Amide Alkaloids from the genus Piper:A Review of its Phytochemistry

Weiyu Zhou, Ming Bai, Xiaoxiao Huang＊, Shaojiang Song＊

Department of Natural Products Chemistry, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, PR China

1 Introduction

Plants have been the source of medicines for thousands of years and species of the genusPiperare among the important medicinal plants used in various systems of medicine [1]. The genus Piper belongs to the Piperaceae family and contains approximately 1000 species of herbs, shrubs, small trees and hanging vines[2]. Piper species such as Piper nigrum L. (pepper)and Piper methysticum (kava) are widely distributed in the tropical and subtropical regions of the world,which are used as food, spice and folk medicines on account of the physiological activities and thus possess a great commercial, economical and medicinal potential [3-5].

Numerous biologically active natural products,such as alkaloids, lignans, flavones, unsat -urated amides, aristolactams, monoterpenes, sesquiterpenes,ketones, propenylphenols, chalcones, long and short chain esters, arylpropanoids and aldehydes,were isolated from many Piper species through phytochemical investigations. Among the compounds,amide alkaloids are typical constituents in the genus Piper [6]. Generally speaking, the vast majority of the known amide alkaloids are based on monomeric and dimeric amide alkaloids.

This review was attempted to offer the timely and comprehensive information about chemical constituents of the genus Piper, to serve as a pointer to their diverse applications.

2 Research progress of amide alkaloids

The genus Piper belongs to the Piperaceae and has over 1000 species distributed in both hemispheres.Among them, the most well-known species arePiper nigrumL. (pepper) andPiper methysticum(kava).The ripened fruit of P.nigrum is the source of white pepper, while the unripened fruit of the same species is the source of black pepper. A narcotic beverage is produced from the roots of P.methysticum in Oceania.Several species of Piper are grown domestically as house plants for their foliage [2].

In the genus Piper, amide alkaloids are the most typical constituents [6]. The vast majority of the known amide alkaloids are based on monomeric and dimeric amide alkaloids. Among them, most of the monomeric amide alkaloids are classified into types on the basis of their chemical structure characteristics and skeletons, including piperidine-,pyridone-, pyrrolidine-, isobutylamine-, aristololactamtype. Furthermore, the great mass of dimeric amide alkaloids possess two representative structural types,viz. cyclobutane- and cyclohexene- type. So far,various amide alkaloids which have been isolated from the genus Piper are listed in Table 1.

2.1 Monomeric amide alkaloids

2.1.1 Piperidine-type amide alkaloids

Table 1 Amide alkaloids from the genus Piper

Continued table 1

Continued table 1

Continued table 1

About twenty-six piperidine-type amide alkaloids were isolated and identified from the genus Piper at present. They are piperlongimin B[2E-octadecenoylpiperidine] (1) [7], anti-epilepsirine(2) [7], piperrolein B (3) [8], dihydropiperine (4) [9],retrofractamide C (5) [8], abdihydropiperine(6) [10], piperanine (7) [11], pipernonaline (8) [11],pipermonaline (9) [8], piperchabamide C (10) [11],piperchabamide B (11) [11], piperoleine B (12) [11],(2E,4E,16Z)-N-(2,4,16-eicosatrienoyl)-piperidine(13) [12], (2E,4E,14Z)-N-(2,4,14-octadecatrienoyl)-piperidine (14) [12], piperdardine (15) [13], 1-[1-oxo-3(3,4-methylenedioxy-5-methoxyphenyl)-2Z-propenyl] piperidine (16) [5], dihydropiperine (17)[14], (E)-1-[3'-4'-(methylenedioxy)-cinnamoyl]piperidine (18) [15], chavicine (19) [16], piperanine(20) [16], piperine (21) [16], piperettine (22) [16],(±)-erythro-1-(1-oxo-4,5-dihydroxy-2E-decaenyl)-piperidine (23) [5], 1-(1,6-dioxo-2E,4E-decadienyl)-piperidine (24) [5], (±)-threo-1-(1-oxo-4,5-dihydroxy-2E-decaenyl) piperidine (25) [5], 1-[l-oxo-3(3,4-methylenedioxy-5-methoxyphenyl)-2Z- propenyl]piperidine (26) [5].

2.1.2 Pyridone-type amide alkaloids

Fig. 1 Piperidine-type amide alkaloids in the genus Piper

At present, nine pyridone-type amide alkaloids were isolated from the genus Piper. They are piperme-thystine (27) [17], cis-piplartine (or 8(Z)-N-(12,13,14- trimethoxycinnamoyl)-pyridin-2-one) (28) [10], N-(3,4-dimethoxycinnamoyl)-Δ3-pyridin-2-one (29) [18], piplartine (30) [19],N-(3-methoxy-4,5-methylenedioxycinnamoyl)-Δ3-pyridin-2-one (31) [18], N-(3-methoxy-4,5-methylenedioxydihydrocinnamoyl)-Δ3-pyridin-2-one (32) [18], 3a,4a-epoxy-5b-piper-methystine(33) [20], awaine (34) [20], kaousine (35) [21].

2.1.3 Pyrrolidine-type amide alkaloids

Fig. 2 Pyridone-type amide alkaloids in the genus Piper

There are about sixteen pyrrolidine-type amide alkaloids isolated and identified from the genus Piper, including pyrrolidine (36) [22],N-[10-(13,14-methylenedioxyphenyl)-7(E),9(E)-pentadienoyl]-pyrrolidine (37) [10], piperlotine E(38) [22], piperlotine D (39) [22], N-[10-(13,14-methylene- dioxyphenyl)-7(E)-pentaenoyl]-pyrrolidine(40) [10], piperlotine C (41) [22], piperlotine B(42) [22], N-[10-(13,14-methylenedioxyphenyl)-7(E),9(Z)-pentadienoyl]-pyrrolidine (43) [10],piperlotine A (44) [22], 1-(m-methoxycinnamoyl)pyrrolide (45) [23], 1-cinnamoyl pyrrolidine(46) [23], piperyline (47) [16], N-cinnamoyl-pyrrolidine(48) [23], peepuloidin (49) [24], 1-[1-oxo-5(3,4-methylenedioxyphenyl)-2Z,4E-pentadienyl] pyrrolidine (50)[25], sarmentomicine (51) [22].

2.1.4 Isobutylamine-type amide alkaloids

Fig. 3 Pyrrolidine-type amide alkaloids in the genus Piper

It is reported that there are a number of isobutylamine-type amide alkaloids in the genus Piper, they are 2E,4E,12E,13-(3,4-methylenedioxyphenyl)-trideca-trienoic acid isobutyl amide (52) [7], 2E,4E-N-isobutyl-dodecenamide(53) [7], 2E,4E-N-isobutyl-octadecenamide(54) [7], GB-N (55) [26], pipercide (56) [27],guineensine (57) [9], N-isobutyl-(2E,4E,14Z)-eicosatrienamide (58) [11], fagaramide (59) [10],(2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]-piperidine (60) [8], N-isobutyl-(2E,4E)-dodecadienamide (61) [11], N-isobutyl-(2E,4E)-decadienamide (62) [11], piperchabamide D (63) [11], sylvamide (64) [28], (2E,4E,8E)-N-isobutyl-9-(7-methoxybenzo [d] [1,3] dioxol-5-yl)nona-2,4,8-trienamide (65) [29], (2E,4E)-N-isobutyldecadienamide (66) [30], guineensine(67) [31], perlongumine (68) [14], dihydroperlongumine (69) [14], pipelonguminine (70) [16],2,4-tetradecadienoic acid isobutyl amide (71) [15],(±)-threo-N-isobutyl-4,5-dihydroxy-2E-octaenamide(72) [5], pellitorine (73) [14], sylamide (74) [15],N-isobutyl-15-(3',4'-methylenedioxyphenyl)-2E,4E,12Z-pentadecatrien amide (75) [32], (2E,14Z)-N-isobutyleicosa-2,14-dienamide (76) [33].

2.1.5 Aristololactam-type amide alkaloids

Fig. 4 Isobutylamine-type amide alkaloids in the genus Piper

Till now, thirteen aristololactam-type amide alkaloids were reported in the genus Piper, including aristolactam BII (77) [9], piperlactam S (78) [34],piperumbellactam D (79) [35], hydroxyaristolam II (80)[35], piperumbellactam A (81) [35], piperumbellactam B (82) [35], piperumbellactam C (83) [35], 10-amino-2,3,4-trimethoxyphenanthrene-1-carboxylic acid lactam (84) [23], cepharadione A (85) [36],cepharanone B (86) [37], (Z)-(E)-N-formouragines(87) [38], (Z)-(E)-formylnornuciferines (88) [38],piperolactam D (89) [39].

2.2 Dimeric amide alkaloids

2.2.1 Cyclobutane-type amide alkaloids

Fig. 5 Aristololactam-type amide alkaloids in the genus Piper

About seven cyclobutane-type amide alkaloids were isolated and identified from the genus Piper at present. They are piplartine dimer A (90) [18],nigramide T (91) [40], nigramide S (92) [40],nigramide Q (93) [40], nigramide R (94) [40],dipiperamides F (95) [33], dipiperamides G(96) [33].

In 2004, four new dimeric alkaloids (91-94)possessing a cyclobutane ring were isolated from the root of Piper nigrum by Kun [16] et al. In 2015, two new dimeric alkaloids (95-96) of the cyclobutane type were isolated from the fruit of Piper nigrum.

2.2.2 Cyclohexene-type amide alkaloids

Fig. 6 Cyclobutane-type amide alkaloids in the genus Piper

About seventeen piperidine-type amide alkaloids were isolated and identified from the genus Piper at present. They are nigramide P (97) [40],nigramide O (98) [40], nigramide L (99) [40], nigramide K (100) [40], nigramide N (101) [40], nigramide M (102) [40], nigramide J (103) [40], nigramide D(104) [40], nigramide H (105) [40], nigramide B(106) [40], nigramide I (107) [40], nigramide F (108)[40], nigramide A (109) [40], nigramide C (110) [40],nigramide G (111) [40], nigramide E (112) [40],chabamine (113) [33].

In 2004, sixteen new dimeric alkaloids (97-112)of the cyclohexene type were isolated from the root of Piper nigrum by Kun [16] et al.

2.3 Other amide alkaloids

Fig. 7 Cyclohexene-type amide alkaloids in the genus Piper

In addition to different types of amide alkaloids stated above, there are also some other amide alkaloids, they are pipyahyine (114) [41],N-benzylcinnamide (115) [9], submultinamide A(116) [10], arboreumine (117) [10], retrofractamide B (118) [11], retrofractamide A (119) [11],piperchabamide E (120) [11], piperlotine J(121) [22], taiwanamides B (122) [23], taiwanamides A (123) [23], langkamide (124) [42], N-2-(3',4',5'-trimethoxyphenyl)ethyl-2-hydroxybenzamide(125) [43], N-cis-feruloyltyramine (126) [44], N-transferuloyltyramine (127) [44], N-p-coumaroyltyramine(128) [44].

3 Conclusion

Fig. 8 Other amide alkaloids in the genus Piper

Phytochemical investigations showed that the constituents of the Piper genus included alkaloids,lignans, flavones, unsaturated amides and other constituents. This paper summarizes that the most significant chemical constituents of this genus are amide alkaloids and their different types on the basis of their chemical structure characteristics and skeletons which lead to distinct pharmacological activities. In this way, we can establish the corresponding relationship between chemical structures and pharmacological effects better. It’s reported that these compounds have different degrees of antioxidant, antitumor, anti-inflammatory,antihypertensive, antidepressant, antifungal,antibacterial, immuno-modulatory and hepatoprotective activities [45]. This paper has certain reference significance for the further development and utilization of the genus Piper.

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