Quinolizidine alkaloids activity

Kinghom, A.D. and Balandrin, M.F. (1984). Quinolizidine alkaloids of the Leguminosae Structural types, analysis, chemotaxonomy and biological activities, in Pelletier, S.W., Ed., Alkaloids chemical and biological perspectives, John Wiley and Sons, New York, pp. 105-148. 

Lopez et al. reported the isolation of three quinolizidine alkaloids such as lupanine (30), 13-a-hydroxylupanine (31), and 17-oxo-lupanine (32) from Lupinus perennis Wild, (family Fabaceae) all these three isolates were found to have potent activity in enhancing glucose-induced insulin release from isolated rat islet cells in a glucose concentration-dependent manner. While the synthetic compound 2-thionosparteine... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

Tetracyclic quinolizidine alkaloids can be divided into two types, both according to chemical structure and, especially, biological activity. These are tetracychc alkaloids, which contain a quinohzidine nucleus, and others with a pyridone nucleus. Here, the first type of alkaloids (with a quinohzidine nucleus) will be discussed. The second type will be considered in the next sub-chapter as pyridone alkaloids. 

Nitraramine and A-hydroxynitraramine were isolated from Nitraria schoberi (194,195). There are active hydrogen absorption bands in the IR spectrum of nitraramine at 3280 and 3530 cm- and a low intensity band at 1660 cm" (double bond). Acetylation of nitraramine (171) gave A-acetyl and A,0-diacetyl derivatives. Hydrogenation over Adams catalyst in acetic acid gave di-hydronitraramine (172) and dihydrodesoxynitraramine (173) (Scheme 30). The presence of peaks typical for quinolizidine alkaloids in the mass spectra of 171-... 

The enzyme, i.e. lysine decarboxylase, that is required for the conversion of lysine into cadaverine, and thus the first step of alkaloid biosynthesis, has been isolated from chloroplasts of L. polyphyllus,28 Like the majority of amino-acid decarboxylases, this enzyme is dependent on pyridoxal 5 phosphate. Its activity was found not to be affected by the presence or absence of quinolizidine alkaloids. Control of the enzyme by simple product feedback inhibition therefore seems unlikely. The operational parameters of this enzyme resemble those of the 17-oxosparteine synthase. Co-operation between the two enzymes would explain why cadaverine is almost undetectable in vivo. 

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. 

Genista tinctoria (dyer s broom) contains 0.3-0.8% of toxic quinolizidine alkaloids, such as anagyrin, cjhisine, and iV-methylcytisine. The last two constituents have peripheral effects similar to those of nicotine, whereas their central activity may be different. Anagjrine is a suspected animal teratogen and cytisine has teratogenic activity in rabbits. 

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. 

In a similar manner, the 2-cyano-6-oxazolopiperidine synthon is useful for the chiral synthesis of in-dolizidine (monomerine piperidine [(+)- and (-)-coniine and dihydropinidine] and quinolizidine alkaloids.2-Hydroxymethyl-1-amino-1-cyclopropanecarboxylic acid (-)-(2I )-hydroxy-(3S)-nonylamine and a-substituted phenylethylamines are obtained in optically active form from (-)-N-cyanomethyl-4-phenyloxazolidine. 

Two novel alkaloids named manadomanzamines A and B were isolated from the Indonesian sponge Acanthostrongylophom spp. [58]. The compounds exhibited activities against HIV-1 and AIDS-opportunistic fungal infections. Oral and intravenous pharmacokinetic studies indicated that the compounds have low metabolic clearance, a reasonably long pharmacokinetic half-life, which supports the value of these compounds as potential leads for further preclinical assessment and possible development [59]. Another marine sponge, Petrosia similis, afforded two compormds belonging to bis-quinolizidine alkaloids, namely petrosin and petrosin A [60]. Cell assays indicated that these compounds inhibited the early steps of HIV replication. In the extracellular HIV-1 RT inhibition assay, the compounds inhibited HIV-1 RT. 

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. 

This chapter is organized in much the same manner as its predecessor, with some subsections expanded whenever warranted. Unless otherwise noted, the structural formulas of optically active compounds in this chapter represent their absolute configurations, and the numbering system employed for the benzo[n]quinolizidine alkaloids is identical with that used previously 1,12). 

Quinolizidine alkaloids, such as sparteine, lupanine and cytisine are relatively weak inhibitors at this target (they strongly affect ACh receptors and Na+ channels see Tables 3-15). The stages which are inhibited are the loading of aminoacyl-tRNA with amino acids and the elongation step. The inhibitory activity was visible in heterologous systems, but protein biosynthesis in the producing plants (here lupins) was not affected [23]. 

Quinolizidine Alkaloids.—Previous results demonstrate that the quinolizidine skeleton in its entirety derives from lysine.Further research has indicated that lysine is a precursor of all the alkaloids of this type in five species of Leguminosae. From the levels of activity observed in the individual alkaloids it was concluded that saturated alkaloids are precursors for those with a pyridone ring. This was supported by the observation that label from radioactive sparteine (24) and lupanine (25) appeared in more highly oxidized alkaloids. (This compares with a similar situation in the biosynthesis of matrine-type alkaloids. ) A metabolic grid for the biosynthesis of quinolizidine alkaloids from lysine was proposed, based on these results,... 

The anthelmintic activity of the quinolizidine alkaloids has been reviewed [394]. It is well recognised that quinolizidine alkaloids deter or repel insects and non-insect herbivores [394], These compounds can interfere with protein biosynthesis and some bind to acetylcholine receptors with high affinity. (-)-N-methylcytisine (233) and (-)-anagyrine (234) were isolated from the roots of Sophora flavescens, a plant used in traditional Chinese medicine as an anthelmintic. N-methyl cytisine was twice as active as anagyrine but only half as active as (-)cytisine and nicotine [395,396] The alkaloids (3-6 pg) inhibited reproduction of B. xylophilus in the cotton balls assay. 

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