Phytochem Rev (2020) 19:615–641 https://doi.org/10.1007/s11101-018-9598-5 (0123456789().,-volV)(0123456789().,-volV) Chemistry and biological activity of alkaloids from the genus Schizanthus Philippe Christen . Sylvian Cretton . Munir Humam . Stefan Bieri . Orlando Mun˜oz . Pedro Joseph-Nathan Received: 15 October 2018 / Accepted: 12 December 2018 / Published online: 1 January 2019 Ó Springer Nature B.V. 2019 Abstract The genus Schizanthus (Solanaceae) com- Keywords Solanaceae Á Tropane ester derivatives Á prises 12 accepted species primarily endemic to Chile. Analysis Á Configurational and positional isomers Á It is characterized by the presence of numerous Absolute configuration tropane alkaloids found as ester derivatives of iso- meric acids like angelic, senecioic, or tiglic, as well as Abbreviations mesaconic, itaconic, and citraconic acids, leading to AC Absolute configuration numerous positional and configurational isomers. Up BA 6-Benzylaminopurine to now 50 alkaloids with these esters have been CE Capillary electrophoresis isolated and most of them are fully characterized. COSY Correlation spectroscopy Analytical methods and techniques engaged during Da Dalton the investigation of this class of compounds, as well as DFT Density functional theory their identification capabilities, are discussed. In ECD Electronic circular dichroism several cases the absolute configuration is also well EI Electron impact established, and some alkaloids are reported as FID Flame ionization detector biologically active. This review summarizes updated FTIR Fourier transform infrared information on the distribution, botanical characteris- GC Gas chromatography tics, phytochemical, and pharmacological knowledges HMBC Heteronuclear multiple bond correlation of this genus up to mid-2018. HPLC High performance liquid chromatography P. Christen (&) Á S. Cretton Á M. Humam Á S. Bieri HPTLC High performance thin-layer School of Pharmaceutical Sciences, University of Geneva, chromatography University of Lausanne, Rue Michel-Servet 1, HRESIMS High-resolution electrospray ionization 1211 Geneva 4, Switzerland e-mail: [email protected] mass spectrometry HSQC Heteronuclear single-quantum O. Mun˜oz correlation Departamento de Quı´mica, Facultad de Ciencias, IR Infrared Universidad de Chile, Casilla 653, Santiago, Chile ITMS Ion trap mass spectrometry P. Joseph-Nathan IUPAC International union of pure and applied Departamento de Quı´mica, Centro de Investigacio´nyde chemistry Estudios Avanzados del Instituto Polite´cnico Nacional, LLE Liquid–liquid extraction Apartado 14-740, 07000 Mexico City, Mexico 123 616 Phytochem Rev (2020) 19:615–641 MEKC Micellar electrokinetic chromatography tropane, indole, pyridine, pyrrolidine, steroidal and MS Mass spectrometry glycoalkaloids (Eich 2008). From them, tropane MW Molecular weight alkaloids occur in several genera like Atropa, Brug- NACE Non aqueous capillary electrophoresis mansia, Datura, Duboisia, Hyoscyamus, Latua, Man- NOESY Nuclear Overhauser effect spectroscopy dragora, Schizanthus, and Scopolia, but also in other NMR Nuclear magnetic resonance families like Brassicaceae, Convolvulaceae, Euphor- PGC Porous graphitic carbon biaceae and Erythroxylaceae (including coca), and NAA 1-Naphthaleneacetic acid more sporadically in Proteaceae and Rhizophoraceae NPD Nitrogen phosphorus detector (Christen 2000; Griffin and Lin 2000). SPE Solid phase extraction In turn, tropane alkaloids are structurally-related TDDFT Time dependent density functional natural products possessing the 8-methyl-8-azabicy- theory clo[3.2.1]octane skeleton, although for simplicity they TLC Thin-layer chromatography are generally referred to as substituted tropanes. This TOFMS Time-of-flight mass spectrometry important class of natural products has already UHPLC Ultra-high performance liquid provided ca. 250 compounds (Christen et al. 2013), chromatography which are divided into two main groups, 3a- and 3b- UV Ultraviolet hydroxytropanes, according to the pseudo-axial or VCD Vibrational circular dichroism pseudo-equatorial orientation, respectively, of the substituent at C-3. The former are the most frequently encountered molecules, whereas 3b-hydroxytropanes are mainly found in the Erythroxylaceae family (e.g. Introduction cocaine). Most representatives are 3-, or 6-hydroxy, 3,6- or 6,7-dihydroxy, or 3,6,7-trihydroxytropanes According to The Plant List (ThePlantList 2013), the esterified with various organic acids. Solanaceae family comprises 115 genera and 2678 For correct nomenclature purposes it should be species distributed in both warm and temperate noted that unsubstituted tropane has a plane of regions of the World with the greatest concentration symmetry that goes through C-3 and the nitrogen of genera and species in South- and Central-America. atom, and bisects the C-6–C-7 bond, which means for This family includes many species of agricultural and instance that 3-hydroxytropane is a meso optically economic relevance. Several of them, such as tomato, inactive molecule. When a substituent is found at C-6 Cayenne pepper, eggplant or potatoes are widely the molecule becomes optically active and now cultivated since they are among the most commonly possesses three stereogenic centers which are defined edible vegetables in the World. The leaves of dried and in Fig. 1 for both enantiomers of 6b-hydroxytropane. fermented tobacco are smoked worldwide. Other The atom numbering is now clockwise or counter- plants from this family are toxic and some of them clockwise according to the S or R absolute configu- are used recreationally or during shamanic ceremonies ration (AC), respectively, of the stereogenic center at (e.g. Datura spp., Brugmansia spp. (tree-datura), C-6, and all three stereogenic descriptors might be Brunfelsia spp.) with poisoning frequently reported. given as shown in Fig. 1. Other species such as Atropa belladonna L., Datura stramonium L. and to a lesser extent Hyoscyamus niger L. are notorious examples of pharmaceutical relevant species. They contain a wide range of N N alkaloids, some of them with considerable therapeutic HO 5 7 1 activities. HO 1 5 The alkaloid content in the Solanaceae family 7 3 3 differs by species and typically accounts between 1R,5S,6R- 1S,5R,6S- modest 0.01 up to 3% (Oksman-Caldentey and Arroo 2000). The recorded types of alkaloids include Fig. 1 Both enantiomers of 6b-tropanol showing atom num- bering and stereochemical descriptors 123 Phytochem Rev (2020) 19:615–641 617 About 40 organic acids have been identified as well as two brother subclades, one of which includes S. esterifying acids so far (Lounasmaa and Tamminen litoralis Phil. and S. porrigens Graham, while the other 1993) which include acetic, tropic, angelic, senecioic, one groups together S. tricolor Grau & Gronb., S. tiglic, cinnamic, mesaconic, itaconic, and citraconic pinnatus Ruiz & Pav., and S. parvulus Sudzuki acids. The numbering of tropane alkaloids has often (Scheme 1) (Mun˜oz-Schick and Moreira-Mun˜oz been confusing in the literature because the strict 2008). application of IUPAC rules is not always followed. Their notation as 3,6/7-disubstituted derivatives has Distribution of the genus frequently been chosen arbitrarily (Humam et al. 2008; Lounasmaa and Tamminen 1993) although a This genus is primarily native to Chile and the species designation like 3,7-dihydroxytropane is incorrect, grow in a large diversity of habitats, from the desert to since IUPAC recommends the use of the smallest the coast in the Tarapaca´ region, as well as from the possible numbers. When a 3,6-dihydroxytropane is high Andes to areas cleared of forest in the southern considered, then four stereogenic descriptors (Mun˜oz Chilean region of Los Lagos (Fig. 2). The distribution et al. 2016), at C-1, C-3, C-5, and C-6 are required for a of S. grahamii and S. hookeri reaches central Chile complete molecular description, and the careful areas bordering Argentina. application of hierarchical digraphs (Zepeda et al. The most widely distributed species is S. pinnatus, 2011) for the unequivocal assignment of stereochem- inhabiting the Coquimbo and Los Lagos regions, ical descriptors can be of great help. while the species with the smallest distributions are S. The development of advanced analytical spectro- lacteus on coast areas of the Antofagasta region, and S. metric and spectroscopic technologies over the last parvulus on the coast and inland in the Choapa two decades allowed the isolation and characterization province of the Coquimbo region (Mun˜oz-Schick and of a large number of new chemical entities. A review Moreira-Mun˜oz 2008). reporting 125 tropane alkaloids identified since 1993 The 12 species comprising the genus Schizanthus together with synthetic approaches has been published are commonly known as little bird, little bird flower, very recently (Afewerki et al. 2018). The present re- little butterfly, or butterfly of the coast. S. pinnatus was view accounts all alkaloids so far isolated from the the first species described by the Spanish explorers and genus Schizanthus, and the biological activities of botanists Ruiz and Pavo´n as early as 1794 (Ruiz and some extracts and pure alkaloids isolated from them Pavo´n 1794), while the last valid species, S. parvulus, are covered up to mid-2018. was described by Sudzuki in 1945 (Sudzuki 1969). Some species have been imported to Europe for cultivation. Several species were described in England Relationships between the Schizanthus species like S. porrigens, and S. grahamii in 1824, while later S. retusus