Indolizidine alkaloids biological activity

The pyrrolizidines and indolizidines are a group of alkaloids that are characterized by the presence of the basic azabicyclo[3.3.0]octane and azabicyclo[4.3.0]nonane frameworks, respectively. These alkaloids exhibit remarkably diverse types of biological activity and have been reported to act as antitumor, hypotensive, anti-inflammatory, carcinogenic, or hepatoxic agents. Various pyrrolizidines and indolizidines have been prepared by 1,3-dipolar cycloaddition.115 Synthesis of these is described in the section 8.2 discussing cycloaddition. 

The preparation of alkaloids (cyclic compounds containing nitrogen atoms) is very important, as most alkaloids are biologically active. Eq. 3.10 shows the preparation of alkaloids (27), a precursor of gephyrotoxin, via an a-amino radical formed from y-thiophenoxylactam (26). Other alkaloids such as indolizidine and pyrrolizidine can be also prepared similarly via a-amino radicals and a-acylamino radicals. 

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

There have been no studies on the biological activity of the above quinolizidine alkaloids. It is expected that they, like the 5,8-disubstituted indolizidines and other lipophilic dendrobatid alkaloids, will be noncompetitive blockers of nicotinic receptor-channels. 

There have been numerous papers related to the total synthesis of bicyclic alkaloids, such as pyrrolizidines, indolizidines, and quinolizidines, because of their interesting biological activities (e.g., anticancer activity). 

During 1993, Daly and co-workers reviewed the alkaloids found in amphibians [5] and Takahata et al. focused on structural assignments and the synthesis of amphibian and polyhydroxylated indolizidines [6]. Wink reviewed the characterisation, natural distribution and biological activity of lupine alkaloids [7] and systematic updates on indolizidine and quinolizidine alkaloids are annually summarized by Michael [8-14]. 

This review describes structural diversity, structural identification and biological activity of simple indolizidine and quinolizidine alkaloids, and covers the period from 1994 to 1999. A review of stereoselective methods for the synthesis of indolizidines and quinolizidines will be pubUshed in this series in the near future. 

Advances in research are performed on the genus Astragalus and about 100 different species have been chemically studied imtill now [249]. The genus appears highly uniform from a chemical point of view, with three kinds of biologically active principles and three diffent groups of toxic compounds. The active constituents are saponins, flavonoids, and polysaccharides, while nitro-compoimds, indolizidine alkaloids and the seleniferous derivatives are included in the poisonous groups. 

Phthalides are valuable synthons for obtaining several biologically active compounds and natural products. Naphthols, anthraquinones and anthraquinone antibiotics, isoquinolones, phthalide isoquinolines, indolizidine and quinolizidine alkaloids, and berbine alkaloids have been synthesised with phthalides as the starting compounds. Some of the syntheses, which have interesting chemistry, are described below. The required phthalides, in some cases, have been synthesised through aromatic lithiation reactions, while in others by more conventional methods. 

The isolation, structural elucidation, and biological activity of the extraordinary metabolite indolizomycin (63) were described in the earlier review on simple indolizidine and quinolizidine alkaloids in Volume 28 of this series (7). The compound was obtained from a mutant Streptomyces strain bioengineered by protoplast fusion of two strains that do not normally produce antibiotics 54). It was reported to be exceedingly unstable, undergoing decomposition within a few hours under neutral conditions at room temperature. 

Secophenanthroindolizidine alkaloids and their secophenanthroquinolizidine analogs were last surveyed in Volume 28 of this series (i). A comprehensive review on the occurrence, structural elucidation, biosynthesis, synthesis, and biological activity of the phenanthroindolizidine alkaloids, including their seco variants, was published in 1987 (57P). The topic was also included in several more general reviews on indolizidine alkaloid chemistry 14,19,563). 

Polyhydroxylated indolizidine alkaloids, due to their biological activity, have attracted considerable synthetic interest. The total synthesis of ( —)-l-qp/-swainsonine (250) from the chiral imine 238 (Scheme 58) and the parallel synthesis of (+ )-2,8,8a-tri-qp/-swainsonine (252) from the enantiomeric threose A-benzylimine 251, prepared from natural L-tartaric acid, provide further examples of the utility of tartaric acid in meeting the challenge of complex syntheses. A stereospecific 4 + 4 homologation utilizing 2-(trimethylsiloxy)furan (178) pro-... 

Wang X, Tsuneki H, Urata N, Tezuka Y, Wada T, Sasaoka T, et al. Synthesis and biological activities of the 3,5-disubstimted indolizidine poison frog alkaloid 239Q and its congeners. Ew J Org Chem 2012 36 7082-92. 

Because they exhibit various fascinating biological activities [1], polyhydroxylated alkaloids that mimic sugar structure arouse a growing interest in the last few years. Naturally occurring iminosugars are classified in five structural families polyhydroxylated pyrrolidines, piperidines, indolizidines, nor-tropanes, and pyrrolizidines (fused pyrrolidines with N at the bridgehead) alkaloids [2]. The pyrrolizidine skeleton with a hydroxyl substituent at C-3 is relatively rare in Nature and appears to be restricted to specific families, while piperidine and pyrrolidine skeleton are conunon in many species. 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Biological Activity of Indolizidine Alkaloids Indolizidine Alkaloids in Insects Elaeocarpaceae Alkaloids... 

A number of alkaloids are derived from perhydroindolizine (indolizidine). Among them, swainsonine (40, (lS)-8afS-octahydro-la,2p,8P-indolizine triol) shows remarkable biological activity as an inhibitor of some types of cancer and a promoter of the organism-specific cancer defence. Several syntheses of swainsonine are reported [227]. 

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