# Collected mass spectrometry data on monoterpene indole alkaloids from natural product chemistry research

E. Ramos, Pierre Le Pogam, Charlotte Fox Alcover, Elvis Otogo N'Nang, Gaëla Cauchie, Hazrina Hazni, Khalijah Awang, Dimitri Bréard, Antonio M Echavarren, Michel Frederich, et al.

► To cite this version:

E. Ramos, Pierre Le Pogam, Charlotte Fox Alcover, Elvis Otogo N'Nang, Gaëla Cauchie, et al. Collected mass spectrometry data on monoterpene indole alkaloids from natural product chemistry research. Scientific Data, 2019, 6 (15), pp.1-6. 10.1038/s41597-019-0028-3. hal-02861053

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DATA DESCRIPTOR

Received: 20 September 2018

Accepted: 25 February 2019

Published online: 03 April 2019

# Collected mass spectrometry data on monoterpene indole alkaloids from natural product chemistry research

Alexander E. Fox Ramos<fnref n="1" />, Pierre Le Pogam<fnref n="1" />, Charlotte Fox Alcover<fnref n="1" />, Elvis Otogo N'Nang<fnref n="1" />, Gaëla Cauchie<fnref n="1" />, Hazrina Hazni<fnref n="1" />,², Khalijah Awang², Dimitri Bréard³, Antonio M. Echavarren⁴,⁵, Michel Frédéric⁶, Thomas Gaslonde⁷, Marion Girardot⁸, Raphaël Grougnet⁷, Mariia S. Kirillova⁴, Marina Kritsanida<fnref n="1" />, Christelle Lémus⁷, Anne-Marie Le Ray³, Guy Lewin<fnref n="1" />, Marc Litaudon⁹, Lengo Mambu¹⁰, Sylvie Michel⁷, Fedor M. Miloserdov⁴, Michael E. Muratore⁴, Pascal Richomme-Peniguel³, Fanny Roussi⁹, Laurent Evanno<fnref n="1" />, Erwan Poupon<fnref n="1" />, Pierre Champy<fnref n="1" /> & Mehdi A. Beniddir<fnref n="1" />

This Data Descriptor announces the submission to public repositories of the monoterpene indole alkaloid database (MIADB), a cumulative collection of 172 tandem mass spectrometry (MS/MS) spectra from multiple research projects conducted in eight natural product chemistry laboratories since the 1960s. All data have been annotated and organized to promote reuse by the community. Being a unique collection of these complex natural products, these data can be used to guide the dereplication and targeting of new related monoterpane indole alkaloids within complex mixtures when applying computer-based approaches, such as molecular networking. Each spectrum has its own accession number from CCMSLIB00004679916 to CCMSLIB00004680087 on the GNPS. The MIADB is available for download from MetaboLights under the identifier: MTBLS142 (https://www.ebi.ac.uk/metabolights/MTBLS142).

## Background & Summary

Monoterpene indole alkaloids (MIAs) constitute a broad class of nitrogen-containing plant-derived natural products composed of more than 3000 members<fnref n="1" />. This natural product class is found in hundreds of plant species from the Apocynaceae, Loganiaceae, Rubiaceae, Icacinaceae, Nyssaceae, and Gelsemiaceae plant families. Throughout the six past decades, the structural intricacies and biological activities of these molecules have captured the interest of many researchers all over the world². Examples of MIAs are the antimalarial drug of choice

<footnote n="1">¹Equipe "Pharmacognosie-Chimie des Substances Naturelles" BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 5 Rue J.-B. Clément, 92290, Châtenay-Malabry, France. ²Centre for Natural Products and Drug Discovery, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Wilayah Persekutuan, Kuala Lumpur, Malaysia. ³EA921, SONAS, SFR QUASAV, UBL/Angers University, Campus du végétal, 42 rue Georges Morel, 49070, Beau couzé, France. ⁴Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Avenue Països Catalans 16, 43007, Tarragona, Spain. ⁵Departament de Química Organica i Analítica, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n, 43007, Tarragona, Spain. ⁶Laboratory of Pharmacognosy, CIRM, University of Liège, Quartier Hopital, 15 Avenue Hippocrate, Sart Tilman, 4000, Liège, Belgium. ⁷Laboratoire de Pharmacognosie, UMR/CNRS 8638 COMETE, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 Avenue de l'Observatoire, 75006, Paris, France. ⁸Laboratoire Écologie et Biologie des Interactions, Équipe Microbiologie de l'Eau, UMR CNRS 7267, Université de Poitiers, 5 rue Albert Turpain, 86073, Poitiers CEDEX 09, France. ⁹Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université Paris-Saclay, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France. ¹⁰Département de Pharmacognosie, Laboratoire PEIRENE-EA 7500, Faculté de Pharmacie, Université de Limoges, 2 rue du Dr Marcland, 87025, Limoges CEDEX, France. Correspondence and requests for materials should be addressed to M.A.B. (email: mehdi.beniddir@u-psud.fr)</footnote>
till the mid of the last century, quinine; the antihypertensive reserpine, and vincristine and vinblastine, which are used directly or as derivatives for the treatment of several cancer types. Recently, much effort was directed toward understanding and manipulating the underlying biosynthetic pathways of MIAs in order to engineer them in microorganisms to allow industrial production of medicinally relevant compounds<sup>3-5</sup>. Although a large amount of knowledge has been accumulated concerning the early steps<sup>6-8</sup> and the assembly of key intermediates, many questions are still unanswered, and the discovery of new members of this family may illuminate unexpected enzymes involved in the biosynthesis of this intriguing group of natural products.

As part of our continuing interest in MIA chemistry<sup>9-12</sup>, we developed a streamlined molecular networking<sup>13</sup> dereplication pipeline based on the implementation of an in-house MS/MS database, constituted of a cumulative collection of MIAs<sup>14</sup>. In order to enrich this database, seven prominent practitioners from the global natural products research community shared their historical collections, leading to the construction of the largest MS/MS dataset of MIAs to date, that we named: Monoterpene Indole Alkaloids DataBase (MIADB) (Fig. 1). The MIADB contains MS/MS data of 172 standard compounds, comprising 128 monoindoles and 44 bisindoles (these compounds are presented in Supplementary Table 1) and covers more than 70% of the known (30/42) MIA skeletons. The information that can be drawn from this dataset is valuable for the scientific community that envisages the isolation of new MIAs.

The purpose of this Data Descriptor is to announce the deposition of the MIADB on the Global Natural Product Social Molecular Networking (GNPS<sup>15</sup>) and MetaboLights<sup>16</sup>. Each spectrum of the MIADB has its own accession number from CCMSLIB00004679916 to CCMSLIB00004680087 on GNPS (accessed via: https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp). The spectral collection is also available for download from MetaboLights under the identifier: MTBLS142<sup>17</sup>.

## Methods

**Sample preparation.** Each of the collected MIA was diluted to a concentration of 1 mg/mL using HPLC-grade (High Performance Liquid Chromatography) with MeOH (Methanol) as solvent. The solution was then transferred in 1.5 mL HPLC vials and analyzed by LC-MS/MS (Liquid Chromatography-tandem Mass Spectrometry). Chemicals and solvents were purchased from Sigma-Aldrich.

**Data acquisition.** Samples were analyzed using an Agilent LC-MS (Liquid Chromatography Mass Spectrometry) system composed of an Agilent 1260 Infinity HPLC coupled to an Agilent 6530 ESI-Q-TOF-MS (ElectroSpray Ionization Quadrupole Time of Flight Mass Spectrometry) operating in positive mode. A Sunfire® analytical C₁₈ column (150 × 2.1 mm; i.d. 3.5 µm, Waters) was used, with a flow rate of 250 µL/min and a linear gradient from 5% B (A: H₂O + 0.1% formic acid, B: MeOH) to 100% B over 30 min. The column temperature was maintained at 25 °C. ESI conditions were set with the capillary temperature at 320 °C, source voltage at 3.5 kV, and a sheath gas flow rate of 10 L/min. Injection volume was set at 5 µL. The mass spectrometer was operated in Extended Dynamic Range mode (2 GHz). The divert valve was set to waste for the first 3 min. There were four scan events: positive MS, window from *m/z* 100–1200, then three data-dependent MS/MS scans of the first, second, and third most intense ions from the first scan event.

MS/MS settings were: three fixed collision energies (30, 50, and 70 eV), default charge of 1, minimum intensity of 5000 counts, and isolation width of *m/z* 1.3. Purine C₅H₄N₄ [M + H]⁺ ion (*m/z* 121.050873) and hexakis(1H,1H,3H-tetrafluoropropoxy)-phosphazene C₁₈H₁₈F₂₄N₃O₆P₃ [M + H]⁺ ion (*m/z* 922.009798) were used as internal lock masses. Full scans were acquired at the resolution of 11 000 (at *m/z* 922) and 4000 at (*m/z* 121). A permanent MS/MS exclusion list criterion was set to prevent oversampling of the internal calibrant.

**Database constitution.** The analysis of each of these substances resulted in 172 files with the standard.d format (Agilent standard data-format). A list of individual compounds for each sample was generated from an Auto MS/MS data mining process implemented in MassHunter® software on every single file. Averaged as well as monocollisional energy MS/MS spectra were generated from the three retained collision energies (30, 50, and 70 eV). Within this list, the molecular formula (as well as the exact mass) of the expected compound (in its charged state) was identified. Then, depuration of the other features was carried out. Finally, each spectrum was converted into the.mgf (Mascot Generic Format) using the export tool of the MassHunter® software.

## Data Records

All data described in this article have been uploaded to GNPS and MetaboLights. Each spectrum of the 172 compounds of the MIADB has its own accession number from CCMSLIB00004679916 to CCMSLIB00004680087 on the Global Natural Product Social Molecular Networking (GNPS) (accessed via: https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp). The spectral collection in its two versions (i.e. averaged and separate collision energy MS/MS spectra at 30, 50, and 70 eV) is available for download from MetaboLights under the identifier: MTBLS142<sup>17</sup>.

**Metadata.** The MS/MS spectra of the MIADB library are recorded with a variety of details including: LC-MS/MS acquisition parameters, instrument details, organism, organism part, smiles and Inchi codes, CAS numbers, CHEBI IDs, retention times, and chemical formula. These metadata are available on the GNPS and MetaboLights websites.
<figure><img src="image_2.png" /><figcaption>**Fig. 1** Construction of the MIADB (red arrows) and application in a molecular networking-based dereplication workflow (blue arrows).</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>**Fig. 2** Full molecular network of the profiled compounds from a methanol extract of *C. roseus* leaves annotated by the MIADB. The cosine similarity score cutoff for the molecular network was set at 0.6, the parent ion mass tolerance at 0.02, the fragment ion mass tolerance at 0.02, the score library threshold at 0.6 and the minimum matched peaks at 6. The cosine similarity score are depicted on the edges.</figcaption></figure>

## Technical Validation

**Spectroscopic validation of MIADB compounds.** The structural identity of the alkaloids being implemented in the MIADB reference metabolite index was established through extensive spectroscopic analyses, including, NMR (Nuclear Magnetic Resonance) and HRMS (High-Resolution Mass Spectrometry). The
<table><caption>Table 1. Matches between the profiled compounds from a methanol extract of *C. roseus* and MIADB.</caption><thead><tr><td>Compound</td><td>Match score</td><td>Comment</td><td>ΔRT (min)</td><td>Confidence level</td></tr></thead><tbody><tr><td>akuammigine</td><td>0.69</td><td>Described in C. roseus</td><td>0.63</td><td>1</td></tr><tr><td>alloyohimbine</td><td>0.76</td><td>Not described in C. roseus</td><td>1.95</td><td>2</td></tr><tr><td>burnamine</td><td>0.62</td><td>Not described in C. roseus</td><td>1.07</td><td>1</td></tr><tr><td>catharanthine</td><td>0.67</td><td>Described in C. roseus</td><td>0.67</td><td>1</td></tr><tr><td>geissoschizine</td><td>0.71</td><td>Described in C. roseus</td><td>1.52</td><td>2</td></tr><tr><td>pericyclivine</td><td>0.79</td><td>Described in C. roseus</td><td>0.00</td><td>1</td></tr><tr><td>perivine</td><td>0.73</td><td>Described in C. roseus</td><td>0.01</td><td>1</td></tr><tr><td>raubasine</td><td>0.64</td><td>Described in C. roseus</td><td>0.26</td><td>1</td></tr><tr><td>serpentine</td><td>0.66</td><td>Described in C. roseus</td><td>6.65</td><td>2</td></tr><tr><td>tabersonine</td><td>0.80</td><td>Described in C. roseus</td><td>1.48</td><td>1</td></tr><tr><td>vindolinine</td><td>0.77</td><td>Described in C. roseus</td><td>1.44</td><td>1</td></tr><tr><td>vobasine</td><td>0.65</td><td>Not described in C. roseus</td><td>0.16</td><td>1</td></tr></tbody></table>

<table><caption>Table 2. MIADB matches with the GNPS library.</caption><thead><tr><td>Compounds (GNPS)</td><td>Match score</td><td>Compounds (MIADB)</td><td>Comments</td></tr></thead><tbody><tr><td>brucine</td><td>0.78</td><td>brucine</td><td></td></tr><tr><td>reserpiline</td><td>0.86</td><td>reserpiline</td><td></td></tr><tr><td>tabernaemontanine</td><td>0.74</td><td>tabernaemontanine</td><td></td></tr><tr><td>voachalotine</td><td>0.93</td><td>voachalotine</td><td></td></tr><tr><td>ajmaline</td><td>0.75</td><td>ajmaline</td><td></td></tr><tr><td>vincamine</td><td>0.78</td><td>vincamine</td><td></td></tr><tr><td>methyl reserpate</td><td>0.83</td><td>methyl reserpate</td><td></td></tr><tr><td>camptothecin</td><td>0.73</td><td>camptothecin</td><td></td></tr><tr><td>reserpine</td><td>0.86</td><td>reserpine</td><td></td></tr><tr><td>strychnine</td><td>0.80</td><td>strychnine</td><td></td></tr><tr><td>akuammigine</td><td>0.86</td><td>raubasine</td><td>epimer</td></tr><tr><td>raubasine</td><td>0.88</td><td>akuammigine</td><td>epimer</td></tr><tr><td>corynanthine</td><td>0.90</td><td>yohimbine</td><td>epimer</td></tr><tr><td>yohimbine</td><td>0.92</td><td>corynanthine</td><td>epimer</td></tr><tr><td>vincosamide</td><td>0.93</td><td>strictosamide</td><td>epimer</td></tr><tr><td>strictosamide</td><td>0.93</td><td>vincosamide</td><td>epimer</td></tr><tr><td>yohimbine</td><td>0.90</td><td>pseudoyohimbine</td><td>epimer</td></tr><tr><td>elegantissine</td><td>0.73</td><td>carapanaubine</td><td>isomer</td></tr><tr><td>yohimbine</td><td>0.89</td><td>alloyohimbine</td><td>epimer</td></tr></tbody></table>

analyses were carried out by the various collaborators having contributed to the establishment of the database. The obtained mass spectra were individually inspected to verify the occurrence of either the protonated molecular or molecular ion as the precursor mass.

**Selected strategies for the validation of the MIADB.** The validation of the MIADB was achieved following two strategies: (i) dereplication of the profiled compounds from a methanol extract of the leaves of *Catharanthus roseus* (L.) G. Don. (Apocynaceae) (see supplementary Tables 2 and 3), and (ii) the dereplication of the MIADB against the MIAs previously available on the GNPS library before the upload of the MIADB.

**Molecular networking-based dereplication of *Catharanthus roseus* methanol extract.** Molecular networking-based dereplication using MIADB-uploaded GNPS libraries was attempted on the methanol extract of *Catharanthus roseus*, the MIAs content of which was thoroughly studied. Accordingly, more than 130 different compounds were reported from the different tissues of the plant¹⁸. In the displayed network, the experimental data of *C. roseus* methanol extract are depicted as green rectangles and nodes representing a consensus of experimental data and database records (i.e., MIADB-uploaded in the GNPS libraries) are displayed as red rectangles (Fig. 2). As expected, molecular networking of the *C. roseus* leaves methanol extract allowed dereplication of previously known metabolites within this plant including: tabersonine, catharanthine, vindolinine, perivine, geissoschizine, pericyclivine, serpentine, raubasine, and akuammigine (Table 1). All the dereplicated compounds were assigned a level of confidence 1 according to Schymanski *et al.*¹⁹ based on HMRS, MS/MS and retention time matching, except for geissoschizine, serpentine; and alloyohimbine. The latter were attributed a level of confidence of 2, due to a delta of retention time (RT) superior to 1.5 min. The molecular networking-based dereplication provided a
comprehensive coverage of *C. roseus* alkaloids by regards to the available standards, despite the noticeable lack of a vinblastine hit. This missing observation is likely due to the vinblastine concentration that is known to be very low in the plant (ranging from 0.0003% to 0.001% w/w dry weight)²⁰. Conversely, some unexpected matches could also be evidenced throughout the obtained dereplication: burnamine and vobasine. Although none of these were previously described in *C. roseus*, both these structural assignments can be deemed reasonable based on biosynthetic considerations. Being an akuammiline-derived MIA, such as akuammine²¹ and the monomer precursors of the bisindoles vingramine and methylvingramine²² that have been reported to occur in *C. roseus*, the detection of burnamine is not unexpected. Likewise, the co-dereplication in the depicted molecular network of the formerly described vobasane-type perivine supports the identification of vobasine within this plant. Such examples emphasize the dereplicative interest of MIADB especially on such a deeply dug plant model. Prior to its GNPS upload, i.e., as an in-house database, the ability of the MIADB to pinpoint tentatively new MIAs was demonstrated through the streamlined isolation of geissolaevine along with its O-methylether derivative and 3',4',5',6'-tetrahydr ogeissospermine from the formerly vastly studied *Geissospermum leave* (Vell.) Miers (Apocynaceae)¹⁴. Altogether, the currently garnered results support the valuable contribution of MIADB either for the straightforward identification of monoterpene indole alkaloids or to highlight putative structural novelty among this privileged structural class. The topology of the obtained network also reveals that a further extent of information could yet be accessed from *C. roseus* extracts. Indeed, most dereplicated MIAs are tightly associated within cluster A. Since clusterization depends on structural similarity, a single match to the MIADB-implemented GNPS allows for the propagation of the structure throughout an entire molecular family, indicating that most if not all the nodes of this cluster refer to MIAs. The seminal contribution of the MIADB to the tandem mass spectrometric databanks of MIA is expected to pave the way for the upload of such data by the numerous teams involved in MIA research all over the world, thereby contributing to making this tool more and more efficient to reach a quick and sharp insight into the MIAs content of any producing organism.

**Dereplication of the MIADB against the MIAs previously available on the GNPS library.** As a second validation assay, the MIADB was dereplicated against the GNPS library. For this purpose, the 172.mgf files were submitted to the GNPS online platform and all the hits between the MIADB and the GNPS were annotated. 19 of the total MIAs were identified as hits by the GNPS platform (Table 2).

These results indicate that the compounds from the 19 matches were correctly identified within the GNPS library, except in the case of epimers or isomers. Indeed, it should be noted that the matching process does not take into account the stereochemistry of the compounds (Table 2).

**Code Availability**

The LC-MS feature detection software (MassHunter®) used in this work is commercially available from Agilent®.

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## Acknowledgements

We gratefully acknowledge the productive collaborations and the fruitful contributions that allowed the generation of this natural products MS/MS database. This research was funded by FONDECYT-CONCYTEC (grant contract number 239-2015-FONDECYT), and by the French ANR grant (ANR-15-CE29-0001). We express our thanks to Séverine Amand (MNHN) for her assistance in the collection of the MIAs from the MNHN chemical library.

## Author Contributions

M.A.B. conceived the project. A.E.F.R., C.A., E.O.N., G.C., and H.H. performed the acquisition of the LC-MS/MS data. P.L.P. performed the technical validation of the MIADB. M.S.K., F.M.M., M.E.M., and A.M.E., performed the total synthesis of grandilodines B and C and lundurine. M.G. and L.M. isolated and collected MNHN compounds. M.K., R.G., T.G., C.L. and S.M. isolated and collected compounds from Université Paris-Descartes. K.A. advised on the extraction aspects of the work conducted by H.H. D.B., A.-M.L., and P.R. collected compounds from Université d'Angers. M.F. isolated and collected compounds from Université de Liège. F.R. and M.L. collected and supervised the isolation of compounds from ICSN. G.L. performed isolation and structure elucidation of lanciferine and vincamajine. L.E. and E.P. conceived and performed the synthetic experimental works related to the obtention of bipleiophylline, voacalgine A, and leucoridine A. A.E.F.R., P.L.P., P.C. and M.A.B. supervised isolation work at Université Paris-Sud and wrote the manuscript. All the authors read and commented the manuscript.

## Additional Information

Supplementary Information is available for this paper at https://doi.org/10.1038/s41597-019-0028-3.

**Competing Interests:** The authors declare no competing interests.

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