www.elsevier.com/locate/biochemsysecoBiochemical Systematics and Ecology 35 (2007) 447e453

Prenylated acetophenones from Melicope obscura andMelicope obtusifolia ssp. obtusifolia var. arborea

and their distribution in Rutaceae

Anne Adsersen*, Ulla W. Smitt, Henrik T. Simonsen,Søren Brøgger Christensen, Jerzy W. Jaroszewski

Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences,

Universitetsparken 2, DK-2100 Copenhagen, Denmark

Received 9 August 2005; accepted 9 April 2006

Abstract

Four prenylated acetophenones 2,6-dihydroxy-4-geranyloxyacetophenone (1), 4-geranyloxy-2,6,b-trihydroxyacetophenone(2), 2,6-dihydroxy-4-geranyloxy-3-prenylacetophenone (3), and 4-geranyloxy-3-prenyl-2,6,b-trihydroxyacetophenone (4) havefor the first time been isolated from Melicope obscura (1 and 2) and Melicope obtusifolia ssp. obtusifolia var. arborea (3 and 4).The distribution of prenylated acetophenones in Rutaceae is reviewed and the results, including the new records, indicate thatprenylated acetophenones are valuable as chemotaxonomic markers for the subfamily Rutoideae, tribe Xanthoxyleae sensu Engler.� 2007 Elsevier Ltd. All rights reserved.

Keywords: Melicope obscura; Euodia obscura; Melicope obtusifolia ssp. obtusifolia var. arborea; Euodia obtusifolia ssp. obtusifolia var. arborea;

Rutaceae; Chemotaxonomy; Prenylated acetophenones

1. Introduction

The genus Melicope J. R. Forst. & G. Forst. (Rutaceae) encompasses 233 species occurring from the Malagasy andIndo-Himalaya regions east to the Hawaiian and Marquesas Islands and south to New Zealand (Hartley, 2001). In therevision by Hartley (2001), all Euodia species from the Malagasy region were transferred to Melicope; six of thesespecies are endemic to Reunion Island and belong to dioecious species of Melicope sect. Lepta. Previous phytochem-ical studies on Melicope species from Reunion Island resulted in the isolation of methoxyflavones from Melicopeobscura, Melicope borbonica and Melicope coodeana (Simonsen et al., 2002, 2003), and coumarins, furanocoumarinsand acetophenones from M. borbonica (Valenciennes et al., 1999; Simonsen et al., 2004). So far there has been noreports on prenylated acetophenones from these endemic species.

* Corresponding author. Tel.: þ45 35306295; fax: þ45 35306041.

E-mail address: aad@dfuni.dk (A. Adsersen).

0305-1978/$ - see front matter � 2007 Elsevier Ltd. All rights reserved.

doi:10.1016/j.bse.2006.04.014

448 A. Adsersen et al. / Biochemical Systematics and Ecology 35 (2007) 447e453

2. Materials and methods

2.1. Plant material

Leaves of M. obscura (Cordem.) T.G. Hartley (syn. Euodia obscura Cordem.) were collected in February 2000 atPlaine de Palmiste, Reunion Island. Leaves of Melicope obtusifolia ssp. obtusifolia var. arborea (Coode) T.G. Hartley(syn. Euodia obtusifolia ssp. obtusifolia var. arborea Coode) were collected in February 2002 at Plaine des Fougeres.The plant material was identified by Dr. D. Strasberg, Universite de la Reunion. Voucher specimen of M. obscura(DFHAA4) and M. obtusifolia ssp. obtusifolia var. arborea (DFHAA5) were deposited in Herbarium C (BotanicalMuseum, University of Copenhagen, Copenhagen).

2.2. Extraction, isolation and identification of acetophenones from M. obscura

Dried and powdered leaves (260 g) were extracted three times with 500 ml of CH2Cl2eMeOH (1:1) for 30 min inan ultrasonic bath, and the combined extracts were evaporated. The residue (47 g) was fractionated by VLC (VLC 1)on silica gel (Millipore 60A/70e200 mm) with CH2Cl2 and EtOAc (0e100%). The CH2Cl2 fraction (9.8 g) was sub-jected to a second VLC (VLC 2) on silica eluted with heptane and EtOAc (0e100%). The fraction from VLC 2 elutedwith 20% EtOAc (3.7 g) was subjected to repeated LC fractionation on silica with heptaneeEtOAc (8:2 and 7:3) aseluent to give 1 as an amorphous powder (179 mg). The fraction from VLC 1 eluted with 20% EtOAc (3.9 g) wassubjected to LC on silica gel using tolueneeEtOAceMeOH (300:80:10) as eluent and 2 was obtained as pale yellowcrystals (597 mg). The 1H and 13C NMR data for 1 and 2 were identical to those found in the literature (Chou et al.,1992). The NMR spectra were recorded at 25 �C on a Bruker AMX 400 spectrometer (proton frequency 400.13 MHz)in chloroform-d, using TMS as internal standard.

2.3. Extraction, isolation and identification of acetophenones from M. obtusifolia ssp. obtusifolia var. arborea

Dried and powdered leaves (805 g) were extracted four times with 2000 ml of 96% ethanol for 30 min in an ultra-sonic bath, and the combined extracts were evaporated. The residue (170 g) was partitioned between EtOAc and water.The EtOAc phase was evaporated and the residue (116 g) was fractionated by VLC on silica gel with heptane, heptaneeCH2Cl2 (1:1) (F2, 14.7 g), CH2Cl2, CH2Cl2eEtOAc (1:1) (F4, 23.3 g) and EtOAc. F2 was subjected to VLC on silicagel using heptaneeEtOAc (0e100%) as eluents. The fractions eluted with 10 and 20% EtOAc were combined andevaporated. The residue (2.3 g) was subjected to repeated LC fractionation on silica gel using heptaneeEtOAc (8:2)and tolueneeEtOAceMeOH (190:10:1) as eluents. From a crystalline fraction (185.6 mg) pure crystals (71.5 mg)of 3 were obtained after crystallisation from CH2Cl2eMeOH. F4 (12 g) was subjected to VLC using CH2Cl2eEtOAc(0e100%) as eluents. Repeated fractionation by LC on silica gel of the CH2Cl2 fraction using tolueneeEtOAceMeOH(300:80:5) and CH2Cl2eEtOAc (19:1 and 18:2) as eluents gave 187 mg of 4. Pure crystals (127 mg) were obtained bycrystallisation from CH2Cl2eheptane. The 1H and 13C NMR data resemble those found in the literature for 3 and 4(Chou et al., 1992; Lin et al., 1993).

O

HO

OR1

OH

R2

1 R1 = CH3, R2 = H2 R1 = CH2OH, R2 = H3 R1 = CH3, R2 = CH2CH=C(CH3)2

4 R1 = CH2OH, R2 = CH2CH=C(CH3)2

449A. Adsersen et al. / Biochemical Systematics and Ecology 35 (2007) 447e453

3. Results and discussion

The distribution of prenylated acetophenones in the Rutaceae seems to be restricted. Quader et al. (1991) reviewedthe distribution of acetophenones in the Rutaceae and reported 17 prenylated acetophenones from the generaMelicope, Acradenia and Acronychia. Currently, approximately 50 prenylated acetophenones are known from 18species of Rutaceae representing the genera Melicope, Acradenia, Acronychia, Bosistoa and Medicosma (Table 1).Structures with cyclized prenyl substituents have been found in all five genera. Prenylated acetophenones with geranylsubstituents and compounds with oxidized acetyl group have until now only been reported from Melicope, andprenylated acetophenone dimers only from Acronychia (Table 2).

Engler (1896, 1931) divided the family Rutaceae into seven subfamilies and assigned the five above mentionedgenera to the subfamily Rutoideae, except the genus Acronychia that was assigned to the subfamily Toddaliodeae.Furthermore, Engler divided Rutoideae into five tribes and assigned Melicope, Bosistoa and Medicosma to the tribeXanthoxyleae and Acradenia to the tribe Boronieae. According to Hartley (1977), Acradenia is equally, if not moreclosely, related to several genera placed in the tribe Xanthoxyleae. A close affinity between Acradenia and Bosistoawas suggested by Quader et al. (1991). This, together with the occurrence of prenylated acetophenones, indicates thatAcradenia could as well be placed in the tribe Xanthoxyleae.

The distinction between Rutoideae and Toddalioideae is now largely discredited. According to Hartley (1981,2001) Acronychia and Melicope are closely allied. Da Silva et al. (1988) proposed a new taxonomic grouping ofRutaceae genera based on chemical characters, which eliminated Toddalioideae and assigned its former genera amongseveral tribes within the subfamily Rutoideae. Thorne (1992) merged Toddalioideae with Rutoideae and analysis ofmolecular data (Chase et al., 1999) supported Thorne’s placement of Toddalioideae in Rutoideae. The restrictedoccurrence of prenylated acetophenones in Rutaceae indicates that they are valuable as chemotaxonomic markersfor the subfamily Rutoideae, tribe Xanthoxyleae, an assumption supported by the isolation of this type of compoundsfrom M. obscura and M. obtusifolia ssp. obtusifolia var. arborea.

Table 1

Species from Rutaceae containing prenylated actephenones

Species Synonym Engler

Subfamily Tribus

Melicope broadbentiana F.M. Bailey Rutoideae Xanthoxyleae

Melicope elleryana (F. Muell.) T.G. Hartley Evodia elleryana F. Muell. Rutoideae Xanthoxyleae

Melicope erromangensis T.G. Hartley Rutoideae Xanthoxyleae

Melicope latifolia (DC.) T.G. Hartley Euodia latifolia DC. Rutoideae Xanthoxyleae

Melicope lunu-ankenda (Gaertn.) T.G. Hartley Euodia lunu-ankenda (Gaertn.) Merr. Rutoideae Xanthoxyleae

Melicope obscura (Cordem.) T.G. Hartley Euodia obscura Cordem. Rutoideae Xanthoxyleae

Melicope obtusifolia ssp. obtusifolia var.

arborea (Coode) T.G. Hartley

Euodia obtusifolia ssp. obtusifolia var.

arborea Coode

Rutoideae Xanthoxyleae

Melicope semecarpifolia (Merr.) T.G. Hartley Euodia semecarpifolia Merr. Rutoideae Xanthoxyleae

Evodia merrillii Kanehira & Sasaki

ex Kanehira

Melicope simplex A. Cunn Rutoideae Xanthoxyleae

Melicope vitiflora (F. Muell.) T.G. Hartley Evodia vitiflora F. Muell. Rutoideae Xanthoxyleae

Bosistoa selwynii T.G. Hartley Rutoideae Xanthoxyleae

Medicosma cunninghamii (Hook.) Hook. f. Rutoideae Xanthoxyleae

Medicosma sessiliflora (C.T. White) T.G. Hartley Melicope sessiliflora C.T. White Rutoideae Xanthoxyleae

Acradenia euodiiformis (F. Muell.) T.G. Hartley Bosistoa euodiiformis F. Muell. Rutoideae Boronieae

Acradenia franklinii Kippist Rutoideae Boronieae

Acronycia octandra (F. Muell.) T.G. Hartley Melicope octandra (F. Muell.) Druce Toddalioideae Toddalieae

Euodia octandra F. Muell.

Acronycia pedunculata (L.) Miq. Acronychia laurifolia Blume Toddalioideae Toddalieae

Acronychia trifoliata Zoll. & Moritzi Toddalioideae Toddalieae

Acronychia vestita F. Muell. Toddalioideae Toddalieae

450 A. Adsersen et al. / Biochemical Systematics and Ecology 35 (2007) 447e453

Table 2

Prenylated acetophenones found in the Rutaceae

Compound Speciesa Reference

Simple acetophenone derivatives

2,4-Dihydroxy-3,5-diprenyl-6-methoxyacetophenone Acronychia pedunculata Sy and Brown (1999)

Acronychia pedunculata Kumar et al. (1989)

Melicope lunu-ankenda Kumar et al. (1990)

Acronychia trifolioata Oyama et al. (2003)

2,4-Dihydroxy-5-prenyl-6-prenyloxyacetophenone Melicope lunu-ankenda Kumar et al. (1990)

Sessiliflorene [3-(2x-hydroxy-3-methylbut-3-enyl)-5-

(3-methyl-1-oxobutyl)-2,4,6-trihydroxyacetophenone]

Medicosma sessiliflora(Melicope sessiliflora)

Chan et al. (1989)

Acronylin (4,6-dihydroxy-2-methoxy-3-prenylacetophenone) Acronychia pedunculata Kumar et al. (1989)

Acronychia pedunculata

(Acronychia laurifolia)

Banerji et al. (1973)

6-O-Demethylacronylin (3-prenyl-2,4,6-trihydroxyacetophenone) Acronychia pedunculata

(Acronychia laurifolia)

Banerji et al. (1973)

Acronyculatin A (2,4-dihydroxy-3-formyl-6-methoxy-5-prenylacetophenone) Acronychia pedunculata Su et al. (2003)

Acronyculatin C (2,4-dihydroxy-6-methoxy-3-

(3-methyl-1-oxobutyl)-5-prenylacetophenone)

Acronychia pedunculata Su et al. (2003)

Acronyculatin D [4,6-dihydroxy-3-(2x-hydroxy-3-methylbut-3-enyl)-

2-methoxyacetophenone]

Acronychia pedunculata Su et al. (2003)

4-Geranyloxy-3-prenyl-2,6,b-trihydroxyacetophenone Melicope semecarpifolia

(Evodia merrillii)

Lin et al. (1993)

Melicope obtusifolia

2-Geranyloxy-4,6,b-trihydroxyacetophenone Melicope semecarpifolia(Evodia merrillii)

Lin et al. (1993)

2,6-Dihydroxy-4-geranyloxy-3-prenylacetophenone Melicope semecarpifolia

(Evodia merrillii)

Chou et al. (1992)

Melicope obtusifolia

4,6-Dihydroxy-2-geranyloxyacetophenone Melicope semecarpifolia

(Evodia merrillii)

Chou et al. (1992)

2,6-Dihydroxy-4-geranyloxyacetophenone Melicope semecarpifolia(Evodia merrillii)

Chou et al. (1992)

Melicope obscura

4-Geranyloxy-2,6,b-trihydroxyacetophenone Melicope semecarpifolia

(Evodia merrillii)

Chou et al. (1992)

Melicope obscura

2,4-Dihydroxy-5-prenyl-6-geranyloxyacetophenone Melicope lunu-ankenda Kumar et al. (1990)

Melicopol (6-geranyloxy-3-methoxy-2,4,b-trixydroxyacetophenone) Melicope broadbentiana Ritchie et al. (1965)

Melicope broadbentiana Balgir et al. (1973)

Methylmelicopol (2,b-dihydroxy-3,4-dimethoxy-6-geranyloxyacetophenone) Melicope broadbentiana Ritchie et al. (1965)

Melicope broadbentiana Balgir et al. (1973)

Compounds with cyclized prenyl unitsOctandrenolone [1-(5-hydroxy-2,2,8,8-tetramethyl-2H,8H-

pyrano[2,3-f]chromen-6-yl)ethanone]

Melicope erromangensis Muyard et al. (1996)

Acronychia octandra

(Melicope octandra)

Free et al. (1976)

Acradenia euodiformis Quader et al. (1991)

O-Methyloctandrenolone [1-(5-methoxy-2,2,8,8-tetramethyl-

2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone]

Melicope erromangensis Muyard et al. (1996)

(þ)-trans-3,4-Dihydro-3,4-dihydroxyoctandrenolone

[(3S*,4R*)-1-(3,4-dihydro-3,4-dihydroxy-2,2,8,8-

tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone]

Melicope erromangensis Muyard et al. (1996)

(þ)-trans-9,10-Dihydro-9,10-dihydroxyoctandrenolone

[(9S*,10R*)-1-(9,10-dihydro-9,10-dihydroxy-2,2,8,8-

tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone]

Melicope erromangensis Muyard et al. (1996)

(þ)-trans-3,4-Dihydro-3,4-dihydroxy-O-methyloctandrenolone

[(3S*,4R*)-1-(3,4-dihydro-3,4-dihydroxy-5-methoxy-

2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone]

Melicope erromangensis Muyard et al. (1996)

451A. Adsersen et al. / Biochemical Systematics and Ecology 35 (2007) 447e453

Table 2 (continued )

Compound Speciesa Reference

(þ)-trans-9,10-Dihydro-9,10-dihydroxy-O-methyloctandrenolone

[(9S*,10R*)-1-(9,10-dihydro-9,10-dihydroxy-5-methoxy-

2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone]

Melicope erromangensis Muyard et al. (1996)

Melifolione a [(6aR, 9S,10aS)-1-(1,9-epoxy-3-hydroxy-

6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-

6H-benzo[c]chromen-4-yl)ethanone]

Melicope latifolia

(Euodia latifolia)

Goh et al. (1990)

Melifolione b [(6aR, 9S,10aS)-1-(1,9-epoxy-3-hydroxy-

6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-

6H-benzo[c]chromen-2-yl)ethanone]

Melicope latifolia

(Euodia latifolia)

Goh et al. (1990)

Franklinone [1-(5-methoxy-2,2,8,8-tetramethyl-2H,8H-

pyrano[3,2-g]chromen-10-yl)ethanone]

Acradenia franklinii Quader et al. (1991)

Baldwin et al. (1961)

Acradenia euodiiformis Quader et al. (1991)

Acradenia euodiiformis

(Bosistoa euodiformis)

Croft et al. (1975)

Pyranoselwynone [1-(5,9x-dihydroxy-2,2,8,8-tetramethyl-9,10-

dihydro-2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone]

Bosistoa selwynii Auzi et al. (1998)

Furanoselwynone [1-[5-hydroxy-8-(1-hydroxy-1-methylethyl)-2,

2-dimethyl-8,9-dihydro-2H-furo[2,3-h]chromen-6-yl]ethanone]

Bosistoa selwynii Auzi et al. (1998)

Isofuranoselwynone [1-[4-hydroxy-2-(1-hydroxy-1-methylethyl)-

7,7-dimethyl-2,3-dihydro-7H-furo[2,3-f]chromen-5-yl]-ethanone]

Bosistoa selwynii Auzi et al. (1998)

Evodione [1-(2,2-dimethyl-5,7,8-trimethoxy-2H-chromen-6-yl)ethanone] Melicope elleryana

(Evodia elleryana)

Kirby and Sutherland (1956)

Alloevodione [1-(2,2-dimethyl-5,6,7-trimethoxy-2H-chromen-8-yl)ethanone] Melicope elleryana(Evodia elleryana)

Kirby and Sutherland (1956)

Alloevodionol [1-(2,2-dimethyl-7-hydroxy-5-methoxy-

2H-chromen-8-yl)ethanone]

Medicosma cunninghamii Sutherland (1949)

Evodionol [1-(2,2-dimethyl-7-hydroxy-5-methoxy-

2H-chromen-6-yl)ethanone]

Melicope simplex Briggs and Locker (1950)

Melicope vitiflora

(Evodia vitiflora)

Kirby and Sutherland (1956)

Medicosma cunninghamii Kirby and Sutherland (1956)

1-(3x,4x-Dihydroxy-5,7-dimethoxy-2,2-

dimethylchroman-8-yl)ethanone

Melicope lunu-ankenda Manandhar et al. (1985)

Isoevodionol [1-(2,2-dimethyl-5-hydroxy-7-methoxy-

2H-chromen-6-yl)ethanone]

Melicope lunu-ankenda Manandhar et al. (1985)

Isoevodionol methyl ether [1-(5,7-dimethoxy-

2,2-dimethyl-2H-chromen-6-yl)ethanone]

Melicope lunu-ankenda Manandhar et al. (1985)

7-O-Methylalloevodionol [1-(5,7-dimethoxy-

2,2-dimethyl-2H-chromen-8-yl)-ethanone

Melicope simplex Briggs and Locker (1950)

Melicope elleryana(Evodia elleryana)

Kirby and Sutherland (1956)

Medicosma cunninghamii Kirby and Sutherland (1956)

Acradenia franklinii Baldwin et al. (1961)

Melicope lunu-ankenda Manandhar et al. (1985)

7-O-Methylevodionol [1-(5,7-dimethoxy-2,2-

dimethyl-2H-chromen-6-yl)ethanone]

Medicosma cunninghamii Sutherland (1949)

Acradenia franklinii Baldwin et al. (1961)

Acronyculatin B [(2R)-1-[4-hydroxy-2-(1-hydroxy-1-methylethyl)-

6-methoxy-7-prenyl-2,3-dihydrobenzofuran-5-yl]ethanone]

Acronychia pedunculata Su et al. (2003)

Acronyculatin E [1-(2,2-dimethyl-5-hydroxy-

7-methoxy-8-prenyl-2H-chromen-6-yl)ethanone]

Acronychia pedunculata Su et al. (2003)

Selwynone [1-(2,2-dimethyl-6-prenyl-3x,5,7-

trihydroxychroman-8-yl)ethanone]

Bosistoa selwynii Auzi et al. (1998)

Sessiliflorol A [1-[5-acetyl-4,6-dihydroxy-2x-(1-hydroxy-1-

methylethyl)-2,3-dihydrobenzofuran-7-yl]-3-methyl-butan-1-one]

Medicosma sessiliflora

(Melicope sessiliflora)

Chan et al. (1989)

Sessiliflorol B [1-[7-acetyl-4,6-dihydroxy-2x-(1-hydroxy-

1methylethyl)-2,3-dihydrobenzofuran-5-yl]-3-methyl-butan-1-one]

Medicosma sessiliflora(Melicope sessiliflora)

Chan et al. (1989)

(continued on next page)

452 A. Adsersen et al. / Biochemical Systematics and Ecology 35 (2007) 447e453

Acknowledgment

We thank Mr. Michael D. Larsen, Ms. Merete W. Nielsen, Mr. Mads R. Olsen and Mr. Thomas D. Nielsen forcollection and Dr. D. Strasberg, Universite de la Reunion for the identification of plant material.

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Table 2 (continued )

Compound Speciesa Reference

Dimeric compoundsAcrovestone [3-[1-(3-acetyl-2,6-dihydroxy-4-methoxy-5-prenylphenyl)-

3-methylbutyl]-2,4,6-trihydroxy-5-prenylacetophenone]

Acronychia pedunculata Wu et al. (1989)

Acronychia vestita Funayama and Cordell (1984)

Acronychia pedunculata

(Acronychia laurifolia)

Banerji et al. (1973)

Acronychia trifoliolata Oyama et al. (2003)

Acrofolione A [3-[1-[5-acetyl-4,6-dihydroxy-2-(1-hydroxy-1-methylethyl)-

2,3-dihydrobenzofuran-7-yl]-3-methyl-butyl]-2,4-dihydroxy-

6-methoxy-5-prenylacetophenone]

Acronychia trifoliata Oyama et al. (2003)

Acrofolione B [3-[1-[7-acetyl-4,6-dihydroxy-2-(1-hydroxy-1-methylethyl)-

2,3-dihydrobenzofuran-5-yl]-3-methyl-butyl]-2,4-dihydroxy-

6-methoxy-5-prenylacetophenone]

Acronychia trifoliata Oyama et al. (2003)

a Names listed in parentheses refer to names used in the reference.

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