Abstract

REVISÃO

Occurrence, biological activities and ¹³C NMR data of amides from Piper (Piperaceae)^## Artigo em homenagem ao Prof. Otto R. Gottlieb (31/8/1920-19/6/2011)

Jeferson C. do Nascimento^I; Vanderlúcia F. de Paula^I; Jorge M. David^II,**e-mail: jmdavid@ufba.br; Juceni P. David^III

^IDepartamento de Química e Exatas, Universidade Estadual do Sudoeste da Bahia, 45206-190 Jequié - BA, Brasil

^IIInstituto de Química, Universidade Federal da Bahia, 40170-290 Salvador - BA, Brasil

^IIIFaculdade de Farmácia, Universidade Federal da Bahia, 40170-290 Salvador - BA, Brasil

ABSTRACT

This manuscript describes an update review with up to 285 references concerning the occurrence of amides from a variety of species of the genus Piper (Piperaceae). Besides addressing occurrence, this review also describes the biological activities attributed to extracts and pure compounds, a compiled ¹³C NMR data set, the main correlations between structural and NMR spectroscopic data of these compounds, and employment of hyphened techniques such as LC-MS, GC-MS and NMR for analysis of amides from biological samples and crude Piper extracts.

Keywords:Piper;¹³C NMR compilation; amides.

INTRODUCTION

Piperaceae is one of the largest families among the basal Angiosperms, with approximately 3,000 species described to date.¹ The family is currently divided into five genera: Macropiper, Zippelia, Piper, Peperomia and Manekia,² consisting of a wide variety of species found commonly around the world. Piper, Peperomia and Manekia occur in Brazil, mainly in the Amazonian and Atlantic forests.³Piper is the largest genus of this family, including more than 1,000 species, and can also be considered the largest genus of the basal angiosperms.⁴

Amides are the major constituents of several species of Piper. Currently, they can be considered alkaloids in accordance with the modern definition by Pelletier.⁵ Natural amides can be classified as open-chain alkamides, aristolactams, 4,5-dioxoaporphines, ceramides, amides with pyrrolidine, piperidone and piperidine groups, cyclobutanamides and cyclohexanamides. The term piperamide is restricted to describe all compounds carrying an aromatic group and an amide group.

In 1997, a review of this genus was published⁶ dealing with chemical distribution and biological activities of amides. In the present review, an update with new chemical constituents of this genus is described and a compilation of ¹³C NMR data and biological activities of these compounds are provided.

Piper SPECIES, TRADITIONAL USES AND BIOLOGICAL ACTIVITIES

Despite the large number of species of Piper, the use of these plants in folk medicine remains limited. One of the most well-known Piper Brazilian medicinal plants is P. corcovadensis, commonly found in North and Northeast regions, and popularly known as "João-brandinho". The leaves of this plant are used for the treatment of rheumatism in the form of poultice and infusions as well for flu and cough. In the Southeast region, the roots and branches of this specie are chewed to relieve toothache due to its anesthetic action on the mucous membrane.⁷

In China, the use of leaves of P. futokasura is recommended in the treatment of cardiac arrhythmias and asthma. In Jamaica, stomach pains are treated with an infusion of leaves from P. aduncum and P. hispidum. Leaves from P. amalago are also employed in Mexico and Brazil for stomach pains and for the treatment of various infections.⁸ Leaves and stems of P. marginatum and P. tuberculatum are used in Brazil, especially in Paraíba State (Brazil) against snake bite and as a sedative.⁹

The roots from P. sarmentosum are used in Thailand as a carminative and digestive. In Malaysia and Indonesia however, the leaves and roots of this plant are used for the treatment of toothache, foot dermatitis, cough and asthma.¹⁰

The genus Piper is also known to produce compounds with insecticidal activity.¹¹ In addition, several others activities are attributed to the species of this genus. The literature reports fungicidal,¹² antinociceptive,¹³ anti-inflammatory,¹⁴ enzymatic inhibition,¹⁵ antiplatelet aggregation,¹⁶ trypanocidal,¹⁷ piscicidal,¹⁸ anticancer,¹⁹ antioxidant,²⁰ allelopathic,²¹ antiophidic,²² antimicrobial,²³ antiplasmodial (antimalarial),²⁴ antileishmanial,²⁵ anxiolytic/antidepressant,²⁶ antituberculosis,²⁷ antidiabetic,²⁸ adipogenesis,²⁹ nematocidal,³⁰ herbicidal,³¹ hepatoprotective,³² and antisecretory and anti-Helicobacter pylori³³ activities.

CHEMISTRY OF Piper

The variability of the chemical constituents of Piperaceae is considerable. Species of this genus produce different metabolic classes such as neolignans,³⁴ lignans,³⁵ lactones,³⁶ terpenes,³⁷ phenylalkanoids/benzenoids,³⁸ hydroquinones,³⁹ alkaloids/amides,⁴⁰ steroids,⁴¹ chalcones/dihydrochalcones,⁴² chromones,⁴³ fatty acids,⁴⁴ ceramides⁴⁵ and flavonoids.⁴⁶ Essential oils of Piper spp.are mainly composed of phenylpropanoids (e.g.: trans-anethole, elemicin, chavicol), monoterpene hydrocarbons (e.g.: α-pinene, myrcene, limonene), sesquiterpene hydrocarbons, (e.g.: α-caryophyllene, germacrene D, bicyclogermacrene) and oxygenated monoterpenes (e.g.: 1,8-cineole, linalool, terpinen-4-ol) and sesquiterpenes (spathulenol, E-nerolidol, caryophyllene oxide).⁴⁷

Among the major classes of natural compounds, amides isolated from Piper present broad structural diversity (Figure 1). Aromatic or aliphatic open chain amides, aristolactams, ceramides, 4,5-dioxoaporphines, amides with pirrol, pyrrolidine, piperidone and piperidine groups are biosynthesized from cinnamic acid derivatives and some aminoacids.⁴⁸ However, the compounds of the cyclobutanamide and cyclohexanamide types are probably formed from cycloaddition reactions.⁴⁹

Occurrence of amides in Piper spp.

Parmar et al.⁶ previously published a review describing the occurrence of amides updated through to 1997. The cited review described the chemical composition of 90 species of Piper. The occurrence of 144 different amides present in 67 Piper species was also described (represented in Table 2 by the symbol &). In the present review, the results of a study of 158 species are described, corresponding to approximately 16% of the genus. Thus, since 1997, 68 new species have been investigated for their chemical (Table 1) and biological activities. These updated studies described the isolation of 133 new compounds in this genus, which corresponds to an increase of around 92% in the number of these metabolites found in the Piper genus, which presently numbers 277 amides (Table 2). Among these new compounds, the isolation of 22 cyclohexanamides,⁴⁹ two new ceramides⁴⁵ and 15 cyclobutanamides,⁵⁰ is noteworthy, all of which present unique skeletal complexes. Comparison of the compounds isolated in the last decade with those previously described by Parmar et al.⁶ indicates increased structural diversity of piperamides, probably due to advances in instrumental techniques of isolation and chemical identification.

Compilation of C-13 NMR data of amides from Piper

In Supplementary Material, a Table containing a ¹³C NMR data compilation of 182 amides isolated from the genus Piper can be found. Prior to the 1990's, there was scant ¹³C NMR data described for these compounds. Moreover, in the previously published data there were a considerable number of signals equivocally assigned. As an example of this observation, the C-2 signal of compound 70 suggests it must be reattributed given it seems to be changed with the C-5'. The same mistake may have occurred with C-6' and C-8' since heteronuclear bidimensional correlation techniques such as HMQC and HMBC were not employed for unequivocal attribution of these compounds.

The β-carbons of conjugated amides are deshielded in comparison to α-carbon due to resonance effects such as those observed for 31, 33, 34, 74 and 107 (Supplementary Material). This effect is also responsible for the acyl carbon resonances which are found to be shielded. The peak of the carbonyl group in piplartine (60) is unshielded (δ 169.2) compared with the acyl group (δ 175.5) of 61 (Δδ 6.3 ppm). The chemical shift in the acyl groups of amides ranges from δ 156.5 to 175.6 ppm. These values are dependent on the present substituents bearing C-2'. For example, the chemical shifts in the acyl groups of 1 and 7 are d 169.6 and the resonances of the same carbon in 2 and 3 are approximately δ 165.0. This protective effect is due to the methoxyl group which donates electrons more than hydroxyl groups. Therefore, these values may be indicative of the location of these groups at C-2' of amides.

The δ ¹³C assignments reported for the carbon atoms C-1''/C-4'', C-1''/C5''; or C-2''/C3'', C-2''/C-4'' for pyrrolidine and piperidine alkamides (Figure 2) has indicated the shifts are different, despite the similarity of the carbons. This fact can be observed in compounds 36,¹⁶38,¹³¹44, 45,¹²¹47,¹⁰97²⁷² and 125²⁷³ (all values ​​given in Table 1S, Supplementary Material, are consistent with those found in the respective articles). Thus, the C-1'' chemical shift is shielded in comparison with C-4'', and the same observation can be made for C-2'' in relation to C-3'' in pyrrolidine derivatives. The same effect is observed for six member rings.²⁷⁴ In some nigramides (237-246)⁴⁹, changes in these values are also seen, indicating the NMR data for these carbons were equivocally attributed. This statement can be explained by the double bond characteristic of the C-N bond. This structural characteristic interferes in the rotational barrier which changes the magnetic shield of C-1' and C-4' (C-5' in six membered rings) of these compounds. A large compression of the carbon electrons located in syn to the acyl group may be due to the repulsion of the electrons of oxygen atom. This compression renders C-1' more shielded in comparison to C-4'.

CONCLUDING REMARKS AND FUTURE PERSPECTIVES

Previously, a review of natural and synthetic amides with insecticidal activity was published.²¹⁴ This showed that some specific amides can be used, alone or in combination, as insecticides, substituting neurotoxic compounds such as carbamates, organophosphates and pyrethroids. In the present review, we reported a wide range of other biological activity attributed to amides isolated from the genus Piper (Table 2). Pipernonaline (124) showed excellent larvicidal activity against Aedes aegypti, comparable to pirimiphos-methyl, the insecticide commonly used;²⁰¹ retrofractamide A (126) offered satisfactory adipogenic activity, can be considered a promising candidate for the development of antidiabetic agents,²⁸ and the N-[trans-cinnamoyl]pyrrolidine (36) inhibitor of platelet aggregation with IC₅₀ of 7.3 mg/mL, comparable with aspirin (IC₅₀ 5.5 mg/mL), an anti-clotting agent used clinically to combat the formation of thrombi.¹³¹ Data demonstrated the biological and medicinal importance of piplartine isolated from the roots of P. chaba, and indicated that E-piplartine may be a promising candidate for use in combinatorial treatments to combat cancer.²⁷⁵

To date, the presence of 277 amides from Piper has been reported while data from chemical shifts in ¹³C NMR is available for 182 compounds. From a phytochemical perspective, approximately 84% of species of Piper have not been investigated. Due to its diverse chemical, biological and structural variability, it is important to conduct regular literature reviews on the subject. Advances in hyphenated techniques such as GC/MS/MS have permitted the simultaneous identification and quantification of amides. These techniques can be used as pharmacologically active analytic markers to standardize extracts or herbs with culinary and medicinal properties such as P. sarmentosum. These methods can also be used for the determination of new constituents present in the volatile oil;²⁷⁶ however, for the identification of new compounds by mass spectra fragments, confirmation of their structures by synthesis or employment of standards in the analysis is mandatory.

The development of an interface between HPLC and mass detectors has permitted analysis of mixtures of non-volatile metabolites in different extracts of various parts of plants. The employment of HPLC-APCIMS for determination and quantification of amides and piperamides in economically important Piper species, such as P. nigrum, has allowed rapid and accurate determination of unsaturated amides, or piperamides, in black pepper and other wild species. APCI allows smooth ionization (in positive or negative scan mode) and also shows some key fragmentations which facilitate the identification of the metabolites. A limitation of this technique is the need for comparison with standards which must be synthetized in some cases.²⁷⁷ This limitation could be resolved by liquid chromatography coupled with the tandem multistage mass spectrometry (MS/MS) method. The application of ion trap MSⁿ in direct structural elucidation is based on characteristic fragmentations and can be used for structural elucidation especially for the minor components in unpurified complex extracts, for which standards are not available. Sun et al. employed this technique for the characterization of amides from the extracts of P. longum. Upon collisional activation of the [M+H]⁺ ion of all the HPLC amide peaks, cleavage of the amide bond can result in losses of the neutral amine moiety (either piperidine or isobutylamine) with subsequent loss of CO to form alkenyl ions. The unique loss of the neutral fragments of 85 and 113 Da would be characteristic for piperidine derived amides. These cleavages with other specific fragmentations have enabled the identification of 43 known amides present in this plant with only a single chromatographic run. However, for the nine new compounds identified, HRMS data were necessary.²⁷⁸ Besides the structural feature advantages which HPLC-MS/MS offers, it can also be used as a sensitive and accurate method for the determination of alkaloid amides in plasma. Determination of piplartine (60) in rat plasma is important to gain a better understanding of its biological effects. The presence of the protonated molecular ion in m/z 317 and the ion fragment observed in m/z 221 permitted the reliable identification of piplartine in estimating concentration in rat plasma of up to 2.0 ng mL^-1 with high reproducibility.²⁷⁹ On the other hand, hyphenated techniques allow conclusive determination of the presence of different metabolites in extracts without previous fractionation, sample treatment, synthesis of standards or compound isolation. Even the use of equipment separately can provide data which indicate the different classes of metabolites present or specific compounds. From crude extract NMR and LC-ESIMS analysis of different Piper species, Yamaguchi et al. confirmed that lignans and other phenolic compounds are present in different contents in adult leaves and seedling leaves. However, the amides showed a similar profile during the developmental stage. In this case, the application of multivariate analysis, such as principal component analysis (PCA) or hierarchical cluster analysis (HCA), is essential.²⁸⁰

SUPPLEMENTARY MATERIAL

Supplementary material as ¹³C NMR data of amides from Piper are available free of charge as PDF file at quimicanova.sbq.org.br.

ACKNOWLEDGMENTS

The authors thank CNPq, CAPES and FAPESB by the financial support and the fellowships.

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Recebido em 30/3/12; aceito em 24/7/12; publicado na web em 26/10/12

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