Punica Alkaloids

The simple piperidine alkaloids, pelletierine, isopelletierine, A/-methylpelletierine, and pseudopelletierine, were isolated (106, 108) from the root bark of Punica granatum (Punicaceae), which had been used as an anthelmintic. Later, it was found that (-)-pelletierine possessed the i -configuration, and isopelletierine was racemic pelletierine (12, 51). 

Biogenetically, pelletierine is derived from lysine via piperidine and a C3 unit (acetate), and pseudopelletierine is formed by oxidative cyclization of A -methyl-pelletierine (Fig. 5.2.4). 

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Piperidine alkaloids a group of alkaloids containing the piperidine ring system. Simple P.a. are the alkyl substituted piperidines which occur sporadically. The other P.a. are classified according to their origin, e.g. Coninm alkaloids (see), Punica alkaloids (see), Sedum alkaloids (see) and Lobelia alkaloids (see). These various groups are structurally different and have different mechanisms of biosynthesis. Other P. a. are found in water lilies, and are biosynthesized from mevalonic acid (see Nuphara alkaloids). A de-hydropiperidine structure is present in the Areca alkaloids (see) and the Betalains (see). 

Pseudopelletierine, 9-pelletiariiu, pseadt mii-ctne, 9-methyl- -gnmaUaume 9-methyl-9-azabicy-clo-[3,3,l] nonan-3-one, the most important representative of the Punica alkaloids, present in the root bark of Punica granalum. M, 153.21, m.p. 54 C, Kp. 246 °C Its structure is based on the meso form of granatane (9-azabicyclo [33,1] nonane). For biosynthesis, see Punica alkaloid... 

Punica alkaloids a group of piperidine alkaloids, originally isolated from the bark of the pomegranate tree (Punica granatum L., official drug Cortex grana-ti), and subsequently isolated from other plant families. Decoctions of the drug, or the isolated alkaloids. 

Occurrence of Punica Alkaloids Punica granatum L. (Pomegranate)... 

In the six-membered series the alkaloids of Punica gr ana turn, isopelletier-ine and methylisopelletierine, have been obtained by treatment of enamines with acetoacetic acid. Isopelletierine (194, R = H) was prepared also by Schopf et al. from d -piperideine (309-311). The reversibility of aldol dimerization (124,131) of enamines has been established by the synthesis of methylisopelletierine (194, R = Me) from dimethyltetrahydroanabasine, accomplished by Lukes and Kovaf (101) (Scheme 19). 

Pseudopelletierine has been obtained from the bark of the pomegranate tree (Punica granatum L.).2-5 The synthesis of the alkaloid from glutaraldehyde, methylamine, and calcium acetonedicarboxylate was first achieved by Menzies and Robinson.6 The synthetic method subsequently was improved by Schopf and Lehmann,7 and others.8 9 The condensation of a dialdehyde with an amine and acetonedicar-boxylic acid to form a heterobicyclic compound (an alkaloid or alkaloid analog, usually employing mild or so-called physiological conditions) is sometimes referred to as a Robinson-Schopf synthesis. 

In addition to lupines, poison-hemlock and Nicotiana spp., other plant species of the genera Genista, Prosopis, Lobelia, Cytisus, Sophora, Pinus, Punica, Duboisia, Sedum, Withania, Carica, Hydrangea, Dichroa, Cassia, Ammondendron, Liparia, and Colidium contain potentially toxic and teratogenic piperidine alkaloids. Many plant species or varieties from these genera may be included in animal and human diets (Keeler and Crowe, 1984). 

L-lysine derived alkaloids Punicaceae Punica granatum Pelletierine Pseudopelletierine Methylpelletierine Anaferine... 

Alkaloids with the piperidine nucleus, such as pelletierine (Punica grana-tum), lobelanine Lobelia inflata) and piperine Piper nigrum), have a typical biosynthesis pathway. It starts with L-lysine and continues via cadaverine (biogenic amine), A -piperideine and A -piperidinium cations and lobelanine, to be synthesized as lobeline. Piperine is synthesized from A -piperideine via piperidine (Figure 49). For the transformation from A -piperideine to A -piperideine cation, the residue from acetyl-CoA is needed, together with SAM activity in the transformation to lobelanine. Piperine is synthesized from piperidine through the formation of amide. 

The alkaloids Af-methylpelletierine (90) and pseudopelletierine (91) of Punica granatum and also anaferine (92) of Withania somnifera are probably related in biosynthesis to sedamine and anabasine. The proposed biosynthesis (Scheme 17) has received support from recent tracer studies.57... 

Galinovsky and his co-workers have re-examined the alkaloids of the bark of Punica granatum L. In a sample, labeled pelletierine hydrobromide, that they obtained from Merck (Darmstadt), the only secondary base present was not j3-(2-pelletierine) but isopelletierine identical with a synthetic sample (12). They further found that methylisopelletierine and isopelletierine retain their optical activity in the presence of acid, but racemize in contact with alkali, and the former racemizes appreciably faster than the latter. If the bases were optically active in the plant they would racemize during the process of extraction and isolation unless the work is done rapidly (13). 

The bark of the pomegranate tree (Punica granatum L.) was first investigated by C. Tanret who isolated from it four alkaloids which he named pelletierine (204), isopelletierine, methylpelletierine, and pseudo-pelletierine (205, 206). Methylpelletierine and pelletierine were observed to be optically active while isopelletierine and pseudopelletierine were inactive. Later, Piccinini (207) found a fifth alkaloid, isomethylpelletierine in the mother liquors obtained from the preparation of pseudopelletierine. Eventually, however, Hess (208) while reinvestigating the bark obtained pseudopelletierine, Piccinini s isomethylpelletierine and a third, optically inactive base, but found no trace of Tanret s optically active methylpelletierine. He could not find any optically active alkaloids and, considering his third base identical with Tanret s isopelletierine (185) renamed the latter base pelletierine. Further, Hess and Eichel (209) considered Tanret s methylpelletierine and Piccinini s isomethylpelletierine as identical but different from methylated pelletierine and named it methyliso-pelletierine (185). 

Einbau in das Sedamin (XLIV) asymmetrisch (727) erfolgt. Die Basen aus Punica granatum (z.B. Methylisopelletierin XLV) entstehen aus Precursoren der Lysinfamilie (193) auch fur die Ormosia- und Lythraceen-Alkaloide wird ein ahnlicher Bildungsweg angenommen (92,349). 

The biosynthesis, occurrence, and biological activities of piperidine alkaloids arising from lysine have been studied Punica granatum. Piper species, and Lobelia inflata). The isolation process, chromatographic purification/analysis, and structure elucidation of the significant alkaloids are discussed. 

While for developing of simple piperidine alkaloids, e.g., pelletierine (Punica granatum), piperine (Piper nigrum et longum), and lobeline (Lobelia inflata), only one molecule of lysine is necessary, for quinolizidine alkaloids - e.g., lupinine (Lupinus luteus), sparteine of antiarrhythmic activity (Sarothamnus scoparius), and cytisine of respiratory stimulant effect (Laburnum species) - two molecules of lysines are indispensable. It was also proved that lycopodine (Lycopodium tristachyum, clubmoss) of quinolizidine structure has no polyketide origin, but it is a modified dimer of pelletierine, which, in turn, is derivable from lysine and acetate. 

In this chapter, we intensively studied the Punica, Piper, and Lobelia piperidine alkaloids. These plants and their main alkaloids are undoubtedly known and used in therapy for ages, but at present, numerous scientific results were also bom on their biological activities and pharmacological and clinical tests further, new alkaloids were isolated and semisynthetic analogues prepared, which could be important in the modem phytotherapy. 

In 1963, Beyerman and Maat [6] already described the synthesis and absolute configuration of Tanret s (-)-pelletierine. The synthesis is described of (-)-pelletierine picrate as identical with Tanret s pelletierine picrate from Punica granatum L. and its antipode by oxidation, respectively, of (-)- and of (+)-sedridine. The sedridines are alkaloids with known absolute configuration of the piperidine asymmetric carbon atom. From this follows the Ds-configuration of (-)-pelletierine. 

The root bark was already recommended in the Ebers Pap3Tus and later in more Pharmacopoeias (e.g., pelletierine tannate in BP 1948) to treat worm infestations and was used as an anthelmintic, primarily against tapeworm, until the first half of the twentieth century. The greatest anthelmintic activity of Punica extracts was chiefly due to isopelletierine [8]. Our daily harmful effects due to the fraction absorbed in the intestine have led to full abandonment of the drug and also its alkaloids [7]. 

In Punica granatum beside the long since known compounds as peUetierine, A -methylpelletierine, anaferine, and pseudopeUetierine, other alkaloids - sedridine, norpseudopelletierine, hydroxypropyl - and propenyl-A -piperideine were also detected further, the absolute configuration of (-)- and (+)-sedridine and (-)-pelletierine were determined. 

The greatest anthelmintic activity of Punica extracts was chiefly due to isopelletierine but the harmful side-effects led to full abandon of the drug (root bark) and its alkaloids. 

Neuhofer H, Witte L, Gorunovic M, Cygan FC (1993) Alkaloids in the bark of Punica granatum L. (Pomegranate) from Yugoslavia. Pharmazie 48(5) 389-391... 

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