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Song, Qi; Fischer, Nikolaus H. Biologically active and neolignans from Magnolia species Journal of the Mexican Chemical Society, vol. 43, núm. 6, noviembre-diciembre, 1999, pp. 211-218 Sociedad Química de México Distrito Federal, México

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Revisión Biologically Active Lignans and Neolignans from Magnolia Species

Qi Song and Nikolaus H. Fischer*

Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, USA

Resumen. Algunos miembros del género Magnolia (familia Magno- Abstract. Members of the genus Magnolia (family Magnoliaceae), liaceae), que tienen un amplio uso en la medicina tradicional, son which have long been used in folk medicine, are rich in lignans, ricos en lignanos, neolignanos, sus oligómeros y en estructuras híbri- neolignans, their oligomers and hybrid structures. This review covers das. Esta revisión cubre la distribución y las actividades biológicas de the distribution and biological activities of this class of natural prod- este grupo de productos naturales. Se incluyen las estructuras quími- ucts. Also, the chemical structures of lignans, neolignans, oligomeric cas de los lignanos, neolignanos, lignanos oligoméricos y lignanos lignans and biosynthetically “mixed” terpenoid lignans from 19 dif- terpenoidales biosintéticamente mixtos, y se discuten sus bioactivi- ferent Magnolia species are summarized and their bioactivities are dades. discussed.

Introduction These dimers are formed biogenetically through the shikimate pathway [14]. Norlignans are defined as Various taxa of the genus Magnolia (family Magnoliaceae) a group of related natural compounds, usually found to co- have long been used in folk medicine, and have attracted con- occur with lignans or neolignans, which have a C16 to C17 core siderable interest with respect to structural determinations of structure, and they are apparently biosynthetically derived their biologically active metabolites for their potential use as from two arylpropane units by loss of one or two carbons, pharmaceuticals and/or agrochemicals. Members of this genus probably through decarboxylations. As summarized in Figs. 1 are known to be rich in a wide variety of biologically active and 2, in this review the lignans, neolignans as well as compounds including lignans, neolignans, terpenoids as well oligomeric lignans, hybrid lignans and norlignans are divided as alkaloids [1]. In many Magnolia species, lignans and into twelve subgroups (A-L) dependent upon common struc- neolignans represent the major chemical constituents. Several tural features. Group B represents substituted tetrahydrofurans reviews covering the structural aspects of lignans are available including 2,5-diaryl-3,4-dimethyltetrahydrofurans and 2,4- [2-7] and their biological activities have also been reviewed diaryl-3,5-dimethyltetrahydrofurans. Hybrid neolignans [8]. However, no comprehensive review of lignans and neolig- (group I) consist of monoterpene- and sesquiterpene-neolig- nans from the genus Magnolia is available. This summary of nans, and group J includes di- and tri-lignans. The skeletal the distribution and chemical structure of lignans and neolig- types of these twelve groups are presented in Figs. 1 and 2. nans from Magnolia also includes a discussion of their biolog- An earlier comprehensive review on the distribution of ical activities. lignans and neolignans in the plant Kingdom is available [15]. As shown in Figs. 1 and 5, lignans are defined as dimers Lignans and neolignans from the genus Magnolia are summa- of phenylpropanoid (C6-C3) units linked by the central carbons rized in Table 1, which lists compounds from 19 different b-b’ (C8-C8’) (A-D) of their side chains [9, 11]. In contrast, species. Lignans have been isolated from various parts of naturally occurring dimers that exhibit linkages other than this Magnolias: tree bark [16, 17], leaves and stems [18-20], root b-b’-type linkage are known as neolignans (Fig. 2) [12, 13]. bark [21], flower buds [22], and seeds [23]. A wide spectrum of biological activities of lignans and neolignans have been reported. This includes cytotoxic, anti-tumor, anti-leukaemia, * Corresponding author. New address: Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences. School of Pharmacy, The anti-viral, anti-microbial, anti-inflammatory, anti-allergy, as University of Mississippi, University, MS 38677, USA. Fax: 662-915-7026; well as anti-fungal, insecticidal and miscellaneous physiologi- E-mail: [email protected] cal effects [5, 8]. They may also play a significantly ecological 212 Rev. Soc. Quím. Méx. Vol. 43, Núm. 6 (1999) Qi Song and Nikolaus H. Fischer role as mediators in plant-fungi, plant-plant, and plant-insect interactions [8]. At the molecular level, they interrupt the syn- thesis of DNA and the transport of nucleotides and are inhibitors of key enzymes [8, 24].

Lignans and neolignans: structure and biological activity Fig. 1. Structural Types of Lignans.

Flower buds of Magnolia salicifolia Maxim. have been used in traditional Kampo and Chinese medicines, especially for (18) was reported to be responsible for the piscici- nasal allergy and nasal empyema. Chloroform extracts of this dal activity of this plant [34], while (25) and its medicinal plant exhibited a remarkable anti-allergy activity in 4’-O-b-D-glucopyranoside (26) from in M. officinalis exhibit- passive cutaneous anaphylaxis (PCA) tests [25, 26]. Along ed remarkable cytotoxic and anti-leukaemic activities [16, 35]. with two other neolignans, magnosalin (1) (Fig. 3) was isolat- Other biological activities of this group of compounds also ed in the course of a search for biologically active principles include the germination inhibitory activity of fargesin (14) from this plant [25, 26]. However, none of the pure com- [36], enhancing toxicity of insecticides of (22) [37] pounds were active [22]. and anti-hypertensive activity of pinoresinol (18) [38]. A number of substituted tetrahydrofuran-type lignans (2- Only two compounds of the arylnaphthalene group, gua- 10) have been isolated from Magnolia species. Magnosalicin iacin (28) [45] and magnoshinin (29) [25, 26] have been iso- (7) was isolated from M. salicifolia [25, 26]. The root bark of lated from M. kachirachira and M. salicifolia, respectively, M. acuminata L., a tall native forest tree of the eastern and but no biological activity was reported. mainly southern United States, which was used in the treat- The spirocyclohexadienone denudatone (30) and futoe- ment of malaria and rheumatism in the past, afforded three none (31) are the only two spiro- (5,5)- undecanoids neolig- compounds, galgravin (2), calopiptin (3) and veraguensin (5) nans found in family Magnoliaceae [3, 6]. They were isolated [21], the latter compound also being present in M. liliflora from the aerial parts of the Japanese ornamental plants M. [20], M. denudata [21] and M. saulangiana [39]. The 2,4- denudata and M. liliflora Desr. [20, 39]. Biogenetically, the diaryl-dimethyltetrahydrofurans fargesol (6) from M. fargesii formation of denudatone (30) can be formulated as an oxida- [27], magnostellin A (8) and B (9) from M. stellata Maxim. tive coupling of propenylphenol or allylphenol derivatives fol- [28] appear to be formed by the formal cleavage of a C-O lowed by stereoselective reactions of a quinone methide inter- bond. Such cleavages might in some cases be a mode of mediate [40]. biosynthesis. Magnostellin B (9) is included here since its Benzofuranoids and hydrobenzofuranoids are well repre- structure can be formally derived from a dioxabicyclooctane sented in the genus Magnolia. In search for Ca2+ -antagonist (C, Figure 1) by C-C cleavage. The determination of the stere- activity on the taenia coli of the guinea pig from the Chinese ochemistry for these types of compounds made extensive use herb hsin-i (M. fargesii), fargesones A (47), B (48), and C of NMR studies, X-ray analysis, chemical interconversions, (49), in which a resorcinol nucleus appears as a substituted and structural comparisons with compounds of known cyclohexenone, were isolated from the flower buds of M. far- absolute configuration [29]. The 2,3-diaryl-3,7-dioxabicyclo[3.3.0]octanes-type lig- nans (Fig. 1, C) represent one of the largest groups of lignans found in the genus Magnolia (Table 1). Among seventeen compounds, aschantin (11), demethoxyaschantin (12), far- gesin (14), magnolin (16), pinoresinol dimethyl ether (19) and liroresinol-B, isolated from flower buds of M. biondii Pump., have demonstrated antagonistic activities against platelet acti- vating factor in the [3H]PAF receptor binding bioassay, which may have potential use in the treatment of inflammation, car- diovasular and pulmonary diseases [30]. Some of these com- pounds are also present in other Magnolia species (Table 1), M. stellata Maxim. [28], M. fargesii [31], M. kobus [19], M. pterocarpa [32], M. officinalis Rehd. et Wils. [33], and M. saulangiana [33]. Flower buds of M. fargesii are also rich in the diaryl-dioxabicyclo[3.3.0]octane lignans, with nine lig- nans being present. This includes phillygenin (13), epimagno- lin (15), de-O-methylmagnolin (17), pinoresinol (18), eudesmin (19) and epimagnolin A (20) [30, 34, 35]. Fig. 2. Structural Types of Neolignans. Biologically Active Lignans and Neolignans from Magnolia Species 213 gesii [41]. The leaves of M. denudata afforded butchellin (32), denudatins A (33) and B (34) [20], which were also present in fresh leaves of M. liliflora [42] and other Magnolia species (Table 1). The above dienones are acid-sensitive, and depen- dent on the solvent used, rearrangements induced by an acidic ion-exchange resin can take two different courses [43]. The structurally related liliflone (44), piperenone (45), and saulan- gianin (46) were isolated from leaves of M. liliflora, and flower buds of M. saulangiana. [42, 44] M. kachirachirai yielded licarin A (36), licarin B (37), kachirachirol A (39) and B (38) as well as eupomatenoids-1 (40) and eupomatenoids-7 (41) [45]. The biphenyl lignanoids (51) and (52) have been isolated and identified as active principles of the Chinese folk medicine Houpo (bark of M. officinalis) with antimicrobial activity [46, 49], central depressent effect [50] as well as inhibition of skin tumors promotion [49]. A number of other Magnolia species including M. biloba [47], M. gran- diflora [23], M. henryi [51], M. liliflora [52], M. obovata [53, 54], M. rostrata [47], M. tripetala [55], M. virginiana [18], and M. watsonii. [56] contain these type of compounds. Hybrid neolignans, oligomeric neolignans, norlignans, and biphenyl-type neolignans, including randainal (56), magnalde- hyde B (57), magnaldehyde C (58), magnolignan A (59), magnolignan B (60), magnolignan C (61), and magnolignan D (62) were previously discussed [16]. The isolation of a different skeletal type of biphenyl ethers, (63) and obovatal (66) from M. obovata Thunb. has been reported [54]. Compound 63 showed strong antibacterial activity against the cryogenic bacterium Strepto- coccus mutans, but was less active than magnolol (51) and honokiol (52). A 1,2-diarylpropane-type neolignan with a new ring skeleton, biondinin A (68) from M. biondii was reported [57]. Compounds 67 and 69 represent two further different skeletal types of this group of neolignans [16, 44]. A significant number of hybrid lignans are of mixed bio- genetic origin with structures that are characterized by cou- pling between lignans and terpenoid units. In search for neu- rotrophic-active ingredients from the bark of M. obovata [17, 58, 60], a series of seven sesquiterpene-type neolignans have been isolated. They are hybrids of eudesmane-type sesquiter- penes linked to biphenyl or biphenylether type neolignans: eudesmagnolol (70), clovanemagnolol (71), caryolanemag- nolol (72), eudesobovatol A (73), eudesobovatol B (74), eudeshonokiol A (75), and eudeshonokiol B (76). A possible biosynthetic pathway of the sesquiterpene-neolignans was proposed by addition of the neolignan moiety acting as a nucleophile to a cation intermediate formed in the course of a transannular cyclization of a germacradiene-type compound resulting in the eudesmol-type sesquiterpene hybrid lignans [59]. Clovanemagnolol (71), caryolanemagnolol (72), and eudesobovatol A (73) accelerated neuritic sprouting and neu- ronal cell network formation but also enhanced choline acetyl- transferase activity in cultured neuronal cells derived from the Fig. 3. Lignans and Neolignans from Magnolia Species. fetal rat hemisphere. The bark of M. officinalis afforded four (figure con’d.) 214 Rev. Soc. Quím. Méx. Vol. 43, Núm. 6 (1999) Qi Song and Nikolaus H. Fischer

(figure con’d.) (figure con’d.) Biologically Active Lignans and Neolignans from Magnolia Species 215

4. Whiting, D. A. Natural Product Reports 1985, 2, 191-211. 5. Whiting, D. A. Natural Product Reports 1987, 4, 499-525. 6. Whiting, D. A. Natural Product Reports 1990, 7, 349-364. 7. Gottlieb, O. R. in: Progress in the Chemistry of Organic Natural Products. Herz, W.; Grisebach, H.; Kirby, G. W. Eds.; Springer- Verlag, Wien 1978, 35, pp1-72. 8. MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 23, 1207-1220. 9. Haworth, R. D. Nature (London) 1941, 147, 225. 10. Haworth, R. D. J. Chem. Soc. 1942, 448-456. 11. Ayres, A. C.; Lioke, J. D. Definition of Neolignans. Cambridge University Press, London, 1990. 12. Gottlieb, O. R. Phytochemistry 1972, 11, 1537-1570. 13. Gottlieb, O. R.; Yoshifa, M. in: Natural Products of Woody Plants. Rowe, J. W., (ed.); Springer, Berlin, 1989. 14. Mann, J. Secondary Metabolism (2nd edn); Oxford University Press, New York, 1987. 15. Cole, J. R.; Weidhopf, R. M. in: Chemistry of Lignans. Rao, C. B. S., (ed.); Andhra University Press, India, 1978. 16. Yahara, S.; Nishiyori, T.; Kohda, A.; Nohara, T.; Nishioka, I. Fig. 4. Abbreviations of Aryl Groups. Chem. Pharm. Bull. 1991, 39, 2024-2036. 17. Fukuyama, Y.; Otoshi, Y.; Miyoshi, K.; Nakamura, K. Tetrahedron 1992, 48, 377-392. monoterpene-type lignans, piperitylmagnolol (77) [49], piper- 18. Nitao, J.; Nair, M. G.; Thorogood, D. L.; Johnson, K. S.; Scriber, itylhonokiol (78), bornylmagnolol (79) and dipiperitylmag- J. M. Phytochemistry 1991, 30, 2193-2195. nolol (80), which represent the first reported monoterpenoid- 19. Iida, T.; Nakano, M.; Ito, K. Phytochemistry 1982, 21, 673-675. 20. Iida, T.; Ichino, K.; Ito, K. Phytochemistry 1982, 21, 2939-2941. neolignans [16]. 21. Doskotch, R. W.; Flom, M. S. Tetrahedron 1972, 28, 4711-4717. Oligomeric lignans and neolignans arise from the cou- 22. Tsuruga, T.; Ebizuka, Y.; Nakajima, J.; Chun, Y.-T.; Noguchi, pling of more than two Ar-C3 units. Trimers (sesquilignans), H.; Iitaka, Y.; Sankawa, U. Chem. Pharm. Bull. 1991, 39, 3265- tetramers (dilignans) and pentamers have been isolated from 3271. Magnolia. From the bark of M. obovata a novel trilignan, 23. El-Feraly, F. S.; Li, W.-S. Lloydia 1978, 41, 442-449. 24. Kimura, M.; Suzuki, J.; Yamada, T.; Yoshizaki, M.; Kikuchi, T.; magnolianin (81), which is a potent 5-lipoxygenase inhibitor, Kadota, S.; Mutsuda, S. Planta Med. 1985, 51, 291-293. was isolated and identified by extensive 2D- NMR studies and 25. Kikuchi, T.; Kadota, S.; Yanada, K.; Tanaka, K.; Watanabe, K.; chemical modifications [61]. M. obovata will continue to Yoshizaki, M.; Yokoi, T.; Shingu, T. Chem. Pharm. Bull. 1983, attract the attention of phytochemists because it provides new 31, 1112-1114. neolignans of novel skeletal types with interesting biological 26. Tsuruga, T.; Ebizuka, Y.; Nakajima, J.; Chun, Y.-T.; Noguchi, H.; Iitaka, Y.; Sankawa, U. Tetrahedron Lett. 1984, 25, 4129-4132. activities. Several dilignans were isolated from M. officinalis, 27. Huang, Y. L.; Chen, C. C.; Chen, Y. P.; Hsu, H. Y.; Kuo, Y. H. including magnolignans F (82), G (83), H (84) and I (85). Planta Med. 1990, 56, 237-238. However, oligomeric lignans are rare in Nature.

Norlignans with a C16 or C17 core unit are usually found to co-occur with lignans or neolignans of similar structures. A num- ber of norlignans, randaiol (86), magnatriol B (87), magnaldehyde D (88), magnalde- hyde E (89) and magnolignan E (90), have been isolated from the bark of M. offici- nalis [16], as well as obovaaldehyde (91) from the fresh leaves of M. obovata [54]. Finally, the bicyclooctanoid neolignan (92) was obtained from M. liliflora [42].

References

1. Hegnauer, R. Dicotyledoneae: Magnolia- ceae to Zygophyllaceae Birkhäuser Verlag, Basel, 1990. 2. Jensen, S.; Hansen, J.; Boll, P. M. Phyto- chemistry 1993, 33, 523-530. 3. Ward, R. S. Natural Product Reports 1993, 10, 1-28. Fig. 5. Biogenesis of Major Types of Lignans and Neolignans. 216 Rev. Soc. Quím. Méx. Vol. 43, Núm. 6 (1999) Qi Song and Nikolaus H. Fischer

Table 1. Distribution of Lignans and Neolignans in the Genus Magnolia.

Str. No. Name of Compound Species References Str. No. Name of Compound Species References

Diaryl-dimethylcyclobutane 25 Syringaresinol M. officinalis 16 (Str. Type A) 26 Syringaresinol 4’-O- M. officinalis 16 1 Magnosalin M. salicifolia Maxim. 25, 26 glucopyranoside M. grandiflora 62 27 (+)-Piperitol M. stellata 28 Substituted Tetrahydrofurans (Str. Type B) Arylnaphthalene Derivatives 2 Galgravin M. acuminata L. 21 (Str. Type D) 3 Calopiptin M. acuminata 21 28 Guaiacin M. kachirachirai 45 4 Galbacin M. kachirachirai Dandy 45 29 Magnoshinin M. salicifolia 25, 26 5 Veraguensin M. liliflora Desr. 20 (M. quinquepeta) Spirocyclohexadienone M. denudata Desr. 21 (Str. Type E) M. saulangiana 39 30 Denudatone M. denudata 20 M. acuminata 44 (= Maglifloenone) M. liliflora 39 6 (-)-Fargesol M. fargesii 27 31 Futoenone M. denudata 20 7 Magnosalicin M. salicifolia 22, 26 M. liliflora 39 8 Magnostellin A M. stellata Maxim. 28 9 Magnostellin B M. stellata 28 Benzofuranoide and hydrobenzofuranoide 10 Magnolenin C M. grandiflora L. 62 (Str. Type F) 32 Burchellin M. denudata 20 2,6-bisaryl-3,7-dioxabicyclo[3,3,0]octane M. liliflora Desr. 42 (Str. Type C) 33 Denudatin A M. denudata 20 11 Aschantin M. biondii Pump. 30 M. liliflora 42 12 Demethoxyaschantin M. biondii 28 M. saulangiana 44 M. stellata 30 34 Denudatin B M. denudata 20 13 (+)-Phillygenin M. fargesii 19 M. liliflora 41 M. kobus 63 M. fargesii 42 14 (+)-Fargesin M. fargesii 30 M. saulangiana 44 M. biondii 32 35 Acuminatin M. acuminata L. 21 M. pterocarpa 63 (=Dehydrodiisoeugenol M. kachirachirai 45 15 (+)-Epimagnolin M. fargesii 31 methylether) 16 Magnolin M. fargesii 16 36 Licarin A M. kachirachirai 45 M. officinalis Rehd. et Wils. 30 (=Dehydrodiisoeugenol) M. biondii 63 37 Licarin B M. kachirachirai 45 38 Kachirachirol B M. kachirachirai 45 17 (+)-De-O-methyl M. fargesii 63 39 Kachirachirol A M. kachirachirai 45 magnolin 40 Eupomatenoid -1 M. kachirachirai 45 18 (+)-Pinoresinol M. fargesii 63 21 Eupomatenoid -7 M. kachirachirai 45 19 (-)-Eudesmin M. fargesii 16 (= Pinoresinol dimethyl M. saulangiana 19 42 Liliflol A M. liliflora 42 ether) M. officinalis 30 43 Liliflol B M. liliflora 42 M. biondii 32 44 Liliflone M. liliflora 42 M. kobus 44 45 Piperenone M. liliflora 42 M. pterocarpa 63 46 Saulangianin M. saulangiana 44 20 (+)-Epimagnolin A M. fargesii 31 47 Fargesone A M. fargesii 41, 63 21 Lirioresinol B M. fargesii 16 48 Fargesone B M. fargesii 41, 63 dimethylether M. officinalis 19 49 Fargesone C M. fargesii 41, 63 M. kobus 30 50 Cyclohexadienone M. saulangiana 44 M. biondii Pump. 64 22 (+)-Sesamin M. kobus 19 Biphenyl lignanoide M. stellata Maxim. 28 (Str. Type G) M. pterocarpa 32 51 Magnolol M. henryi Dunn 17 23 Kobuain M. kobus 19 M. liliflora 18 M. stellata 28 M. virginiana 23 M. obovata Thunb. 47 24 Epieudesmin M. kobus 19 (M. hypoleuca Sieb. et Zucc.) Biologically Active Lignans and Neolignans from Magnolia Species 217

Str. No. Name of Compound Species References Str. No. Name of Compound Species References

M. officinalis 49 68 Biondinin A M. biondii 12 M. rostrata 51 69 1-(4-hydroxy-3- M. officinalis 16 M. biloba 52 methoxyphenyl-2-[4- M. grandiflora 55 (w-hydroxypropyl)-2- M. tripetala 56 methoxyphenoxy] M. watsonii Hook. fil. 65 propane-1,3-diol 52 Honokiol M. henryi 17 M. liliflora 18 Hybrid neolignans M. virginiana 23 (Str. Type I) M. obovata 47 70 Eudesmagnolol M. obovata 59, 60 M. officinalis 49 71 Clovanemagnolol M. obovata 60 M. rostrata 51 72 Caryolanemagnolol M. obovata 17 M. biloba 52 73 Eudesobovatol A M. obovata 58 M. grandiflora 55 74 Eudesobovatol B M. obovata 58 M. tripetala 56 75 Eudeshonokiol A M. obovata 59 M. watsonii Hook. fil. 65 76 Eudeshonokiol B M. obovata 59 53 Honokiol M. henryi 18 77 Piperitylmagnolol M. officinalis 16 monomethylether M. virginiana 23 78 Piperitylhonokiol M. officinalis 16 M. grandiflora 51 79 Bornylmagnolol M. officinalis 16 M. tripetala 55 80 Dipiperitylmagnol M. officinalis 16 54 Dehydrodieugenol M. henryi 51 55 Dehydrodieugenol M. henryi 51 Oligomeric lignans and neolignans monomethylether (Str. Type J) 56 Randainal M. officinalis 16 81 Magnolianin M. obovata 16 57 Magnaldehyde B M. officinalis 16 82 Magnolignan F M. officinalis 16 58 Magnaldehyde C M. officinalis 16 83 Magnolignan G M. officinalis 16 59 Magnolignan A M. officinalis 16 84 Magnolignan H M. officinalis 16 60 Magnolignan B M. officinalis 16 85 Magnolignan I M. officinalis 16 61 Magnolignan C M. officinalis 16 62 Magnolignan D M. officinalis 16 Norlignans 63 Obovatol M. henry 51 (Str. Type K) M. obovata Thunb. 54 86 Randaiol M. officinalis 16 M. watsonii 56 87 Magnatriol B M. officinalis 16 64 Obovatol methylether M. henryi 51 88 Magnaldehyde D M. officinalis 16 M. obovata 54 89 Magnaldehyde E M. officinalis 16 M. watsonii 56 90 Magnolignan E M. officinalis 16 65 Isomagnolol M. henryi 51 91 Obovaaldehyde M. obovata 54 66 Obovatal M. obovata 54 Miscellaneous 1,2-Diarylpropane (Str. Type L) (Str. Type H) 92 Liliflodion M.liliflora 42 67 Aurein M. saulangiana 44 218 Rev. Soc. Quím. Méx. Vol. 43, Núm. 6 (1999) Qi Song and Nikolaus H. Fischer

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