysis confirmed that this species belongs, in fact, to the Nostocales rather than the Stigonematales [15]. That said, a wide range of bioactive compounds with both potential environmental (_i.e._, ecological, environmental toxicology) and biomedical significance have been isolated and characterized from the Stigonematales (Figure 2). Interestingly, multiple polychlorinated aromatic compounds, specifically including the polyphenols ambigol A, B and C, 2,4-dichlorobenzoic acid and a carbazole alkaloid, tjipanazole D (Figure 2), have been isolated from the order; and, in turn, associated with diverse biological activity including antibacterial, anti-parasitic (_i.e._, _Plasmodium_, _Trypanosoma_), molluscicidal and cytotoxic activity, as well as inhibition of cyclooxygenase (an enzyme responsible for inflammatory responses) and HIV-1 reverse transcriptase [16; 17]. The diversity of chlorinated compounds, in particular, is perhaps notable in light of the very recent identification of a halogenase from the order (see Section 5, Biosynthesis of Indole Alkaloids from the Stigonematales) which is uniquely capable of chlorinating \"freestanding\" substrates [18]. More recently, studies of the capsular polysaccharides from the species, _Mastigoladus laminosus_, identified apparent cytotoxicity, as well as inhibition of cell migration and invasion, in a human carcinoma cell line, and specifically pointed to a role of secreted metalloproteinases in this regard; however, chemical characterization of the polysaccharides remains to be accomplished [19]. Not surprisingly, given the recognized diversity of non-ribosomal peptides from cyanobacteria, several bioactive peptides have been, likewise, identified from the Stigonematales, including several depsipeptides and bistratamides [20; 21; 22; 23]. With respect to depsipeptides, haplosin (Figure 2) was isolated from _Hapalosiphon welwitschii_, and specifically shown to inhibit P-glycoprotein-mediated multidrug resistance (MDR) activity more effectively, in fact, than clinically utilized verapamil [21]. And, more recently, stigonemappeptin (Figure 2), specifically containing the unusual amino acid, Ahp, _i.e._, (3-amino-6-hydroxy-2-piperidone), was isolated from freshwater field samples of the genus, _Stigonema_, and found to act as a protease (_i.e._, elastase, chymotrypsin) inhibitor [22]. \"Bistratatamide-type\" peptides (Figure 2) have also been isolated from order. Members of this unusual class of macrocyclic peptides containing thiazole and oxazole rings, and named for the bistratamides originally isolated from a marine worm _Lissoclinum bistratum_[24], have been isolated, in fact, from other cyanobacterial taxa (e.g., nostocyclamide from _Nostoc_ spp. [25; 26]).