ALKALOIDS FROM THE HIPPEASTRUM GENUS: CHEMISTRY AND BIOLOGICAL ACTIVITY JEAN PAULO DE ANDRADEA, NATALIA BELÉN PIGNIA, LAURA TORRAS-CLAVERIAA, YING GUOA, STRAHIL BERKOVB, RICARDO REYES-CHILPAC, ABDELAZIZ EL AMRANID, JOSÉ ANGELO S. ZUANAZZIE, CARLES CODINAA, FRANCESC VILADOMATA, JAUME BASTIDAA* (Received June 2012; Accepted September 2012) ABSTRACT In recent years alkaloids from the genus Hippeastrum have been shown to exhibit a broad spectrum of biological activities, including antiparasitic, antiproliferative, apoptosis-induced, psychopharmacological, acetylcholinesterase-inhibitory, among others. This work presents a brief chemical and biological review of the alkaloids found in the genus Hippeastrum. www.relaquim.com Keywords: Amaryllidaceae, “hippeastroid” clade, Hippeastrum, montanine, candi- mine, 11β-hydroxygalanthamine. RESUMEN En los últimos años, los alcaloides aislados del género Hippeastrum han mostrado un amplio espectro de actividades incluyendo, entre otras, la antiparasitaria, an- tiproliferativas, inductoras de apoptosis, psicofarmacológicas y como inhibidores de la acetilcolinesterasa. En este trabajo se presenta una breve revisión química y biológica de los alcaloides del género Hippeastrum. www.relaquim.com Palabras clave: Amaryllidaceae, clado “hippeastroid”, Hippeastrum, montanina, candimina, 11β-hidroxigalantamina. aDepartament de Productes Naturals, Biologia Vegetal i Edafologia. Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, España bAgroBioInstitute, 8 Dragan Tzankov Blvd., Sofia, 1164, Bulgaria cInstituto de Química, Universidad Nacional Autónoma de México. Circuito Exterior s/n. Ciudad Universi- taria, Coyoacán, 04510, México DF dFaculté des Sciences Aîn –Chock, Laboratoire de Synthèse, Extraction et Etude Physico-Chimique des Molécules Organiques, BP5366, Mâarif – Casablanca, Morocco eFaculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, 90610-000, Porto Alegre, Brasil *Corresponding author. Tel.: +34 934020268; fax: +34 934029043. E-mail address: [email protected] (J. Bastida). 83 84 J.P. DE ANDRADE, N. B. PIGNI, L. TORRAS-CLAVERIA, ET AL. 1. INTRODUCTION tetraploid and extra-Andean “hippeastroid” clades. In addition, a probable Brazilian Hippeastrum is a well-known ornamental origin of the Hippeastrum genus has been Amaryllidaceae genus from South Ameri- accepted, based on its nrDNA ITS sequen- ca, particularly Brazil. The Amaryllidaceae ces (Meerow et al., 2000). The Hippeastrum family is one of the 20 most important genus comprises approximately 70 species alkaloid-containing plant families, compri- (Judd et al., 1999), 34 being found in Brazil sing about 1100 perennial bulbous species with 22 endemics (Dutilh, 2010). Although classified in 85 genera. A particular cha- few of them have been studied to date, racteristic of Amaryllidaceae plants is the compounds with remarkable biological consistent presence of a large, exclusive activity have been isolated in Hippeastrum and still expanding group of isoquinoline species. Presented here is a brief overview alkaloids, the majority of which are not of the phytochemical and biological studies known to occur in any other plant family of the Hippeastrum genus up to May, 2012. (Bastida et al., 2006). Their highly particular skeleton arrange- ments and broad spectrum of biological ac- 2. GEOGRAPHICAL DISTRIBUTION, tivities have prompted numerous chemical TAXONOMICAL ASPECTS and pharmacological studies of this group of alkaloids. As an example, the well-known The Hippeastrum genus is distributed from Amaryllidaceae alkaloid galanthamine (50) Mexico and the West Indies to Argentina, is a long-acting, selective, reversible and the majority in eastern Brazil, the Peruvian competitive inhibitor of the acetylcholi- Andes and Bolivia. It basically consists of nesterase enzyme (Thomsen et al., 1998) large herbs of annual leaves, mostly hys- as well as acting as an allosterically po- teranthous, sessile, rarely persistent, and tentiating ligand in nicotinic acetylcholine subpetiolate. Generally, the leaves are more receptors (Maelicke et al., 2001). Due to than 2 cm wide. The scape is hollow with 2 these attributes, galanthamine (50) is one free bracts. The flowers (2-13) are usually of the most important drugs used for the large and mostly purple or red. They are clinical management of Alzheimer’s disease funnelform, zygomorphic, declinate, usua- (AD) and is also useful in poliomyelitis and lly with a short tube and paraperigonal other neurological diseases. It is marketed fibriae or with a callose ridge present at as a hydrobromide salt under the name of the throat. The stamens are fasciculate and Razadyne® (formerly Reminyl®). As a result declinate-ascendent. The stigma is trifid or of these and other activities demonstrated shortly 3-lobed. The seeds are dry, flatte- by the other skeleton-types (da Silva et al., ned, obliquely winged or irregularly discoid, 2006; McNulty et al., 2007; Giordani et al., hardly ever turgid and globose or subglobo- 2010a, 2011a), plants from the Amaryllida- se, with a brown or black phytomelanous ceae family are currently seen as an impor- testa (Dahlgren et al., 1985; Meerow and tant source of new and bioactive molecules. Snijman, 1998). The Amaryllidaceae are found mainly A diploidism of 2n=22 is characteristic in the Southern Hemisphere, especially in of the Hippeastrum genus, which is inar- South Africa and South America, which are guably monophyletic with the exception considered to be the primary and secondary of a single species, Hippeastrum blumena- centers of diversification, respectively, of vium. This was first described as Griffinia this family (Ito et al., 1999). Recent nrDNA blumenavia Koch and Bouche ex Carr and ITS sequence studies have divided the Ame- further studies are required to clarify its rican Amaryllidaceae species in Andean correct position (Meerow et al., 2000). Alkaloids from the Hippeastrum genus: chemistry and biological activity Rev. Latinoamer. Quím. 40/2(2012) 85 The beauty of their flowers has led L-tyrosine (Bastida et al., 2006). Most of to numerous Hippeastrum species being them can be classified into nine skeleton- grown as ornamentals after hybridization types (Figure 1), namely lycorine, crinine, (Meerow and Snijman, 1998), although in haemanthamine, narciclasine, galantha- horticultural circles the use of the name mine, tazettine, homolycorine, montanine “Amaryllis” for this genus persists (Meerow and norbelladine (Bastida et al., 2006). et al, 1997). Ortho-para’ phenol oxidative coupling of the precursor O-methylnorbelladine re- sults in the formation of a lycorine-type 3. BIOSYNTHESIS AND STRUCTURAL TYPES skeleton, from which homolycorine-type OF AMARYLLIDACEAE ALKALOIDS compounds proceed. Para-para’ phenol oxidative coupling leads to the formation As mentioned above, the consistent pre- of crinine, haemanthamine, tazettine, nar- sence of an exclusive group of isoquinoline ciclasine and montanine structures. The alkaloids is the outstanding feature of the galanthamine-type skeleton is the only Amaryllidaceae plant species. Amaryllida- one that originates from para-ortho’ phenol ceae alkaloids are formed biogenetically by oxidative coupling (Bastida et al., 2006). In intramolecular oxidative coupling of the key the present review, the numbering system intermediate O-methylnorbelladine, derived according to Ghosal et al. (1985) has been from the amino acids L-phenylalanine and adopted for the structures (Figure 1). L-Phe L-Tyr 3 HO 4 2 HO HO 5' 1 5 HO 4' 6' 6 CHO HO 3' 1' NH H N HO 2' 2 Protocatechuic aldehyde Norbelladine Tyramine O-methylation HO MeO para-ortho' orto-para' NH HO OH 2 3 OH O-methylnorbelladine 1 2 O 4 HO 1 3 10b 10 MeO 10a 4a 10 H para-para' 9 11 10b 4 12 9 10a O 4a 11 8 H 6a 7 6 NMe 8 6a N 12 2 2 O 7 6 3 OH 3 OMe 1 1 11 Galanthamine Lycorine 11 OH 10 4 10 9 10a 4a 4 O 10b O 9 10a 10b 4a 12 H 12 H 8 6a N 8 6a N O 7 6 O 7 6 Haemanthamine Crinine 12 11 MeN 4 3 4a 10 H 10bH 2 MeO 9 10a OH 1 OMe 2 H 3 1 3 OH 8 6a 6 O 4 OMe 2 1 MeO 7 2 10 H H 11 4a 10 11a 9 10a 10b 4 1 10a 3 O O 10 NMe O 9 4a OH 10a 12 OH O 9 10b 11 12 4a Homolycorine 4 O 8 6a 6 NH OH O 8 6a H 7 8 6a O 7 6 N O 7 6 OH O Tazettine Montanine Narciclasine Figure 1. Biosynthetic pathway of the main skeleton-type found in the genus Hippeastrum. 86 J.P. DE ANDRADE, N. B. PIGNI, L. TORRAS-CLAVERIA, ET AL. Some new structural subgroups have 4. DISTRIBUTION OF ALKALOIDS IN THE been proposed recently (Ünver, 2007). GENUS HIPPEASTRUM Graciline and plicamine-type alkaloids have been found in species of Galanthus, Phytochemical studies of the genus Hip- Cyrthanthus and Narcissus (Ünver et al., peastrum, as well as of other genera of the 1999; Brine et al., 2002; de Andrade et al., Amaryllidaceae family, started in the early 2012). The biogenetic pathway of gracilines 1950s. The alkaloids reported in the genus possibly originates from the 6-hydroxy de- Hippeastrum are summarized in Table 1 rivatives of haemanthamine-type alkaloids and their respective structures are shown (Noyan et al., 1998), while plicamine-type in Figure 2. The first phytochemical study alkaloids most probably proceed from the was described with varieties of H. vittatum, tazettine-type skeleton, considering their which yielded the alkaloids tazettine (39) structural similarities. Augustamine-type and lycorine (1) (Boit, 1954). Two years la- alkaloids represent a very rare structure ter, a new phytochemical study of the same found in Crinum species (Ali et al., 1983; species yielded the alkaloids haemantha- Machocho et al., 2004). Galanthindole (62) mine (26), homolycorine (14), hippeastrine is another example of an unusual com- (15), and vittatine (27), as well as tazettine pound isolated from the Galanthus genus (39) and lycorine (1) (Boit, 1956). In 1957, and also found in Hippeastrum genus. It a study of H. bifidum only yielded lycorine has been classified as a new skeleton-type (1) (Boit and Döpke, 1957). One year later, (Ünver et al., 2003), although the possibility galanthamine (50) was found for the first that it is an artifact from the homolycori- time in a Hippeastrum species, specifically ne series should be considered.