Theionbrunonines A and B: Dimeric Vobasine Alkaloids Tethered by a

Letter Cite This: Org. Lett. 2018, 20, 6596−6600

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Theionbrunonines A and B: Dimeric Vobasine Alkaloids Tethered by a Thioether Bridge from Mostuea brunonis Elvis Otogo N’Nang,†,§ Guillaume Bernadat,† Elisabeth Mouray,⊥ Brice Kumulungui,§ Philippe Grellier,⊥ Erwan Poupon,† Pierre Champy,*,† and Mehdi A. Beniddir*,† É quipe “Pharmacognosie-Chimie des Substances Naturelles” BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue J.-B. Clément, 92290 Châtenay-Malabry, France § Laboratoire de Microbiologie, Université des Sciences et Techniques de Masuku, BP769 Franceville, Gabon ⊥ Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Muséum National d’Histoire Naturelle, CNRS, Sorbonne Universités, CP52, 57, rue Cuvier, 75005 Paris, France

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†

S Supporting Information *

ABSTRACT: Theionbrunonines A and B (1 and 2), the first examples of monoterpene bisindole alkaloids linked by a thioether bridge, were isolated from the stems of Mostuea brunonis, guided by a molecular networking-based dereplication strategy. Their structures were elucidated by a combination of spectroscopic data and ECD calculations. A plausible biosynthetic pathway for 1 and 2 was postulated. Theionbrunonines A and B (1 and 2) showed moderate antiplasmodial activities in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 μM.

T

was profiled by HPLC-HRMS/MS (positive-ion mode). All the HRESIMS/MS spectra obtained were then preprocessed via the MZmine 2 software24 and organized as a molecular network and subsequently dereplicated against the MIADB25 spectral library (hosted by the GNPS26). The dereplication process afforded 14 hits, with two of them being previously described in the stems of M. brunonis (Supporting Information (SI)). A cursory examination of the global molecular network (SI) hinted at the presence of a cluster (A) constituted of three nodes at m/z 707.363, 693.348, and 723.358 reminiscent of bisindole masses. Therefore, two of them (i.e., 707.363 and 693.348) were targeted by MS-guided isolation through repetitive RP-HPLC for further structural elucidation.27 Theionbrunonine A (1) was obtained as a white amorphous powder. The IR spectrum showed bands due to NH (3400 cm−1) and ester carbonyl functions (1720 cm−1), while the UV spectrum showed characteristic indole absorption maxima at 288 and 298 nm. The molecular formula of 1 was established to be C42H50N4O4S by its HRESIMS data at m/z 707.3628 [M + H]+ (calcd 707.3626) corresponding to a double-bond equivalent value of 20. The 1H and 13C NMR data of 1 (Table 1) provided evidence for approximately half of the expected proton and carbon resonances, which were assigned as belonging to three methyls, three methylenes, nine methines, and six quaternary carbons. The spectroscopic data prompted

he sheer wealth of structures encountered in the monoterpene indole alkaloid family constitutes a breathtaking cabinet of curiosities for any keen chemist.1−3 Interestingly, this group of natural products includes a vast array of monomers, further enlarged by the occurrence of far more complex oligomeric representatives. As such, the past decade saw a constant and astounding evolution in the diversity of the linkage fashion of the constituting monomers4−12 as well as in the molecular architecture complexity13,14 of the resulting oligomers.15 Although a large amount of knowledge has been accumulated concerning their biosynthesis,16,17 many questions are still unanswered, and the discovery of new members of this family may illuminate unexpected enzymes involved in the underlying biosynthetic pathways of this intriguing group of natural products. In this regard, as part of our research program directed toward the streamlined reinvestigation of previously studied plants,7,9,18,19 we endeavored toward the phytochemical study of the stems of Mostuea brunonis Didr. (Gelsemiaceae) by a molecular networking-based dereplication strategy.20 Previous phytochemical investigations of this plant reported the isolation of monomeric quinoline, indole, and oxindole alkaloids but no oligomers.21,22 Herein, we report the isolation and structural elucidation of theionbrunonines A and B (1 and 2), representing the first naturally occurring monoterpene bisindole alkaloids featuring a thioether bridge.23 Furthermore, we describe their antiplasmodial and cytotoxic activities and discuss their presumable biosynthetic origin. In order to mine for previously undescribed monoterpene indole alkaloids, an alkaloid extract of the stems of M. brunonis © 2018 American Chemical Society

Received: September 16, 2018 Published: October 10, 2018 6596

DOI: 10.1021/acs.orglett.8b02961 Org. Lett. 2018, 20, 6596−6600

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Organic Letters Table 1. 1H and

13

C NMR Data for Theionbrunonines A and B (1 and 2) in MeOH-d4 1

2 3 5 6 7 8 9 10 11 12 13 14 15 16 18 19 20 21 2′ 3′ 5′ 6′ 7′ 8′ 9′ 10′ 11′ 12′ 13′ 14′ 15′ 16′ 18′ 19′ 20′ 21′ 16-CO2Me 16-CO2Me 4-N-Me 16′-CO2Me 16′-CO2Me 4′-N-Me

2

δH, mult (J, Hz)a

position

δCb 137.2 43.1 60.6 21.3 108.4 130.3 118.5 121.1 124.2 112.3 137.6 37.9 33.2 46.0 12.6 126.1 133.1 51.6 137.2 43.1 60.6 21.3 108.4 130.3 118.5 121.1 124.2 112.3 137.6 37.9 33.2 46.0 12.6 126.1 133.1 51.6 51.4 170.0 40.5 51.4 170.0 40.5

4.53, dd (13.5, 2.7) 4.20, m 3.34, m; 2.46, dd (13.3, 11.4)

7.71, 7.18, 7.22, 7.34,

br d (7.6) m m dd (7.3, 1.4)

1.04, 3.46, 2.57, 1.63, 5.35,

q (13.5); 1.93, ddd (13.5, 6.0, 2.7) m m d (6.5) q (6.5)

2.86, d (14.5); 1.87, d (14.5) 4.53, dd (13.5, 2.7) 4.20, m 3.34, m; 2.46, dd (13.3, 11.4)

7.71, 7.18, 7.22, 7.34,

br d (7.6) m m dd (7.3, 1.4)

1.04, 3.47, 2.57, 1.63, 5.35,

q (13.5); 1.93, ddd (13.5, 6.0, 2.7) m m d (6.5) q (6.5)

2.86, d (14.5); 1.87, d (14.5) 2.56, s 2.63, s 2.56, s 2.63, s

δH, mult (J, Hz)a

δC b

4.50, dd (10.0, 3.1) 4.08, br t 3.28, m; 2.53, m

7.65, 7.17, 7.20, 7.32,

br d m m br d (7.6)

1.09, 3.44, 2.51, 1.60, 5.27,

m; 1.90, m m m brd q (6.5)

1.95, m; 2.69, br d (14.5) 4.53, dd (10.0, 3.1) 4.23, br t 2.70, m; 3.34, m

7.63, 7.14, 7.19, 7.29,

br d m m d (7.6)

1.11, 3.51, 2.46, 1.62, 5.32,

m; 1.95, m m m br d q (6.5)

2.14, d (14.5); 2.85, d (14.5) 2.53, s 2.57, s 2.58, s

137.2 43.1 60.6 21.3 108.8 130.2 118.4 121.0 124.1 112.2 137.2 37.8 33.5 46.1 12.6 124.8 134.2 51.6 137.1 43.2 53.2 23.6 109.0 130.28 118.7 120.8 124.0 111.9 137.7 37.7 33.7 45.9 12.5 125.3 133.4 41.7 51.3 170.6 40.9 51.5 170.2

a

Data recorded at 400 MHz. bData recorded at 100 MHz.

us to speculate that 1 might be a homodimeric compound. Further analysis of the NMR data revealed a high degree of similarity with those previously reported for vobasine (3),28 which was likewise dereplicated by the molecular networkingbased analysis outlined above (SI). The noticeable difference between 1 and 3 was the replacement of the keto group C-3 (δC = 189.9) in 3 with a thiomethine (δH = 4.53, δC = 43.1) in 1. The HMBC correlations from H-3 to C-3′ and H-3′ to C-3 (Figure 2) in addition to the necessity of including a sulfur atom in 1, as required by the molecular formula, led us to propose that the sulfur served as a thioether bridge linking the two vobasinyl moieties at C-3 and C-3′ (Figure 1).29 The relative configuration of 1 was assigned mainly using 1H NMR data, 1H−1H coupling values, and NOESY correlations. The NOESY correlations of H-15/H-15′ to H3-18/H3-18′

Figure 1. Structures of theionbrunonines A and B (1 and 2) and vobasine (3).

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DOI: 10.1021/acs.orglett.8b02961 Org. Lett. 2018, 20, 6596−6600

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Organic Letters established the E-configuration of the ethylidene side chains (Figure 2). The configurations of C-16/C-16′ were assigned as

of the similarity of the NOESY correlations. The absolute configuration of compound 2 was determined by comparing its experimental ECD spectrum with the spectrum of 1 (SI). A plausible biogenetic pathway for 1 and 2 is proposed in Scheme 1. Since vobasine (3) was detected in the course of the Scheme 1. Plausible Biosynthetic Pathway of Theionbrunonines A and B (1 and 2)

Figure 2. Selected 2D NMR correlations for 1.

S* by the characteristic highly shielded chemical shifts (δH = 2.56) of the methoxy groups at C-16/C-16′, due to the anisotropic effect of the indole ring.30 At last, a H-3/H-3′ βorientation was assigned by comparing the coupling constant values of H-3 and H-3′ (dd, J = 13.5, 2.7 Hz) with the literature.30 Collectively, NOESY correlations observed between (i) H-3/H-3′ and H-15/H-15′, (ii) H-15/H-15′ and H-16/H-16′, and (iii) H-16/H-16′ and H-5/H-5′ further confirmed the relative configuration of 1 (Figure 2, see SI for a 3D graphic model of 1). The absolute configuration of 1 was elucidated by comparing its ECD experimental data with a computationally derived theoretical spectrum (Figure 3). The consensus of

dereplicative analysis of M. brunonis alkaloid extract, the biosynthetic route of 1 and 2 could be reasonably traced back to this precursor. The sequence may be initiated by the reduction of 3 into vobasinol (4)31 which after protonation and dehydration would lead to the intermediate i. A conjugate addition of L-cysteine onto C-3 should lead to intermediate ii that could either undergo a decarboxylation reaction to yield pagisulfine (5)32 or undergo C−S bond cleavage catalyzed by a C−S lyase33,34 to afford sulfur intermediate iii. Finally, the latter could, on its turn, further attack the C-3 of intermediates i and iv leading to theionbrunonines A and B (1 and 2), respectively. Even though C−S lyase enzymes have been described in the tissues of plants belonging to the Amaryllidaceae, Brassicaceae, and Fabaceae,35 to the best of our knowledge, there are no reports available that describe the identification of a C−S lyase in plants of the Gelsemiaceae family. A genomic analysis of M. brunonis would further shed light on this hypothesis. Theionbrunonines A and B (1 and 2) were evaluated for their antiplasmodial activity toward the chloroquine-resistant strain of Plasmodium falciparum FcB1 and for their cytotoxic activity against the MRC-5 (human fetal lung fibroblast) cell line. 1 and 2 showed moderate antiplasmodial activity, with IC50 values of 2.5 ± 0.7, and 2.1 ± 0.1 μM, respectively. Remarkably, no cytotoxicity was observed for both compounds at 20 μM.

Figure 3. ECD spectra of 1 (experimental and calculated at the B3LYP/6-31G* level).

quantum mechanical calculations, along with the NOESYderived relative stereochemistry, allowed us to assign the absolute configuration of 1 as 3R, 3′R, 5S, 5′S, 15R, 15′R, 16S, and 16′S. Theionbrunonine B (2) was isolated as a white amorphous powder. Its molecular formula was determined to be C41H48N4O4S from its protonated molecular ion at m/z 693.3479 [M + H]+ in the HRESIMS, indicating a molecular weight of 14 mass units lower than 1. The 1H and 13C NMR spectra of 2 (Table 1) are strikingly similar to those of theionbrunonine A (1). The main difference between 2 and 1 is the absence of one of the two N-methyl groups. This observation, in combination with an analysis of COSY, HSQC, and HMBC spectra, strongly suggested that 2 corresponds to 4′-N-demethyl theionbrunonine A. The relative configuration of 2 was determined to be identical with that of 1 on the basis 6598

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Organic Letters

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(13) Hirasawa, Y.; Miyama, S.; Hosoya, T.; Koyama, K.; Rahman, A.; Kusumawati, I.; Zaini, N. C.; Morita, H. Org. Lett. 2009, 11, 5718−5721. (14) Liu, Z.-W.; Zhang, J.; Li, S.-T.; Liu, M.-Q.; Huang, X.-J.; Ao, Y.L.; Fan, C.-L.; Zhang, D.-M.; Zhang, Q.-W.; Ye, W.-C.; Zhang, X.-Q. J. Org. Chem. 2018, 83, 10613−10618. (15) Kitajima, M.; Takayama, H. Chapter Four - Monoterpenoid Bisindole Alkaloids. In The Alkaloids: Chemistry and Biology; Knölker, H.-J., Ed.; Academic Press: 2016; Vol. 76, pp 259−310. (16) Caputi, L.; Franke, J.; Farrow, S. C.; Chung, K.; Payne, R. M. E.; Nguyen, T.-D.; Dang, T.-T. T.; Carqueijeiro, I. S. T.; Koudounas, K.; Dugé de Bernonville, T.; Ameyaw, B.; Jones, D. M.; Vieira, I. J. C.; Courdavault, V.; O’Connor, S. E. Science 2018, 360, 1235−1239. (17) Dang, T.-T. T.; Franke, J.; Carqueijeiro, I. S. T.; Langley, C.; Courdavault, V.; O’Connor, S. E. Nat. Chem. Biol. 2018, 14, 760−763. (18) Beniddir, M. A.; Genta-Jouve, G.; Lewin, G. J. Nat. Prod. 2018, 81, 1075−1078. (19) Fox Ramos, A. E.; Alcover, C.; Evanno, L.; Maciuk, A.; Litaudon, M.; Duplais, C.; Bernadat, G.; Gallard, J.-F.; Jullian, J.-C.; Mouray, E.; Grellier, P.; Loiseau, P. M.; Pomel, S.; Poupon, E.; Champy, P.; Beniddir, M. A. J. Nat. Prod. 2017, 80, 1007−1014. (20) Yang, J. Y.; Sanchez, L. M.; Rath, C. M.; Liu, X.; Boudreau, P. D.; Bruns, N.; Glukhov, E.; Wodtke, A.; de Felicio, R.; Fenner, A.; Wong, W. R.; Linington, R. G.; Zhang, L.; Debonsi, H. M.; Gerwick, W. H.; Dorrestein, P. C. J. Nat. Prod. 2013, 76, 1686−1699. (21) Onanga, M.; Khunog-Huu, F. Séances Acad. Sci., Ser. C 1980, 291, 191−193. (22) Dai, J.-R.; Hallock, Y. F.; Cardellina, J. H.; Boyd, M. R. J. Nat. Prod. 1999, 62, 1427−1429. (23) For a recent review describing other examples of thioether bridge-containing alkaloids (i.e., Nuphar alkaloids), see: Zhan, Z.-J.; Ying, Y.-M.; Ma, L.-F.; Shan, W.-G. Nat. Prod. Rep. 2011, 28, 594− 629. (24) Pluskal, T.; Castillo, S.; Villar-Briones, A.; Orešič, M. BMC Bioinf. 2010, 11, 395. (25) MIADB is a MS/MS spectral database of 172 monoterpene indole alkaloids that can be accessed online on the GNPS. See: https://gnps.ucsd.edu/ProteoSAFe/libraries.jsp (accessed Aug 27, 2018). (26) Wang, M.; Carver, J. J.; Phelan, V. V.; Sanchez, L. M.; Garg, N.; Peng, Y.; Nguyen, D. D.; Watrous, J.; Kapono, C. A.; Luzzatto-Knaan, T.; Porto, C.; Bouslimani, A.; Melnik, A. V.; Meehan, M. J.; Liu, W.T.; Crusemann, M.; Boudreau, P. D.; Esquenazi, E.; SandovalCalderon, M.; Kersten, R. D.; Pace, L. A.; Quinn, R. A.; Duncan, K. R.; Hsu, C.-C.; Floros, D. J.; Gavilan, R. G.; Kleigrewe, K.; Northen, T.; Dutton, R. J.; Parrot, D.; Carlson, E. E.; Aigle, B.; Michelsen, C. F.; Jelsbak, L.; Sohlenkamp, C.; Pevzner, P.; Edlund, A.; McLean, J.; Piel, J.; Murphy, B. T.; Gerwick, L.; Liaw, C.-C.; Yang, Y.-L.; Humpf, H.U.; Maansson, M.; Keyzers, R. A.; Sims, A. C.; Johnson, A. R.; Sidebottom, A. M.; Sedio, B. E.; Klitgaard, A.; Larson, C. B.; Boya P, C. A.; Torres-Mendoza, D.; Gonzalez, D. J.; Silva, D. B.; Marques, L. M.; Demarque, D. P.; Pociute, E.; O’Neill, E. C.; Briand, E.; Helfrich, E. J. N.; Granatosky, E. A.; Glukhov, E.; Ryffel, F.; Houson, H.; Mohimani, H.; Kharbush, J. J.; Zeng, Y.; Vorholt, J. A.; Kurita, K. L.; Charusanti, P.; McPhail, K. L.; Nielsen, K. F.; Vuong, L.; Elfeki, M.; Traxler, M. F.; Engene, N.; Koyama, N.; Vining, O. B.; Baric, R.; Silva, R. R.; Mascuch, S. J.; Tomasi, S.; Jenkins, S.; Macherla, V.; Hoffman, T.; Agarwal, V.; Williams, P. G.; Dai, J.; Neupane, R.; Gurr, J.; Rodriguez, A. M. C.; Lamsa, A.; Zhang, C.; Dorrestein, K.; Duggan, B. M.; Almaliti, J.; Allard, P.-M.; Phapale, P.; Nothias, L.-F.; Alexandrov, T.; Litaudon, M.; Wolfender, J.-L.; Kyle, J. E.; Metz, T. O.; Peryea, T.; Nguyen, D.-T.; VanLeer, D.; Shinn, P.; Jadhav, A.; Muller, R.; Waters, K. M.; Shi, W.; Liu, X.; Zhang, L.; Knight, R.; Jensen, P. R.; Palsson, B. O.; Pogliano, K.; Linington, R. G.; Gutierrez, M.; Lopes, N. P.; Gerwick, W. H.; Moore, B. S.; Dorrestein, P. C.; Bandeira, N. Nat. Biotechnol. 2016, 34, 828−837. (27) The compound at m/z 723.358 was found unstable after its isolation and could not be characterized. However, its occurrence in the cluster and the difference of 16 Da compared to compound 1

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02961. Experimental procedures and 1D and 2D NMR spectra for 1−2 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Elvis Otogo N’Nang: 0000-0001-5904-7645 Guillaume Bernadat: 0000-0001-8955-0364 Erwan Poupon: 0000-0002-1178-6083 Pierre Champy: 0000-0003-2852-5098 Mehdi A. Beniddir: 0000-0003-2153-4290 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are very grateful to ANBG (Agence Nationale des Bourses du Gabon) for the fellowship 828988C (E.O.N.). In addition, this work was supported by the French ANR grant ANR-15CE29-0001. We thank Dr. Grégory Genta-Jouve (Université Paris-Descartes) for fruitful discussions, Karine Leblanc (BioCIS) for her assistance in the preparative HPLC purifications, Jean-Christophe Jullian (BioCIS) for performing the NMR analyses, Dr. Arnaud Leroy (Chiral-IST) for the acquisition of the CD spectra, and Dr. Jérôme Bignon (ICSN) for the cytotoxic assays. The IT Department of Université Paris-Sud is acknowledged for providing computing resources.

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