Piper amides

Vanillyl piper-amide (6)-Gingerol Synthetic Ginger 15 0.8... 

Plants of the genus Piper, in particular P. nigrum, have been valued from antiquity to the present day for their organoleptic and medicinal properties. Indeed, black pepper, from the dried fruit of the latter species, remains the most widely consumed and important spice in the modern world [1,2] and is still used in traditional medicine [3]. In recent years, attention has also focused on the insecticidal properties of some Piper species [4]. Interest in insecticides of natural origin has been heightened by environmental and other problems associated with widespread use of broad spectrum synthetic pesticides. Two earlier reviews [4,5], of somewhat limited scope, focus specifically on a few unsaturated Piper amides in the context of their insecticidal potential. 

The amides are characteristically straight-chain, usually unsaturated compounds, and many incorporate an aromatic group (frequently 3, 4 -methylenedioxyphenyl) at the terminus remote from the amide function. Amides with and without a distal aromatic group are frequently produced by the same plant. Isobutylamine, pyrrolidine and piperidine predominate as the amine components of the Piper amides, although other amide classes, e.g., -pentyl or isopentylamides may be occasionally encountered [6]. In the case of at least one Piper species, P. guineense, attention has been drawn to the existence, which is intuitively predictable, of geographic variations in the relative proportions of amide constituents found in a species [7]. 

In light of current knowledge on the biosynthesis of Sedum and other piperidine alkaloids, one can surmise that the piperidine and piperideine moieties of the amides are, in fact, both probably produced from pyridoxal-bound L-lysine and cadaverine, a pathway proposed and elegantly elucidated by Leistner and Spenser in the early 1970 s (cf. [13]). In a similar manner, biosynthesis from omithine/putrescine could produce the pyrrolidine ring found in many of the Piper amides. On the other hand. 

Whereas many of the Piper amides, particularly those embodying the methylenedioxyphenyl group, are relatively stable, a number of the aliphatic unsaturated compounds, for example pellitorine, 5, have been reported to be very unstable [4, 56, 81, 127]. The propensity of cinnamic and piperic acid amides to undergo light-promoted E/Z isomerism has been noted, and dictates caution in drawing conclusions concerning the stereochemical composition of related naturally-occurring material [6]. 

The observation that the urinary metabolite of safrole, 3-piperidyl-l-(3, 4 -methylenedioxyphenyl)-l-propanone is mutagenic and is structurally somewhat reminiscent of certain Piper amides, has led to the suggestion that some of these compounds should, perhaps be considered as potential mutagens or carcinogens [141]. Whether or not this proves to be a problem warranting major concern, it is well to note that mono-N-substituted amides can react with nitrite under acidic conditions, with formation of potentially carcinogenic N-nitroso products [131]. 

Five amides, 50(n=4,6), 55, 5 and 6(n=6), isolated from P. guineense were investigated by Candy and co-workers [10] with respect to their knockdown and lethal activity against adult houseflies, as well as the rates of recovery of M. domestica from the effects of sublethal doses of the amides. As with other insecticides, rapid and potent knockdown activity on topical application of the amides depends, apart from the intrinsic toxicities of the individual compounds, on their ability to penetrate the cuticle and relevant membranes en route to the site of action. Attempts to correlate knockdown activity in the P. guineense amide series with polarity on this basis seemed to show some inconsistencies, perhaps as a result of steric factors [10,102]. The rate of recovery from the effects of sub-lethal doses of insecticides is associated, inter alia, with processes that lead to removal of the toxicant, so that recovery from treatment with Piper amides embodying the methylenedioxyphenyl group, which retards the action of mixed function oxidases, is slower than recovery from the effects of the less stable aliphatic amides. 

The chemistry of pepper has long been studied and the pungent principle of black pepper—a piperidine alkaloid, piperine 134—was isolated as early as 1877 (201). Its synthesis from the acid and piperidine was accomplished in 1882. (202). The corresponding pyrrolidine alkaloid trichostachyne (135) was isolated some 100 years later from several Piper species (see below). The cooccurence of piperidine and pyrrolidine alkaloids is a common feature of the chemistry of pepper. In many cases, the crude alkaloid extract is first cleaved with acids or bases and then each alkaloid is reconstituted by selective amidation. For the sake of unity, this chapter will be limited to comments on pyrrolidines, even in cases where they are minor alkaloids. 

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. 

Amide derivatives of unsaturated aliphatic fatty acids (Cio-Cie) are especially common in members of the Asteraceae, Piper-aceae, and Rutaceae. Among these, the isobutyl amides have pronounced insecticidal activity (119). Most of these compounds have not proven useful as commercial insecticides because of their irritating properties to mammals and their instability. 

A series of structurally similar compounds derived by acetate extension of phenylpropanoid precursors is also found in the Piperaceae. Pipercide from Piper nigrum (Piperaceae) was insecticidal, but the mixture of amides from this plant was significantly more toxic and it appears that co-occurring compounds exert synergistic effects (120). 

The pungency of the fruits of black pepper (Piper nigrum Piperaceae), a widely used condiment, is mainly due to the piperidine alkaloid piperine (Figure 6.24). In this structure, the piperidine ring forms part of a tertiary amide structure, and is incorporated via piperidine itself, the reduction product of A1 -pipcridcine (Figure 6.22). 

A new Piperaceae amide, pipercide (27), obtained from the fruits of Piper nigrum, shows insecticidal activity against the adzuki bean weevil.25 New pungent compounds of the capsaicinoid group have been isolated from the fruits of Capsicum annuum var. annuum.26... 

Piper, J.R. et al. (1982) Syntheses of alpha- and gamma-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism, J. Med. Chem. 25, 182-187. Wright, J.E. et al. (1993) Methotrexate and gamma-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts, Biochem. Pharmacol. 46, 871-6. 

The two sulfur-containing amides entadamides A (93) and B (94) have been isolated from the seeds and entadimides A and C (95) from the leaves of Entada phaseoloides Merr. (valid name Entada rheedii Spreng.) (Legu-minosae) (99-101). The known isobutylamide alkaloid pellitorine (N-isobutyl-2 ,4 -decadienamide) is found in the aerial parts of Piper ri-besoides Wall. (102). Pellitorine has also been isolated from the fruits of P. 

Sylvatine (C24H3303N mp 112° [a]D +0°) isolated from this plant was shown to be an amide of piperic acid. Mass and other spectra indicated structure 148 and confirmation was achieved by reduction, hydrolysis, and/or oxidation, the product of the latter process being 5-methylhexanoic acid (136). 

The chemistry of the pungent compounds of pepper has been under study since the isolation of piperine in 1820. Piperine was shown to be a piperidide of piperic acid, and had the trans. trans configuration. The three other possible isomers were soon postulated, and they were named isopiperine (cis.trans). isochavicine (trans. cis) and chavicine (cis.cis) even before they were synthesized. The assignment of the isomeric configuration starts from the amide end. 

Several new alkaloids have been isolated from pepper species. Tricholeine, for example, occurring in the stems of Piper trichostachyon, is the pyrrolidine amide (2) of fra s-9-(3,4-methylenedioxyphenyl)-A8-nonenoic acid, the structure being established by spectroscopic and degradative studies.4 Piper guineense seeds contain okolasine (6-methoxytrichostachine) (3),5 which is probably identical to the earlier known wisanidine. 4,5-Dihydro-wisanidine (4) is also found in the same... 

Attempts to prepare l-Z-lysergoyl-4-phenylpiperazine (1, Ri, R2 = (CH2CH2)2NC6H5) were unsuccessful. The expected amide was isolated in very low yield which was insufficient for complete identification. However, bis(4-phenyl-l-piper-azinyl)phosphinic chloride (4) was obtained in 32% yield. Compound 4 was identical with the product obtained from the reaction of 2 equiv of 1-phenylpiperazine with 1 equiv of POCl3 in the presence of Et. This was the only instance where compounds of type 4 were isolated from the reaction mixture in our synthesis of numerous lysergamides. 

This compound, the hexa-hydro pyridine has just been referred to, and also previously, in connection with penta-methylene di-amine (p. 194). In both these connections its constitution has been established. As its name indicates, it is obtained from pepper in which it is present in amide combination with an acid known as piperic acid. The compound thus formed is the alkaloid of black pepper and is called pipeline. 

The fruit of the plant Piper nigrum is the common black pepper of the household. This fruit yields an alkaloid known as pipeline present to about 4 to 9 per cent in commercial pepper. On hydrolysis the alkaloid yields piperidine or hexa-hydro pyridine and an acid known as piperic acid. Piperine is thus considered as a piperidine amide of piperic acid. Physiologically this alkaloid acts like quinine but is less active and is uncertain. It is only rarely used in medicine. 

Piper guineense Schumach et Thonn West African black pepper, Ashanti pepper Piperaceae Neuromuscular activity, contraceptive, antiparasitic, aphrodisiac Abdominal disorders, chest complaints, used as an enema. Bronchitis, Headache, An1helmintic,Caries, diarrhea, hemorrhoids, antibiotic. Alkaloidal amide, 12, 16, 17... 

Thus the kava alkaloids contain either a cinnamoyl or phenylpropionyl moiety. One would expect that a homologous series of such alkaloids may exist in the P. methysticum plant, since Achenbach and Karl (1971) isolated a series of substituted cinnamic, benzoic and phenyl propionic acids. These acids would be expected to react readily with amines to form the amide alkaloids. However, such a series of alkaloids does not appear to occur in the P. methysticum plant, although several similar alkaloids have been isolated from other Piper species, such as P. longum which yields piplactine, piperlongumine and piperlongiuninine (Chatterjee and Dutta, 1967). 

Vandopsis longicaulis Certain tumour-inhibitory plants of the Piperaceae and Rhizophoraceae families have yielded amides, e.g. A -dibydropiperine (9) occurs in Piper novae-hollandiae Miq. Macrocyclic alkaloids, e.g. azimine (10), have been fully defined. Further evidence for the nature of Lythrum bases has been obtained by synthesis of the overall skeleton. The key step in the synthesis involved formation of the 17-membered ring (11) (12). Directions for the isolation and degradation of piperine (9, with y,5-double bond) have been included in a unique laboratory text. ... 

For the tumour-inhibiting activity of amides from Piper novaehollandiae (Piperaceae) see ref. 128. Tumour-inhibiting extracts have also been obtained from Brugueria spp. (Rhizophoraceae), but it is not clear whether this activity is partly associated with tannins or with tannin-free compounds. 

Amide 130 was isolated from Piper amalgo and its structure was determined using MS, IR, lH NMR, and hydrolysis to give piperidine [407],... 

Miles CO, Lane GA, di Menna ME, Garthwaite I, Piper EL, Ball OJ-P, Latch GCM, Allen JM, Hunt MB, Bush LP, Min FK, Fletcher I, Harris PS. High levels of ergonovine and lysergic acid amide in toxic Achnatherum inebrians accompany infection by an Acremonium-like endophytic fungus. J Agric Food Chem 44 1285-1290, 1996. 

Plants of the Compositae, Piperaceae and Rutaceae families [2] have been used as ingredients in many medicinal preparations and as food spices and many of them are used as insecticides [6]. Several long-chain unsaturated amides have been isolated from these plants, and they can be classified into two main structural types (a) (2 , 4 )-dienamides derived from straight-chain fatty acids and isobutylamine, pyrrolidine or piperidine units (1-22) (Chart 1), and (b) amides with the piperonal unit derived mainly from piperic acid in combination with the above mentioned amines (23-34) (Chart 2). 

Pellitorine (1) has been isolated from several plants fruits of Piper sarmentosum [7], roots of Anacyclus pyrethrum [8] and seeds of Piper sylvaticum and presents insecticidal activity [10]. The Z-isomer (2), isolated from Piper guineense [11], has similar activity. Another component of the dried fruits of Piper sarmentosum, known in Thailand as Cha-plu , is sarmentine (3) which is used as an expectorant [7]. The corresponding piperidine derivative (4) is an Achillea amide [12]. 

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