Antimicrobial cytotoxic alkaloids

Tetracyclic /3-carboline alkaloids, known as canthines, have a peri-fused indolo[3,2,Tnaphthyridine structure. Over 40 members of this class of compound have been isolated, and they are of interest on account of their broad range of pharmacological effects (antimicrobial, cytotoxic, antibacterial, anticancer). 

The export of benzophenanthridines into the apoplast appears advantageous as the high antimicrobial potency of these root-made alkaloids protects the plant from pathogenic soil microbes. At the same time, the cytotoxic alkaloids are separated from the cellular interior thus avoiding self-intoxication by DNA intercalation or enzyme inhibition (see below). Nevertheless, the excreted alkaloids do not escape the control of the producing cell. Cultured cells of Eschscholzia rapidly take up external benzophenanthridines, preferentially sanguinarine. 

The isolation and characterization of piclavines Al—A4 (2499—2502) (Figure 51), cytotoxic and antimicrobial indolizidine alkaloids obtained from the Bermudan ascidian Clavelina picta, were described in the previous review in this series. The only synthesis of a piclavine to have been reported at that stage, that of piclavine A4 (2502), was by Jefford and coworkers.Subsequent publications have dealt with the synthesis of aU four alkaloids. 

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The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

The sulfur-containing (3-carboline alkaloid, 1-ethyl-4-methyl-sulfone-P-carboline (2) was isolated from the New Zealand bryozoan Cribricellina cribraria, along with several other (3-carboline alkaloids. l-Ethyl-4-methyl-sulfone-P-carboline (2) exhibited only modest antimicrobial activity, especially compared to some of the other alkaloids isolated, which were both cytotoxic and antimicrobial [27]. 

Fused tetracyclic and pentacyclic alkaloids constitute a relatively new class of natural products isolated mostly from ascidians and sponges. Cytotoxic, antimicrobial and antiviral activities have been reported for many of these compounds. The manzamine alkaloids, Fig. (33) are characterized by a complex pentacyclic diamine linked to C-l of P-carboline moiety. Manzamine have been isolated mainly from six different genera of marine sponges Haliclona, Pellina, Xestospongia, Ircinia, Pachypellin and Amphimedon. 

Thompson et al. have investigated the ecological role of the brominated isoxazoline alkaloids, aerothionin (Structure 2.84) and homoaerothionin (Structure 2.89), in Californian specimens of A. fistularis.134 139 The alkaloids caused behavioral modification in marine invertebrates, were toxic to dorid nudibranchs other than one specialized feeder, inhibited the settlement and/or metamorphosis of invertebrate larvae, and were strongly antimicrobial and cytotoxic. Sponges exuded significantly more of these two alkaloids when wounded,155 and, consistent with their defensive role, the metabolites were found to be localized in spherulous cells close to the aquiferous exhalant canals.156... 

Secondary metabolites with similar structural types and pharmacophoric groups can be seen in several bacteria (where they are often termed antibiotics if they have antimicrobial or cytotoxic properties). Since eukaryotic cells had taken up a-proteobacteria (which became mitochondria) and cyanobacteria (which became chloroplasts), they also inherited a number of genes that encode enzymes for pathways leading to secondary metabolites. Therefore, we may speculate that early plants already had the capacity of building defense compounds and that alkaloids were among the first. Since the numbers and types of herbivores and other enemies have increased within the last 100 million years, angiosperms have had to face more enemies and as a consequence have developed a more complex pattern of defense and signal compounds. 

Carbazole alkaloids have drawn considerable attention from synthetic chemists due to their significant biological activities, including antimicrobial, antiviral, and cytotoxic properties.Two simple carbazole alkaloids, glycozolinine and glycozolidine (107) were... 

Indo-Pacific sponges of the genus Fascaplysinopsis produce a series of bis-indole alkaloids known as the fascaplysins (51) and reticulatines (52), some of which are p-carbolinium ion alkaloid salts of terpene carboxylates. Fascaplysin (44), which was reported by Ireland and coworkers, at the University of Utah, from a Fijian collection of Fascaplysinopsis sp., is a fused pentacyclic pigment exhibiting antimicrobial and cytotoxic properties. Crews... 

Many of the P-carboline and isoquinoline alkaloids described here display potent, and often selective, cytotoxicity (Table 1, 2) or exhibit antimicrobial activity (Table 3). Specific activity in enzyme-based assays and other activity is described below. 

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