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22:02, qui jun 19

Acesso Aberto/TP



Artigo

Fragmentation of deprotonated plumeran indole alkaloids by electrospray ionization tandem mass spectrometry

Yan R. RoblesI; Ricardo VessecchiI; Ivo J. C. VieiraII; Raimundo Braz-FilhoII,III,#; Antonio E. M. CrottiI,*

I. Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto - SP, Brasil
II. Laboratório de Ciências Químicas, Centro de Ciências e Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro (UENF), 28013-602 Campos dos Goytacazes - RJ, Brasil
III. Departamento de Química Orgânica, Instituto de Química, Universidade Federal Rural do Rio de Janeiro (UFRRJ), 23897-000 Seropédica - RJ, Brasil

Received: 02/07/2025
Accepted: 04/14/2025
Published online: 05/09/2025

Endereço para correspondência

*e-mail: millercrotti@ffclrp.usp.br

RESUMO

The fragmentation of four deprotonated plumeran indole alkaloids (PIAs), namely aspidospermidine (1), demethoxypalosine (2), aspidocarpine (3), and aspidolimine (4), previously isolated from Aspidosperma spruceanum has been investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the negative ion mode. The fragmentation pathways have been established on the basis of accurate mass data. Our results demonstrated that the main product ions of deprotonated 1-4 result from remote hydrogen rearrangements. The most abundant product ion in the product ion spectrum of 2, 3, and 4 was the result of a ketene loss (methylketene for 2 and 3, and a ketene for 4) directly from the precursor ion. The product ion of m/z 183 was diagnostic for compound 2, whereas the radical loss of •CH3 occurred only for 3 and 4, which display an aromatic methoxyl group in their structures. These results indicated that ESI(-)-MS/MS could be also used for the identification of PIAs 1-4 in crude extracts using LC-ESI-MS/MS, especially when the extracts are more complex.

Palavras-chave: deprotonated molecule; gas-phase fragmentation reactions; indole alkaloids; negative ion electrospray.

INTRODUCTION

The genus Aspidosperma, belonging to the family Apocynaceae, is native to the Americas, and predominantly located between Mexico and Argentina.1 The species of this genus are commonly used in folk medicine, where they are regarded for their potential antimalarial and contraceptive properties.1 They are also used in the treatment of conditions such as leishmaniasis, inflammation of the uterus and ovaries, diabetes, gastrointestinal disorders, cancer, fever, and rheumatism.1 From a chemical standpoint, these species are important sources of alkaloids, particularly indole-type alkaloids.1,2

Plumeran indole alkaloids (PIAs), including aspidospermidine (1), demethoxypalosine (2), aspidocarpine (3), and aspidolimine (4) (Figure 1), are frequently extracted from various species of the Aspidosperma genus. Aspidospermidine represents the most basic structure among a series of PIAs characterized by a pentacyclic [6.5.6.5]ABCDE ring framework. The antiplasmodial,3 antihypertensive,4 antileishmanial,5 and antiplasmodial3 activities of these compounds have been reported.

 

 

Over the last decades, liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) has emerged as the main tool in metabolomics (i.e., the comprehensive study of metabolome, the entirety of metabolites, or a set of metabolites).6 Unlike the classical approach, which requires the compound to be first isolated to be identified, metabolomics represents an alternative that accelerates the discovery of new biologically active compounds, since it allows for the identification of the metabolites of a biological system without the need for isolation.7 In untargeted metabolomics,8 data on the accurate mass, molecular mass, and m/z of the product ion spectra can be used to guide the search for metabolites in natural products databases (e.g., such as Dictionary of Natural Products,9 and AntiBase10) or in mass spectrometry databases (e.g., Global Natural Products Social molecular networking (GNPS), MassBank,11 and METLIN,12 among others). On the other hand, in target metabolomics, different mass spectrometry scan modes (e.g., multiple reaction monitoring, or MRM) are used to quantify one or more pre-selected metabolites belonging to a specific class of metabolites.13 In this scenario, the knowledge of the gas-phase fragmentation pathways of compounds may play a key role in both targeted and untargeted metabolomics studies.14 Despite the vertiginous increase in the number of compounds available in natural products and mass spectrometry databases, data on the gas-phase fragmentation of plumeran indole alkaloids are still scarce.15

Taking into account that only studies on the fragmentation of protonated indole alkaloids 1-4 using ESI-CID-MS/MS (electrospray ionization-collision induced dissociation-tandem mass spectrometry) have been reported,15 here we report an ESI(-)­MS/MS (electrospray ionization tandem mass spectrometry in the negative ion mode) study on the fragmentation pathways of deprotonated compounds 1-4 using tandem mass spectrometry analysis in combination with computational chemistry in order to describe the deprotonated species.

 

EXPERIMENTAL

Chemicals

Aspidospermidine (1), demethoxypalosine (2), aspidocarpine (3), and aspidolimine (4) were previously isolated from the methanol stem bark extract of A. spruceanum.16 Acetonitrile (HPLC grade), purchased from Aldrich (Steinheim, Germany), and Milli-Q (Millipore, Bedford, MA) deionized distilled water were used throughout the experiments. Samples were prepared at a concentration of 0.1 mg mL-1 from the respective stock solutions (1.0 mg mL-1) by dilution in acetonitrile/water (4:1 v/v).

Mass spectrometry

Mass spectral analyses were performed on an UltroTOF-Q Bruker Daltonics (Billerica, MA) mass spectrometer fitted with an electrospray ion source operating in the negative ion mode, and equipped with a hybrid quadrupole-time-of-flight mass analyzer. Samples were infused into the ESI source at a flow rate of 5 µL min-1. The source block and desolvation temperature was 150 ºC. An optimum energy of 3.5 kV was applied at the capillary emitter. This energy was found to maximize the number of ions with the m/z corresponding to the deprotonated molecule ([M - H]-) of each compound. The deprotonated molecule (precursor ion) was selected and fragmented by collision-induced dissociation (CID) using N2 as collision gas. The accurate masses were obtained by use of TFA-Na+ (sodiated trifluoroacetic acid) as the internal calibrant, which was observed at m/z 112.98556 (CF3CO2-) and m/z 248.96039 ([(CF3COONa)CF3COO]-).17 The Δm/z observed in all the experiments ranged from 0.5 to 8 ppm depending on the mass of the theoretical masses of the ions.

Computational Chemistry

All the structures had the geometries optimized in B3LYP/6-31+G(d,p) level,18,19 using Gaussian 09 suite program.20 Minimum at potential energy surface were characterized by calculations of harmonic vibrational frequencies. All the possible deprotonated species were considered using ∆Gacid (gas-phase acidity) in order to suggest the most stable deprotonation site in the gas-phase.21,22 ∆Gacid was computed through the following deprotonation reaction: MHg → Mg- + Hg+ by considering the Gibbs energies calculated at 298.15 K using B3LYP/6-31+G(d,p). Gibbs energy for the proton was considered as described by Range et al.23

 

RESULTS AND DISCUSSION

Structure-fragmentation relationships in PIAs 1-4

It is well-known in the literature that the energy transferred to the precursor ion upon collision-induced dissociation (CID) plays a key role in the product ion spectrum profile.24-26 In general, low collision energies produce few product ions, which are formed from the lowest activation barrier pathways. On the other hand, high collision energies can result in extensive fragmentation of the precursor ion by making possible the fragmentation through higher activation barrier pathways.27,28 Thus, to minimize the effect of the collision energy on the product ion spectra and better understand the role played by the structural features on the gas-phase fragmentation pathways of deprotonated compounds 1-4, the product ion spectra of 1-4 were obtained in collision energies (Elab) from 0 to 50 eV. Based on the plots of the relative intensity of the main product ions versus Elab (Figure 2), we selected Elab = 20 eV as the "optimal energy" (i.e., the maximum number of product ions with relative intensity higher than 5% without extensive fragmentation of the precursor ion).

 

 

The product ion spectra of compounds 1-4 at Elab = 20 eV are shown in Figure 3. The accurate mass data, errors, relative intensities, ion formula, and the peak assignments are depicted in Table 1. A detailed analysis of these spectra revealed interesting structure-fragmentation relationships. For example, in the product ion spectrum of demethoxypalosine (2), which differs from aspidospermidine (1) by one acyl group at the nitrogen atom of the indoline moiety, the product ion of m/z 281 arises from the neutral loss of the acyl group as CH3CH=C=O (56 mass units) from the precursor ion (m/z 339). The product ion of m/z 281 of 2 is an isobaric ion of the precursor ion of 1 (m/z 281). Indeed, the product ions of 1 are similar to those observed in the spectrum of 2, indicating that the fragmentation of 2 is mostly not affected by the stereochemical differences compared to 1. Most of these product ions result from the losses of 41 (C2H3N), 80 (C6H8), 121 (C8H11N), 156 (C11H10N), 188 (C12H16N2), and 237 (C17H19N) mass units. In contrast, the diagnostic product ion of m/z 183 was observed only in the spectrum of demethoxypalosine (2), which indicates that its formation must be related to the acyl group at the nitrogen of the indoline group.

 

 

 

 

Although aspidocarpine (3, m/z 383), and aspidolimine (4, m/z 369) display an additional hydroxyl and methoxyl group in their structures compared to aspidospermidine (1), the number of product ions is considerably lower, even at higher Elab values. Besides the neutral loss of the acyl group from the precursor ion, a methyl radical loss (loss of 15 mass units) can also occur for compounds 3 and 4. This process is diagnostic for aromatic methoxyl groups in the structure of aspidocarpine and aspidolimine. An overview of the fragmentation pathways of compounds 1-4 is given in Scheme 1.

 

 

Deprotonation of compounds 1-4

Gas-phase deprotonations are important to describe the reactivity of anions. The pioneer works of Brauman et al.21,29-31 about gas-phase basicities of amines and alcohols opened a new field for understanding the intrinsic effects of structure and reactivity. For this reason, exploring the reactivity in the gas phase from the formation of deprotonated species is attractive to understand the stability of the generated ions during MS and MS/MS experiments.21,32,33

Gas-phase acidity (∆Gacid) of conjugated amides has been studied using computational chemistry with MS/MS experiments and the deprotonation site was identified as being preferentially at the N atom, instead of the expected in the C-H α-carbonyl bond.34,35 Thus, the search for the most stable deprotonation sites can be exploited using some descriptors, such as atomic charges, bond dissociation energies and ∆Gacid.

According to the literature,36 the removal of the hydrogen from the most acid site during the ionization process produces the thermodynamically most stable deprotomer (thermodynamic control). In this case, the fragmentation reactions are preceded by energy transference to the center-of-mass of this deprotomer (i.e., the precursor ion) upon the CID process. This can lead to an increase in its internal energy content or convert the precursor ion into a less stable deprotomer, then triggering the fragmentation. On the other hand, the removal of hydrogen from less basic sites produces less stable deprotomers, which can fragment more easily (kinetic control).

It is well-known that gas-phase acidity (∆Gacid) values depend on intrinsic factors, mainly the stabilization of the negative charge in the deprotomer (i.e., the conjugate basis).21,37,38 In this study, the ∆Gacid values have been calculated to suggest the most acid sites in the structures of 1-4. Because C-H bonds are weakly acidic,35,39 only the most acid hydrogen atoms in the structures of 1-4 were considered.

We have tested main deprotonations and the most acidic H atoms have been identified through the values of gas-phase acidity computed using B3LYP/6-31+G(d,p), as shown in Scheme 2. In the case of compound 1, the hydrogen of the N-H bond of the indoline moiety is the most acid acidic (Scheme 2). For compound 2, the α-carbonyl hydrogen of the acyl group is the most acidic hydrogen atom. Finally, the phenol hydroxyl is the most acid site in the structure of compounds 3 and 4. These differences in the deprotonation sites result in differences in fragmentation pathways, as will be discussed in this paper.

 

 

Fragmentation of deprotonated aspidospermidine (1) and demethoxypalosine (2)

The formation of the main product ions of deprotonated 1 (m/z 281) is shown in Scheme 3. Most of the product ions result from remote hydrogen rearrangements and occur with the retention of the negative charge at the nitrogen atom. Pathway I involves the opening of ring E and produces the intermediate ion A1.1, whereas pathway II is initiated by the opening of ring D and the consequent formation of the intermediate ion A1.3. A remote hydrogen rearrangement results in the ring C opening and converts A1.1 into the intermediate A1.2. The elimination of C8H11N from A1.2 produces D (m/z 160), which is the base peak in the product ion spectrum of aspidospermidine (1). The product ion D can also be formed from A1.3 (pathway IIa), as shown in Scheme 3. In this case, the formation of D involves the ring C opening and the consequent conversion of A1.3 into A1.4. The neutral loss of C6H8 from A1.4 (pathway IIa1) produces C (m/z 201), which produces D after C2H3N neutral loss. On the other hand, the product ion D can also be formed through pathway IIa2 after C8H11N neutral loss (Scheme 3). The formation of the isobaric ions D1 and D2 by three different pathways could explain why product ion D is the base peak in the product ion spectrum of 1. The formation of the product ions E (m/z 125), F (m/z 93), G (m/z 67), and H (m/z 44) involves the intermediate ion A1.5, the less stable form of the equilibrium with A1.3, which is stabilized by the negative charge delocalization. Three competitive hydrogen rearrangements from A1.5 can result in the opening of ring C (pathway IIb2), and E (pathway IIb1), or in the formation of a three-membered ring (pathway IIb3) to produce the intermediate ions A1.9, A1.7 and A1.8, respectively (Scheme 3). The intermediate ion A1.9 can be converted into A1.10 after ring E opens through a remote hydrogen rearrangement, as shown in Scheme 3. The formation of E (m/z 125) occurs with the radical loss of C11H10N. Although the formation of E from A1.10 violates the "Even-Eletron Rule",40,41 its occurrence is feasible due to the cleavage of an allylic bond and loss of a resonantly stabilized radical.42 On the other hand, The product ion H (m/z 44) can be formed from A1.7 after the loss of C17H19N through a remote hydrogen rearrangement.

 

 

It is well-known that the negative charge migration from oxygen or nitrogen to carbon is a highly disfavored process.43,44 Although F and G are resonantly stabilized, the carbon atoms in their structures poorly accommodate the negative charge due to the carbon's low electronegativity, so their relative intensities in the product ion spectra obtained at Elab = 20 eV are low (Figure 3). However, the intensities of F and G increase with higher collision energies. Similarly, at Elab higher than 35 eV, the product ion H (m/z 44) is the most intense in the product ion spectrum of 1 (Figure 2a).

Demethoxypalosine (2) differs from aspidospermidine (1) by an acyl group at the nitrogen of the indole moiety instead of hydrogen. This makes the α-carbonyl hydrogen of the acyl group the most acidic hydrogen of the structure of 2. Because the aforementioned acyl group (i.e., a propionyl group) at the indoline group is lost as methyl-ketene (C3H4O, 56 mass units) to form the product ion B, which has the same m/z as the precursor ion of 1 (m/z 281), most of the product ions in the spectrum of deprotonated 2 have the same m/z as those of deprotonated 1 (Figure 3, Table 1). On the other hand, the product ion K (m/z 183), which was not observed in the spectrum of 1, is the most abundant in the spectrum of deprotonated 2. The formation of this product ion is related to the presence of the acyl group, as shown in Scheme 4. The carbanionic carbon of the enolate A2 abstract H16 to form a double bond between C16 and C2 and produce the intermediate ion A2.1 (Scheme 4). This step is favored by the spatial proximity between Cα and H16 and is driven by the charge delocalization between the oxygen and nitrogen atoms. The neutral loss of methylketene from A2.1 produces B2 (m/z 281), which is converted into the diagnostic ion K after two consecutive hydrogen rearrangements and the consequent neutral loss of C7H14 (Scheme 4). The deprotometer A2 can also fragment following pathway II and produce B1 (m/z 281), from which the ions C, D, E, F, G, and H can be formed by the same mechanisms depicted in Scheme 3.

 

 

Fragmentation of deprotonated aspidocarpine (3), and aspidolimine (4)

Similarly to demethoxypalosine (2), aspidocarpine (3) and aspidolimine (4) also display an acyl (4) or propionyl (3) group at the indole nitrogen. However, in the case of 3 and 4, the phenol hydroxyl is the most acidic site in the molecular structure. Therefore, the deprotomer A3 is the most stable for compounds 3 and 4. In principle, the energy transferred to the deprotonated molecules of 3 and 4 could promote a proton migration from other less acidic sites (e.g., the α-carbonyl hydrogen of the acyl group at the indoline nitrogen) to the oxygen of the phenolate ion, forming less stable deprotomers. However, this would result in the charge migration from a highly electronegative oxygen to a poorly electronegative carbon. Therefore, the low number of product ions in the spectra of 3 and 4 can be understood based on the high energy content required to convert the deprotomer A3 into A2.

The product ions B, I, and J of deprotonated 3 and 4 are due to methylketene (for 3), ketene (for 4), or a methyl radical loss (for 3 and 4) from the precursor ion. The formation of these product ions occurs with charge retention, as shown in Scheme 5. Methyl radical losses have also been reported for other deprotonated phenolic compounds.45

 

 

ESI(+)-MS/MS versus ESI(-)-MS/MS

Aguiar et al.15 investigated the gas-phase fragmentation of protonated plumeran indole alkaloids (PIA) 1-4. The authors identified a series of diagnostic product ions and identified these compounds in a crude extract of Aspidosperma spruceanum based on accurate mass ESI(+)-MS/MS data. A comparison between our data with those reported by Aguiar et al.15 indicates that the fragmentation of protonated 1-4 produces a higher number of product ions as compared to the fragmentation of deprotonated 1-4. This difference is due to the carbon's ability to accommodate the positive charge, which makes possible the occurrence of fragmentation pathways that involve charge migration. The same does not occur in the case of a negative charge, as previously discussed in this paper: although the fragmentation processes involving charge migration can occur, they require high collision energies to produce ions with significant relative intensities in the mass spectra.

The formation of most of the product ions of deprotonated and protonated 1-4 involves hydrogen rearrangements. Some of these rearrangements lead to the opening of rings C, D, or E and are driven by the formation of intermediate ions that display increased degrees of freedom as compared to their precursors. Radical losses occur from both protonated and deprotonated 1-4. In the case of protonated 1-4, losses of •C2H5 and •C2H3 (for 1-4), H• (only for 1 and 2), and •CH3 (only for 3 and 4) were reported. In this study, only the •CH3 loss from the aromatic methoxyl group of deprotonated 3 and 4 were observed. The methoxyl group is also involved in methanol loss during the fragmentation of protonated 3-4. However, this loss was not observed in the fragmentation of the corresponding deprotonated molecules.

In general, ESI(-)-MS/MS produces informative product ion spectra for compounds 1 and 2 and "poor" spectra for deprotonated compounds 3 and 4. On the other hand, ESI(+)-MS/MS afforded very informative spectra for protonated 1-4. Although the choice of ESI(+)-MS/MS for the analysis of the plumeran indole alkaloids 1-4 seems obvious, other factors must be also taken into account to choosing the mode of analysis. For example, ESI(+)-MS/MS can be used for the analysis of a wide range of natural products, whereas the use of ESI(-)-MS/MS is limited due to the need for relatively acidic hydrogen in the analyte structure. Therefore, depending on the complexity of the crude extract, the use of ESI(-)-MS/MS could eventually produce more simple LC-MS chromatograms and should be also considered.

 

CONCLUSIONS

The gas-phase fragmentation reactions of deprotonated aspidospermidine (1), demethoxypalosine (2), aspidocarpine (3), and aspidolimine (4) were investigated by accurate mass electrospray ionization tandem mass spectrometry (ESI(-)-MS/MS). Product ion spectra of deprotonated 1 and 2 provided very useful product ions at a collision energy (Elab) of 20 eV without extensive fragmentation. On the other hand, at 20 eV, only a few product ions were observed in the product ion spectrum of deprotonated 3 and 4. The main product ions result of remote hydrogen rearrangements. The most abundant product ion in the product ion spectrum of 2, 3, and 4 was the result of a ketene neutral loss (methylketene for 2 and 3, and a ketene for 4) directly from the precursor ion. The product ion of m/z 183 was diagnostic for compound 2, whereas the radical loss of •CH3 occurred only for 3 and 4, which display an aromatic methoxyl group in their structures. Although the number of product ions of deprotonated 1-4 is lower as compared with those of protonated 1-4, ESI(-)-MS/MS can be also used for the identification of the plumeran indole alkaloids 1-4 in crude extracts using LC-ESI-MS/MS, especially when the extracts are more complex.

 

ACKNOWLEDGMENTS

The authors thank José Carlos Tomaz and Prof. Norberto Peporine Lopes for the mass spectrometry analyses. This research was funded by the National Council for Scientific and Technological Development (CNPq, proc. 310648/2022-0).

 

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Editor handled this article: Jorge M. David

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