chemical constituents of plants from the genus melia

REVIEW

Chemical Constituents of Plants from the Genus Melia

by Lei Zhaoa), Chang-Hong Huo*a), Li-Ru Shenb), Yan Yanga), Qing Zhanga), and Qing-Wen Shi*a)

a) Department of Natural Product Chemistry, School of Pharmaceutical Sciences, Hebei MedicalUniversity, 361 Zhongshan East Road, 050017, Shijiazhuang, Hebei Province, P. R. China

(phone: þ8631186265634; e-mail: [email protected])b) Tangshan People�s Hospital, 65 Shengli Road, 063001 Tangshan, Hebei Province, P. R. China

Contents

1. Introduction2. Chemical Constituents

2.1. Terpenoids2.1.1. Limonoids2.1.2. Protolimonoids and Further Derivatives2.1.3. Degraded Limonoids2.1.4. Other Terpenoids

2.2. Steroids2.3. Alkaloids2.4. Flavonoids2.5. Anthraquinones2.6. Others

3. Biological Activities3.1. Antiviral Activities3.2. Inhibition of iNOS and Cyclooxygenase-23.3. Antifeeding and Insecticide Effects3.4. Antitumor and Cytotoxic Activities3.5. Agonist of L-type Ca2þ Channels3.6. Antibacterial and Antifungal Activities

4. Conclusions

1. Introduction. – Although the genus Melia of the Meliaceae family contains aboutfive poorly defined species in the Old World tropics [1], almost every part of the plantsof this genus are used as traditional herbal medicines, such as being anthelmintics, forthe treatment of leprosy, eczema, asthma, malaria, fevers, and venereal diseases [2] [3],as well as cholelithiasis, acariasis, and pain [4] [5]. The genus Melia is well-known as arich and valuable source of bioactive limonoids. Two widely known limonoids areazadirachtin from Azadirachta indica (syn. to Melia azadirachta or Melia indica) andtoosendanin from Melia toosendan, both are used as insecticides and have beencommercialized in the US and China [6]. The modern pharmacology research has

CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 839

� 2010 Verlag Helvetica Chimica Acta AG, Z�rich

revealed that limonoids have a range of biological activities, including antibacterial,antifungal, and antiviral activities, and marked insect antifeedant and cytotoxicactivities [7], so much attention has been paid to Melia species.

To facilitate further research work, in this article, we review the structures andbiological properties of the known constituents from Melia.

2. Chemical Constituents. – The Genus Melia produces a wide range of compounds,1 – 229 (Table), including terpenoids, steroids, alkaloids, flavonoids, anthraquinones,and some other compounds, but are best known for the production of limonoids whichare tetranortriterpenoids with a b-substituted furanyl ring at C(17a).

2.1. Terpenoids. The known terpenoids of the genus Melia isolated over the past fewdecades include limonoids, 1 – 122 [8 – 63], protolimonoids, and further derivatives,123– 168 [28] [30] [31] [54] [67 – 87], degraded limonoids, 169– 181 [11] [65] [88] [89],and other types of terpenoids, 182– 188 [69] [90 – 93].

2.1.1. Limonoids. Limonoids have attracted considerable interest because of theirbiological activities and variety of structures. To date, 122 limonoids have been isolatedfrom Melia species [8 – 63], and can be divided into five classes of limonoids based onwhich of the four triterpenoid skeleton rings had been oxidatively opened [7], i.e., 56havanensin-class limonoids, 1– 56, 61 nimbin-class limonoids, 57 –117, 4 gedunin-classlimonoids, 118– 121, and a andirobin-class limonoid, 122.

Among the above compounds, neoazedarachin D (28) is the first natural 29-endo-derivative to be found in C(19)/C(29) bridged acetal limonoids [12]. 7,14-Epoxyaze-darachin B (33) is the first limonoid discovered bearing a highly strained oxetane ring.The biogenetic formation of this compound can be presumably explained by anintramolecular nucleophilic attack of the OH group at C(7) on the C(14) position of theepoxide ring (Scheme) [11]. Toosendanal (35) is the first report of a limonoid havingC(1)/C(29) and C(19)/C(29) acetal bridges [18]. In 1999, Luo et al. isolated two novelazadirachtin derivatives, azadirachtin M (110) and azadirachtin N (113) from the seedkernels of A. indica. The former is a biodegradation product of azadirachtin (106) andbelongs to neither the azadirachtin group (where C(29) is a methoxycarbonyl group)nor the meliacarpin group (where C(29) is a Me group). It is the first compound whereC(29) is a hydroxymethyl group that has been isolated from A. indica. The degree ofoxidation at C(29) in compound 110 is between those of azadirachtin H andazadirachtin I, so azadirachtin M could be considered as an intermediate of thebiosynthesis between the meliacarpin group and the azadirachtin group [61].Volkensinin (114) is a nimbin-class limonoid which contains a unique five-memberedC ring [64]. Spirosendan (117) isolated from the root bark of M. toosendan possesses anew skeleton with a spiro-structure [25]. To date, only three limonoid glycosides, 53–55, were isolated from the seeds of M. azedarach [38– 40].

2.1.2. Protolimonoids and Further Derivatives. Twenty tirucallane-type protolimo-noids, which have a C¼C bond at C(7) and Me group at C(14), 123– 142, have beenreported from the genus Melia [67 –76]. Ten apotirucallane-type protolimonoids, whichhave undergone the apo-euphol rearrangement to form a C¼C bond at C(14) with theMe group shifted to C(8), 143–152, were isolated from Melia species[28] [30] [54] [68] [77– 81]. Among them, meliavolkensins A and B (151 and 152, resp.)have a new type of substituted tetrahydropyran ring side chain [81].

CHEMISTRY & BIODIVERSITY – Vol. 7 (2010)840

On the other hand, five apotirucallane-type protolimonoid derivatives, 164– 168,have also been isolated form A. indica [83] [86] [87]. Meliacinin (166) represents thefirst dinortriterpenoid with an apotirucallane skeleton with a seco D ring ofdeoxygedunin type. Azadironic acid (167) is a tetranorapotirucallane with open sidechain and may be regarded as a degradative intermediate between the intact eight C-atom side chain of triterpenes and the furan or hemiacetal ring in meliacins orbutenolides during biosynthesis [86].



Table. Chemical Constituents from the Genus Melia

Compound Sourcea) Ref.

1 Azedarachin A M. azedarach [8]M. toosendan [9]

2 12-O-Acetylazedarachin A M. azedarach [8]3 12-O-Acetylazedarachin B (29-isobutylsendanin) M. azedarach [8] [10]

M. toosendan [9]4 Azedarachin C M. azedarach [8]5 Azedarachin B M. azedarach [11]

M. toosendan [12]6 Sendanin M. azedarach var. japonica [13]7 12-Hydroxyamoorastatin M. azedarach [10] [14]

M. azedarach var. japonica [15]8 28-Deacetylsendanin (Toosendanin) M. azedarach [10] [16]

M. toosendan [17] [18] [19]9 12-O-Deacetyltrichilin H M. azedarach [20]

10 12-Acetyltrichilin B M. azedarach [21]11 7,12-Diacetyltrichilin B M. azedarach [21]12 Trichilin H M. azedarach [21] [22]

M. toosendan [9] [18]13 Trichilin B M. azedarach [21]14 Trichilin D (Meliatoxin A1) M. azedarach [21–23]15 Meliatoxin A2 M. azedarach [21] [23]16 Trichilin K M. toosendan [9]17 Trichilin L M. toosendan [9]18 Trichilin I M. toosendan [9]19 Trichilin J M. toosendan [9]20 12-Deacetyltrichilin I M. azedarach [22]21 1-Acetyltrichilin H M. azedarach [22]

M. toosendan [12]22 3-Deacetyltrichilin H M. azedarach [22]23 1-Acetyl-3-deacetyltrichilin H M. azedarach [22]24 1-Acetyl-2-deacetyltrichilin H M. azedarach [22]25 1,12-Diacetyltrichilin B M. azedarach [22]26 Neoazedarachin A M. toosendan [12]27 Neoazedarachin B M. azedarach [11]

M. toosendan [12]28 Neoazedarachin D M. toosendan [12]29 Meliatoxin B1 M. azedarach [22] [23]

M. toosendan [18]30 Meliatoxin B2 M. azedarach var. australasica [23]31 12a-Hydroxyamoorastatone M. toosendan [12]

M. azedarach var. japonica [15]32 Isochuanliansu M. toosendan [12]

M. azedarach [24]33 7,14-Epoxyazedarachin B M. azedarach [11]34 Meliartenin M. azedarach [14]35 Toosendanal M. toosendan [18]36 Trichilinin D M. toosendan [25]37 Trichilinin E M. toosendan [25]38 1-O-Cinnamoyltrichilinin M. volkensii [26]


Table (cont.)


39 Trichilinin B M. toosendan [27]40 Trichilinin C M. toosendan [27]41 Meliavolkinin M. volkensii [28]42 1,3-Diacetylvilasinin M. volkensii [28]43 Nimbolin A M. birmanica [29]44 Meliavolkin M. volkensii [30]45 Compositin M. dubia [31]46 Azadirone M. azadirachta [32]

M. toosendan [33]47 Azadiradione M. azadirachta [32]48 Epoxyazadiradione M. azadirachta [32]49 Nimonol A. indica [34]50 14,15-Epoxynimonol A. indica [35]51 6a-O-Acetyl-7-deacetylnimocinol A. indica [36]52 17-Hydroxyazadiradione M. azadirachta [37]53 6-Acetoxy-11a-hydroxy-7-oxo-14b,15b-epoxymeliacin-

1,5-diene-3-O-a-l-rhamnopyranosideM. azedarach [38]

54 6,11-Diacetoxy-7-oxo-14b,15b-epoxymeliacin-1,5-diene-3-O-b-d-glucopyranoside

M. azedarach [39]

55 6-Acetoxy-3b-hydroxy-7-oxo-14b,15b-epoxymeliacin-1,5-diene-3-O-b-d-xylopyranoside

M. azedarach [40]

56 Sendanal M. azedarach [41] [42]57 1-Deacetylnimbolinin A M. toosendan [25]58 Nimbolinin B M. toosendan [25]

M. azedarach [42–45]59 1-Deacetylnimbolinin B M. toosendan [25]

M. azedarach [43]60 Volkensin M. volkensii [46]61 Ohchinolide C M. toosendan [33]62 1-O-Deacetyl-1-O-tigloylohchinolide B M. azedarach [47]63 1-O-Deacetyl-1-O-benzoylohchinolide B M. azedarach [47]64 1-O-Deacetyl-1-O-tigloylohchinolide A M. azedarach [47]65 1-O-Deacetylohchinolide B M. azedarach [47]66 1-O-Deacetylohchinolide A M. azedarach [47]67 Ohchinolide A M. azedarach [43] [47]68 Ohchinolide B M. azedarach [43] [47]69 15-O-Deacetyl-15-O-methylnimbolidin A M. azedarach [20]70 15-O-Deacetyl-15-O-methylnimbolidin B M. azedarach [20]71 15-O-Deacetylnimbolidin B M. azedarach [20]72 Nimbolidin F M. toosendan [33]73 Nimbolidin C M. toosendan [48]74 Nimbolidin D M. toosendan [48]75 Nimbolidin E M. toosendan [48]76 Nimbolidin B M. toosendan [48]

M. azedarach [43–45]77 Nimbolidin A M. azedarach [43]78 28-Deoxonimbolide A. indica [49]79 Nimbolide A. indica [49]80 Nimbin A. indica [50]81 3-O-Acetylohchinolal M. toosendan [33]


Table (cont.)


82 1-O-Detigloyl-1-O-benzoylohchinolal M. azedarach [47]83 1-O-Detigloyl-1-O-cinnamoylohchinolal M. azedarach [47]84 Salannal (Ohchinolal) M. azedarach [42] [44] [45] [47]

M. azedarach var. japonica [51]85 Ohchinal M. azedarach var. japonica [52]86 Ohchinin acetate M. azedarach var. japonica [52]87 Deacetylsalannin M. azedarach [44] [45]

M. azedarach var. japonica [52]88 Salannin M. toosendan [33] [48]

A. indica [50]M. azedarach [38] [42] [44] [45]M. dubia [31]

89 Ohchinin M. azedarach var. japonica [51]90 Meliacarpinin A M. azedarach [53]

M. toosendan [12]91 Meliacarpinin B M. azedarach [53]92 Meliacarpinin C M. azedarach [53]

M. toosendan [12]93 Meliacarpinin D M. azedarach [53] [54]

M. toosendan [12]94 Meliacarpinin E M. azedarach [44]95 1-Tigloyl-3,20-diacetyl-11-methoxymeliacarpinin M. azedarach [55]96 3-Tigloyl-1,20-diacetyl-11-methoxymeliacarpinin M. azedarach [55]97 1-Cinnamoyl-3-hydroxy-11-methoxymeliacarpinin M. azedarach [55]98 1-Deoxy-3-methacrylyl-11-methoxymeliacarpinin M. azedarach [55]99 3-Acetyl-1-methacryloyl-11-methoxymeliacarpinin M. azedarach [54]

100 3-Acetyl-11-methoxy-1-(2-methylpropanoyl)-meliacarpinin

M. azedarach [54]

101 1-Deoxy-11-methoxy-3-tigloylmeliacarpinin M. azedarach [56]102 1,3-Dicinnamoyl-11-hydroxymeliacarpin M. azedarach [57]103 1-Cinnamoyl-11-hydroxy-3-methacryloylmeliacarpin M. azedarach [57]104 3-Acetyl-1-cinnamoyl-11-hydroxymeliacarpin M. azedarach [57]105 1-Cinnamoyl-3-feruloyl-11-hydroxymeliacarpin M. azedarach [57]106 Azadirachtin A. indica [50]107 1-Cinnamoyl-3,11-dihydroxymeliacarpin M. azedarach [58]108 11-Epiazadirachtin D A. indica [59]109 11-Epiazadirachtin H A. indica [60]110 Azadirachtin M A. indica [61]111 13,14-Desepoxyazadirachtin A A. indica [62]112 1-Cinnamoylmelianolone M. azedarach [63]113 Azadirachtin N A. indica [61]114 Volkensinin M. volkensii [64]115 12-O-Methylvolkensin M. toosendan [18]116 Melianolide M. azedarach [45]117 Spirosendan M. toosendan [25]118 7-Deacetyl-7-oxogedunin M. azedarach [65]119 Meliacinol A. indica [36]120 Gedunin M. azadirachta [32]121 7a-Acetoxy-14b,15b-epoxygedun-1-en-3-ol-

3b-O-b-d-glucopyranosideM. azedarach [66]


Table (cont.)


122 Methyl angolensate M. azedarach [65]123 Odoratone A. indica [67] [68]124 21,23 : 24,25-Diepoxytirucall-7-en-21-ol M. azedarach [69]125 Melianone M. azedarach [70]126 Azedarachic acid M. azedarach [71]127 Meliastatin 1 M. dubia [72]128 Meliastatin 2 M. dubia [72]129 Meliastatin 3 M. dubia [72]130 Meliastatin 4 M. dubia [72]131 Meliastatin 5 M. dubia [72]132 Dubione A M. dubia [72]133 Dubione B M. dubia [72]134 Methyl kulonate M. dubia [72]

M. azedarach [73]M. volkensii [74]

135 Kulinone M. dubia [72]M. azedarach [73]

136 16-Hydroxybutyrospermol M. dubia [72]137 12b-Hydroxykulactone M. volkensii [74]138 6b-Hydroxykulactone M. volkensii [74]139 Kulactone M. dubia [72]

M. azedarach [73]M. volkensii [74]

140 Kulolactone M. azedarach [73]141 Cinamodiol M. azedarach [75]142 Sendanolactone M. azedarach [76]143 1a,7a-Diacetoxyapotirucall-14-ene-3a,21,22,24,25-pentaol A. indica [68]144 Meliavolkenin M. volkensii [77]145 21-O-Methyltoosendapentol M. toosendan [78]146 21-O-Acetyltoosendantriol M. toosendan [79]147 Melianin B M. volkensii [28]

M. azedarach [54]148 Meliavolin M. volkensii [30]149 Meliavolen M. volkensii [80]150 Melianinone M. volkensii [80]151 Meliavolkensin A M. volkensii [81]152 Meliavolkensin B M. volkensii [81]153 23-O-Methylnimocinolide A. indica [82]154 7-O-Deacetyl-23-O-methyl-7a-O-senecioylnimocinolide A. indica [82]155 Salimuzzalin A. indica [83]156 Azadironolide A. indica [84]157 Isoazadironolide A. indica [84]158 Melianin C M. volkensii [28]159 Azadiradionolide A. indica [84]160 Meliatetraolenone A. indica [67]161 Azadirachtolide A. indica [85]162 Deoxyazadirachtolide A. indica [85]163 Compositolide M. dubia [31]164 Azadirolic acid A. indica [83]165 Azadiradionol A. indica [83]


Table (cont.)


166 Meliacinin A. indica [86]167 Azadironic acid A. indica [86]168 Zafaral A. indica [87]169 3-Teracrylmelazolide A M. azedarach [65]170 3-Teracrylmelazolide B M. azedarach [65]171 Melazolide A M. azedarach [65]172 Azedararide M. azedarach [88]173 Pyroangolensolide M. azedarach [65]174 12a-Acetoxyfraxinellone M. azedarach [88]175 Fraxinellone M. azedarach [65] [88]176 Fraxinellonone M. azedarach [88]177 9a-Hydroxyfraxinellone M. azedarach [65] [11]178 9b-Hydroxyfraxinellone M. azedarach [65]179 30-Hydroxyfraxinellone M. azedarach [65]180 12a-Acetoxy-9a-hydroxyfraxinellone M. azedarach [11]181 12a-Hydroxyfraxinellone M. azedarach [11]182 24-Methylenecycloartanone M. azedarach [69]183 24-Methylenecycloartanol M. azedarach [69]184 Isomultiflorenone M. azedarach [89]185 Nimbiol M. azadirachta [90]186 Sugiol M. azadirachta [90]187 Melia-ionoside A M. toosendan [91]188 Melia-ionoside B M. toosendan [91]189 (E)-Volkendousin M. volkensii [92]190 (Z)-Volkendousin M. volkensii [92]191 Meliavosin M. volkensii [92]192 Toosendanoside M. toosendan [93]193 Toosendansterol A M. toosendan [94]194 Toosendansterol B M. toosendan [94]195 (Z)-2b,3b-Dihydroxy-5a-pregn-17(20)-en-16-one M. azedarach [54]196 2,19-Epoxymeliavosin M. volkensii [92]197 Azedarachol M. azedarach var. japonica [95]198 2b,3b,4b-Trihydroxypregnan-16-one A. indica [68]199 b-Sitosterol M. azadirachta [90]

M. azedarach [69]200 b-Sitosterol-b-d-glucoside A. indica [96]

M. azedarach [69]201 Stigmast-4-en-3-one M. azedarach [69]202 Campest-4-en-3-one M. azedarach [69]203 3b-Hydroxystigmast-5-en-7-one M. azedarach [69]204 3b-Hydroxycampest-5-en-7-one M. azedarach [69]205 4,14a-Dimethyl-5a-ergosta-8,24(28)-dien-3b-ol A. indica [96]206 4a-Methyl-5a-ergosta-8,24(28)-dien-3b-ol A. indica [96]207 Cycloeucalenol M. azedarach [69]208 Cycloeucalenone M. azedarach [69]209 Azadironol A. indica [83]210 4,8-Dimethoxy-1-vinyl-b-carboline M. azedarach var. japonica [97]211 4-Methoxy-1-vinyl-b-carboline M. azedarach var. japonica [97]212 4’,5-Dihydroxyflavone-7-O-a-l-rhamnopyranosyl-

(1!4)-b-d-glucopyranosideM. azedarach [98]

2.1.3. Degraded Limonoids. Thirteen degraded limonoids, 169– 181, were obtainedfrom the roots of M. azedarach [11] [65] [88]. Since they are small and rather simplecompounds showing partial structures in common with limonoids, they are regarded asimportant intermediates for the total synthesis of limonoids, and, in fact, severaldegraded limonoids have already been synthesized [103].

2.1.4. Other Terpenoids. To date, except for the above-mentioned limonoids,protolimonoids and further derivatives, only three other triterpenoids, 182– 184, wereisolated from M. azedarach [69] [89]. Two aromatic tricyclic diterpenes, nimbiol (185)and sugiol (186), were reported from the trunk bark of M. azadirachta [90]. Two newionone glucosides, melia-ionosides A and B (187 and 188, resp.) were isolated from theleaves of M. toosendan [91].


Table (cont.)


213 Melianxanthone M. azedarach [99]214 1,8-Dihydroxy-2-methylanthraquinone-3-O-b-d-

galactopyranosideM. azedarach [100]

215 1,5-Dihydroxy-8-methoxy-2-methylanthraquinone-3-O-a-l-rhamnopyranoside

M. azedarach [100]

216 Scopoletin M. azedarach [101]217 (� )-Pinoresinol M. azedarach [101] [102]218 Melianoninol M. azedarach [103]219 Nimbothalin A. indica [104]220 Tridecylbenzene A. indica [89] [104]221 Vanillic acid M. azedarach [69]222 Vanillic aldehyde (Vanillin) M. azedarach [69] [102]223 trans-Cinnamic acid M. azedarach [69]224 4-Hydroxy-3-methoxycinnamaldehyde M. azedarach [101] [102]225 Propane-1,2,3-triyl (9E,9’E,9’’E)-tris-dodec-9-enoate M. azedarach [89]226 Eicosane M. azedarach [89]227 Pentadecane M. azedarach [89]228 a-Linolenic acid A. indica [49]229 Triacontan-1-ol M. azedarach [69]

a) Since the species of the genus Melia were poorly defined, to avoid further confusion, all plant sourcescited in the Table are identical with those reported in the original literatures.

Scheme. Plausible Biogenetic Route from 5 to 33 [39]

2.2. Steroids. Ten pregnanes, 189–198, were obtained from Melia species[54] [68] [92 –95]. In 1988, a new pregnane glycoside, named toosendanoside (192),and two new pregnane steroids, named toosendansterols A and B (193 and 194, resp.),were isolated from leaves of M. toosendan [93] [94]. In 1985, azedarachol (197), a newsteroid ester, has been identified as an antifeedant against a Japanese insect pest fromthe root bark of M. azedarach var. japonica [95]. Furthermore, eleven other typesteroids, 199–209, have also been reported from this genus [69] [83] [90] [96].

2.3. Alkaloids. In 2000, two b-carboline alkaloids (210 and 211), which inhibitedinducible nitric oxide synthase (iNOS) and cyclooxygenase-2 activities, were isolatedfrom the cortex of M. azedarach L. var. japonica [97].

2.4. Flavonoids. A flavone glycoside (212) and a new xanthone (213) were isolatedfrom the stem bark of M. azedarach [98] [99].

2.5. Anthraquinones. Two anthraquinones, 214 and 215, were isolated from the stembark of M. azedarach [100].

2.6. Others. So far, only one hydroxycoumarin, scopoletin (216), has been isolatedfrom the seed kernels of M. azedarach [101]. Two lignans, 217 and 218, were isolatedfrom M. azedarach [101 –103]. Two novel nonterpenoidal constituents, nimbothalin(219) and tridecylbenzene (220), have been isolated from the leaves of A. indica [105].Nine other compounds, 221– 229, have also been reported from M. azedarach and A.indica [49] [69] [89] [101] [102].

3. Biological Activities. – 3.1. Antiviral Activities. Toosendanin (8) purified from thefruit of M. azedarach exerted an antiviral effect on herpes simplex virus-1 (HSV-1) inVero cells. Its IC50 value was 1.46 mg/ml without cytotoxicity at 400 mg/ml on Vero cells[16] [17]. In 2006, Barquero et al. have reported the isolation of a tetranortriterpenoid(CDM; 107) from partially purified leaf extracts of M. azedarach (MA) that reducedboth vesicular stomatitis virus (VSV) and HSV-1 multiplication. CDM can block VSVentry and the intracellular transport of VSV-G protein, confining it to the Golgiapparatus, by pre- or post-treatment, respectively. Considering that MA could be actingas an immunomodulator preventing the development of herpetic stromal keratitis inmice, Barquero et al. also examined an eventual effect of CDM on NF-kB signalingpathway. The results indicate that CDM is able to impede NF-kB activation in HSV-1-infected conjunctival cells and leads to the accumulation of p65 NF-kB subunit in thecytoplasm of uninfected treated Vero cells. In conclusion, CDM was shown to be apleiotropic agent that not only inhibits the multiplication of DNA and RNA viruses bythe same mechanism of action but also modulates the NF-kB signaling pathway [58].

3.2. Inhibition of iNOS and Cyclooxygenase-2. In 2000, Lee et al. reported that twob-carboline (¼ 9H-pyrido[3,4-b]indole) alkaloids (210 and 211) , isolated from M.azedarach, primarily inhibit iNOS and cyclooxygenase-2 activities via the suppressionof de novo synthesis of these two enzymes, and the inhibition of iNOS expression maybe associated with the inhibition of NF-kB activation [97].

3.3. Antifeeding and Insecticide Effects. The insect antifeedant activities of theisolated compounds 1, 3, 5, 11 –19, 21, 26 –28, 31, 32, 58, 60, 73– 76, 88, 94, 101– 104, and106 have been tested by the conventional leaf disk method against the larvae ofdifferent species (i.e., Spodoptera eridania, S. exigua, S. littoralis, and S. frugiperda), andmost of these compounds exhibited antifeedant activities in different degrees


[9] [12] [21] [42] [44] [46] [48] [57]. Meliacarpinin E (94) showed significant antifeedantactivity against the third-instar larvae of the Japanese pest insect S. eridania at 50 ppm,corresponding to a concentration of 1 mg/cm2 [44], followed by compounds 1, 5, and 13(200 ppm) [9] [12] [21]. Three new meliacarpins, 102 –104, and azadirachtin (106) wereevaluated for their insecticidal activity against neonate larvae of the polyphagous pestS. littoralis. Compound 104 was the most active derivative. Its LC50 and EC50 values(0.48 and 0.27 ppm, resp.) are comparable to those of azadirachtin (LC50 0.32 ppm andEC50 0.11 ppm). It is obvious that the nature of the ester substituent at C(3) plays animportant role for the insecticidal activity of these compounds. The most activecompound 104 contained a small and relatively hydrophilic AcO group at C(3),whereas compound 102 with a bulky and more lipophilic cinnamoyl group exhibited theweakest activity. These results confirm previous findings on quantitative structure –activity relationships of azadirachtin derivatives, namely that the insecticidal activity ofthe respective natural products depends on the polarity of ring A and on the size of theester substituents [57].

The insecticidal activities of the isolated compounds 51, 123, 153, 154, 160, 166, and167 have been reported. 6a-O-Acetyl-7-deacetylnimocinol (51) showed toxicity onfourth instar larvae of mosquitoes (Aedes aegypti) with an LC50 value of 21 ppm [36].Compounds 153 and 154 showed insect-growth-regulating effect on mosquitoes (A.aegypti) with LC50 53 ppm and 2.14 ppm, respectively. The senecioyloxy substituent atC(7) in 154 results in a significant increase of activity [82]. Meliatetraolenone (160) andodoratone (123) showed toxicity on the fourth instar larvae of mosquitoes (Anophelesstephensi) with LC50 values of 16 and 154 ppm, respectively [67]. Meliacinin (166) andazadironic acid (167) showed toxicity against mosquito (A. stephensi) with LC50 valuesof 13 and 4.5 ppm, respectively [86].

3.4. Antitumor and Cytotoxic Activities. Compounds 5, 27, 33, 177, 180, and 181exhibited significant lethality activity in the Brine shrimp test (BST), in particular,azedarachin B (5) exhibited highly potent lethality in BST with an LC50 value of0.0098 mm. On the other hand, azedarachin B also exhibited significant cytotoxicactivity at IC50 0.0049 mm. The structural feature with a 14,15-epoxide ring and a C(19)/C(29) bridged acetal ring is probably responsible for its cytotoxic and BST activities[11]. Compound 99 also exhibited significant lethal activity (LC50¼19 mg/ml) in theBST [54]. The cytotoxic effect against KB cell of a number of known compoundsisolated from genus Melia was evaluated. Trichilin H (12) and toosendanin (8) werehighly cytotoxic against KB cells in vitro [18]. In 1994, Ahn et al. reported thatcompounds 7, 8, and 31, were significantly cytotoxic towards five human tumor cell lines(A-549, SK-OV-3, SK-MEL-2, XF-498, and HCT-15) [15]. Kim et al. reported thatcompound 8 had more sensitive and selective inhibitory effects on in vitro growth ofhuman cancer cell lines in comparison with adriamycin [17]. In 2005, Zhang et al.investigated the growth inhibition and apoptosis-induced effect of compound 8 onhuman cancer cells. The result showed that this compound significantly suppressed theproliferation of tested human cancer cell lines. The IC50 values were less than 1.7�10�7

m,and U937 was the most sensitive cell line with a IC50 of 5.4�10�9

m [106]. The cytotoxicactivities of compounds 12, 14, 20– 25, and 29, isolated from M. azedarach, against P388lymphocytic leukemia cells in vitro were examined and their IC50 values weredetermined. As can be seen, all of those trichilins with a 14,15-epoxide, a C(19)/C(29)


bridged acyl acetal ester system, a 11-ketone and furanyl moiety showed significantcytotoxic activities. Especially the compounds 14, 20, and 22, which have one or twoAcO groups in the structures, exhibited strong activities. The activities of compounds12, 21, 22, 24, and 25, which have more than three AcO groups in the structures,decreased slightly. When the 14,15-epoxide structure was cleaved, as in compound 29,the cytotoxic activity decreased greatly [22]. Compounds 9, 65, 66, and 71 exhibitedsignificant inhibitory activity against HeLa S3 cancer cells [20] [47]. Volkensinin (114)showed weak cytotoxicities against six human tumor cell lines [64]. In 2002, eleveneuphane-type triterpenes were isolated from the bark of Melia dubia. Among them,nine compounds, 127– 131 and 134–136, were found to significantly inhibit growth ofthe P388 cancer cell line [72]. Meliavolin (148) and meliavolkin (44), were significantlyactive in the BST, and meliavolkin (44) even showed cytotoxic activity equivalent tothat of adriamycin against the human breast tumor cell line (MCF-7) [30].Meliavolkenin (144) was significantly active in the BST test (LC50 0.55 mg/ml), and itwas moderately cytotoxic against three human tumor cell lines (ED50 10.33, 4.30, and0.67 mg/ml in A-549, MCF-7, and HT-29 cells, resp.) [77]. Meliavolkensins A and B (151and 152, resp.) showed selective cytotoxicities toward the human colon tumor cell line(H-29) [81].

Besides the terpenoids, several pregnanes, (E)-volkendousin (189), and itsacetonide derivative showed cytotoxic activities equivalent to that of adriamycin inthe human prostate tumor cell line (PC-3), while (Z)-volkendousin (190), meliavosin(191), and 2,19-epoxymeliavosin (196) showed weaker activities with marginallysignificant selectivity for the human breast tumor cell line (MCF-7) [92]. Pregnane 195exhibited significant activity in BST with an LC50 value of 2.1 mg/ml [54].

3.5. Agonist of L-type Ca2þ Channels. In 2004, Li and Shi investigated the effects ofcompound 8 on L-type voltage-dependent Ca2þ channels in cultured neonatal ratventricular cells, using the whole-cell patch-clamp method. Compound 8 irreversiblyincreased the L-type Ca2þ current in a concentration-dependent manner and shiftedthe maximum of the current/voltage relationship from 8.3�3.7 to 1.7�3.7 mV, withoutmodifying the threshold potential of the current [107].

3.6. Antibacterial and Antifungal Activities. A new limonoid glycoside, 53, showsantibacterial activity against four organisms [38]. In a radiorespirometric bioassayagainst Mycobacterium tuberculosis, compounds 137, 138, and 134 exhibited minimuminhibitory concentrations (MICs) of 16, 4, and 16 mg/ml, respectively [74]. In 2003,extracts from different parts of M. azedarach were studied as potential antifungalagents for selected phytopathogenic fungi. In a serial agar dilution method, hexaneand EtOH extracts from fruit, seed kernels, and senescent leaves exhibited fungi-static activity against Aspergillus flavus, Diaporthe phaseolorum var. meridionales,Fusarium oxysporum, Fusarium solani, Fusarium verticillioides, and Sclerotiniasclerotiorum. Both the hexane extract from senescent leaves and the EtOH extractfrom seed kernels were highly effective on all tested fungi, with MIC values rangingfrom 0.5 to 25 mg/ml and 0.5 to 5 mg/ml, respectively. In addition, three compoundsdisplaying activity against F. verticillioides were isolated from the EtOH seed kernelextract and were characterized as vanillin (222), 4-hydroxy-3-methoxycinnamaldehyde(224), and (� )-pinoresinol (217), with MIC values of 0.6, 0.4, and 1.0 mg/ml,respectively [102].


4. Conclusions. – The plants of the genus Melia are well-known as rich sources ofbioactive limonoids. Protolimonoids and further derivatives are also distinctiveconstituents in this genus. The studies on chemical constituents in recent years havedisclosed many different biological activities of the isolated compounds, such asantibacterial, antifungal, and antiviral activities, inhibition of iNOS and cyclooxyge-nase-2, insect antifeedant and growth regulating properties, and cytotoxic activities.Nevertheless, the compounds isolated from this genus have not yet received enoughattention, marked cytotoxicity against tumor cell lines and insect antifeedant suggestthat further extensive biological screening of compounds from this genus is warranted.

This work was supported by the Science Foundation of Hebei Medical University, Department ofEducation, Hebei Province (2006129), China Postdoctoral Science Foundation (20070410869), andScientific Research Foundation of Hebei Province (08B032).

REFERENCES

[1] B. T. Styles, T. D. Pennington, Blumea 1975, 22, 419.[2] K. R. Kirtikar, B. D. Basu, �Indian Medicinal Plants�, Lalit Mohan Basu, Allahabad, 1935, Vol. 1,

p. 542.[3] T. R. Govindachari, Curr. Sci. 1992, 63, 117.[4] Quan Guo Zhong Cao Yao Hui Bian Edita, �Quan Guo Zhong Cao Yao Hui Bian�, People Health

Press, Beijing, 1996, p. 137.[5] J. O. Kokwaro, �Medicinal Plants of East Africa�, East African Literature Bureau, Nairobi, 1976,

p. 157.[6] K. Awang, C. S. Lim, K. Mohamad, H. Morita, Y. Hirasawa, K. Takeya, O. Thoison, A. H. A. Hadi,

Bioorg. Med. Chem. 2007, 15, 5997.[7] D. A. Mulholland, B. Parel, P. H. Coombes, Curr. Org. Chem. 2000, 4, 1011.[8] R. C. Huang, H. Okamura, T. Iwagawa, K. Tadera, M. Nakatani, Phytochemistry 1995, 38, 593.[9] J.-B. Zhou, H. Okamura, T. Iwagawa, M. Nakatani, Phytochemistry 1996, 41, 117.

[10] H. Itokawa, Z.-S. Qiao, C. Hirobe, K. Takeya, Chem. Pharm. Bull. 1995, 43, 1171.[11] Y. Fukuyama, M. Nakaoka, T. Yamamoto, H. Takahashi, H. Minami, Chem. Pharm. Bull. 2006, 54,

1219.[12] J.-B. Zhuo, K. Tadera, Y. Minami, F. Yagi, J. Kurawaki, K. Takezaki, M. Nakatani, Biosci.

Biotechnol. Biochem. 1998, 62, 496.[13] M. Ochi, H. Kotsuki, K. Hirotsu, T. Tokoroyama, Tetrahedron Lett. 1976, 17, 2877.[14] M. C. Carpinella, M. T. Defago, G. Valladares, S. M. Palacios, J. Agric. Food Chem. 2003, 51, 369.[15] J.-W. Ahn, S.-U. Choi, C.-O. Lee, Phytochemistry 1994, 36, 1493.[16] M. Kim, S. K. Kim, B. N. Park, K. H. Lee, G. H. Min, J. Y. Seoh, C. G. Park, E. S. Hwang, C. Y. Cha,

Y. H. Kook, Antiviral Res. 1999, 43, 103.[17] H. M. Kim, G. T. Oh, S. B. Han, D. H. Hong, B. Y. Hwang, Y. H. Kim, J. J. Lee, Arch. Pharmacal Res.

1994, 17, 100.[18] K. Tada, M. Takido, S. Kitanaka, Phytochemistry 1999, 51, 787.[19] C. C. Chung, T. H. Hsie, S. F. Chen, H. T. Liang, Huaxue Xuebao 1975, 33, 35.[20] H. Zhou, A. Hamazaki, J. D. Fontana, H. Takahashi, C. B. Wandscheer, Y. Fukuyama, Chem.

Pharm. Bull. 2005, 53, 1362.[21] M. Nakatani, R. C. Huang, H. Okamura, H. Naoki, T. Iwagawa, Phytochemistry 1994, 36, 39.[22] K. Takeya, Z. S. Qiao, C. Hirobe, H. Itokawa, Bioorg. Med. Chem. 1996, 4, 1355.[23] P. B. Oelrichs, M. W. Hill, P. J. Vallely, J. K. MacLeod, T. F. Molinski, Phytochemistry 1983, 22, 531.[24] J. X. Xie, A. X. Yuan, Acta Pharm. Sin. 1985, 20, 188.[25] M. Nakatani, M. Shimokoro, J.-B. Zhou, H. Okamura, T. Iwagawa, K. Tadera, N. Nakayama, H.

Naoki, Phytochemistry 1999, 52, 709.


[26] M. S. Rajab, M. D. Bentley, J. Nat. Prod. 1988, 51, 840.[27] J.-B. Zou, H. Okamura, T. Iwagawa, Y. Nakamura, N. Nakayama, K. Tadera, M. Nakatani,

Heterocycles 1995, 41, 2795.[28] L. L. Rogers, L. Zeng, J. F. Kozlowski, H. Shimada, F. Q. Alali, H. A. Johnson, J. L. McLaughlin, J.

Nat. Prod. 1998, 61, 64.[29] M. M. Rao, E. M. Krishna, P. S. Gupta, P. P. Singh, Indian J. Chem., Sect. B 1979, 17, 177.[30] L. Zeng, Z.-M. Gu, X.-P. Fang, P. E. Fanwick, C.-J. Chang, D. L. Smith, J. L. McLaughlin,

Tetrahedron 1995, 51, 2477.[31] K. K. Purushothaman, K. Duraiswamy, J. D. Connolly, Phytochemistry 1984, 23, 135.[32] D. Lavie, E. C. Levy, M. K. Jain, Tetrahedron 1971, 27, 3927.[33] J.-B. Zhou, Y. Minami, F. Yagi, K. Tadera, M. Nakatani, Phytochemistry 1997, 46, 911.[34] G. Suresh, N. S. Narasimhan, N. Palani, Phytochemistry 1997, 45, 807.[35] T. R. Govindachari, R. Malathi, G. Gopalakrishnan, G. Suresh, S. S. Rajan, Phytochemistry 1999, 52,

1117.[36] B. S. Siddiqui, F. Afshan, Ghiasuddin, S. Faizi, S. N. H. Naqvi, R. M. Tariq, Phytochemistry 2000, 53,

371.[37] S. Siddiqui, S. Fuchs, J. L�cke, W. Voelter, Tetrahedron Lett. 1978, 19, 611.[38] S. D. Srivastava, J. Nat. Prod. 1986, 49, 56.[39] S. D. Srivastava, Planta Med. 1987, 53, 100.[40] K. Rusia, S. K. Srivastava, Proc. Natl. Acad. Sci., India, Sect. A: Phys. Sci. 1988, 58, 33.[41] M. Ochi, H. Kotsuki, T. Tokoroyama, Chem. Lett. 1978, 7, 621.[42] M. Nakatani, R. C. Huang, H. Okamura, T. Iwagawa, K. Tadera, Chem. Lett. 1995, 24, 995.[43] W. Kraus, M. Bokel, Chem. Ber. 1981, 114, 267.[44] R. C. Huang, K. Tadera, F. Yagi, Y. Minami, H. Okamura, T. Iwagawa, M. Nakatani, Phytochemistry

1996, 43, 581.[45] R. C. Huang, Y. Minami, F. Yagi, Y. Nakamura, N. Nakayama, K. Tadera, M. Nakatani, Heterocycles

1996, 43, 1477.[46] M. S. Rajab, M. D. Bentley, A. R. Alford, M. J. Mendel, J. Nat. Prod. 1988, 51, 168.[47] H. Zhou, A. Hamazaki, J. D. Fontana, H. Takahashi, T. Esumi, C. B. Wandscheer, H. Tsujimoto, Y.

Fukuyama, J. Nat. Prod. 2004, 67, 1544.[48] M. Nakatani, J.-B. Zhou, N. Nakayama, H. Okamura, T. Iwagawa, Phytochemistry 1996, 41, 739.[49] M. S. Nair, S. Gopal, D. Issac, Phytochemistry 1997, 46, 1177.[50] A. P. Jarvis, S. Johnson, E. D. Morgan, M. S. J. Simmonds, W. M. Blaney, J. Chem. Ecol. 1997, 23,

2841.[51] Y. Fukuyama, I. Miura, M. Ochi, Bull. Chem. Soc. Jpn. 1983, 56, 1139.[52] M. Ochi, H. Kotsuki, T. Kataoka, T. Tada, T. Tokoroyama, Chem. Lett. 1978, 7, 331.[53] M. Nakatani, R. C. Huang, H. Okamura, T. Iwagawa, K. Tadera, H. Naoki, Tetrahedron 1995, 51,

11731.[54] Y. Fukuyama, M. Ogawa, H. Takahashi, H. Minami, Chem. Pharm. Bull. 2000, 48, 301.[55] K. Takeya, Z.-S. Qiao, C. Hirobe, H. Itokawa, Phytochemistry 1996, 42, 709.[56] M. Nakatani, R. C. Huang, H. Okamura, T. Iwagawa, Chem. Lett. 1993, 22, 2125.[57] F. I. Bohnenstengel, V. Wray, L. Witte, R. P. Srivastava, P. Proksch, Phytochemistry 1999, 50, 977.[58] A. A. Barquero, F. M. Michelini, L. E. Alche, Biochem. Biophys. Res. Commun. 2006, 344, 955.[59] N. Ramji, K. Venkatakrishnan, K. M. Madyastha, Phytochemistry 1998, 49, 265.[60] N. Ramji, K. Venkatakrishnan, K. M. Madyastha, Phytochemistry 1996, 42, 561.[61] X. Luo, Y. Ma, S. Wu, D. Wu, J. Nat. Prod. 1999, 62, 1022.[62] T. R. Govindachari, G. Gopalakrishnan, Phytochemistry 1997, 45, 397.[63] S. M. Lee, J. A. Klocke, M. F. Balandrin, Tetrahedron Lett. 1987, 28, 3543.[64] L. L. Rogers, L. Zeng, J. L. McLaughlin, Tetrahedron Lett. 1998, 39, 4623.[65] M. D�Ambrosio, A. Guerriero, Phytochemistry 2002, 60, 419.[66] M. Saxena, S. K. Srivastava, Indian J. Chem., Sect. B 1986, 25, 1087.[67] B. S. Siddiqui, F. Afshan, T. Gulzar, R. Sultana, S. N.-H. Naqvi, R. M. Tariq, Chem. Pharm. Bull.

2003, 51, 415.


[68] X.-D. Luo, S.-H. Wu, Y.-B. Ma, D.-G. Wu, Fitoterapia 2000, 71, 668.[69] K. E. Schulte, G. R�cker, H. U. Matern, Planta Med. 1979, 35, 76.[70] D. Lavie, M. K. Jain, I. Kirson, Tetrahedron Lett. 1966, 7, 2049.[71] W. M. Zhao, C. Q. Fan, Z. Zhang, Chin. Chem. Lett. 1999, 10, 289.[72] G. R. Pettit, A. Numata, C. Iwamoto, H. Morito, T. Yamada, A. Goswami, P. J. Clewlow, G. M.

Cragg, J. M. Schmidt, J. Nat. Prod. 2002, 65, 1886.[73] C.-K. Chiang, F. C. Chang, Tetrahedron 1973, 29, 1911.[74] C. L. Cantrell, M. S. Rajab, S. G. Franzblau, N. H. Fischer, J. Nat. Prod. 1999, 62, 546.[75] A. Kelecom, M. M. O. Cabral, E. S. Garcia, J. Braz. Chem. Soc. 1996, 7, 39.[76] M. Ochi, H. Kotsuki, T. Tokoroyama, T. Kubota, Bull. Chem. Soc. Jpn. 1977, 50, 2499.[77] L. Zeng, Z. M. Gu, C. J. Chang, K. V. Wood, J. L. McLaughlin, Bioorg. Med. Chem. 1995, 3, 383.[78] A. Inada, M. Konishi, T. Nakanishi, Heterocycles 1989, 28, 383.[79] T. Nakanishi, A. Inada, M. Nishi, T. Miki, R. Hino, T. Fujiwara, Chem. Lett. 1986, 15, 69.[80] L. Zeng, Z.-M. Gu, P. E. Fanwick, C.-J. Chang, D. L. Smith, J. L. McLaughlin, Heterocycles 1995, 41,

741.[81] L. Zeng, Z.-M. Gu, C.-J. Chang, D. L. Smith, J. L. McLaughlin, Bioorg. Med. Chem. Lett. 1995, 5,

181.[82] B. S. Siddiqui, F. Afshan, Ghiasuddin, S. Faizi, S. N. H. Naqvi, R. M. Tariq, J. Chem. Soc., Perkin

Trans. 1999, 2367.[83] B. S. Siddiqui, Ghiasuddin, S. Faizi, Phytochemistry 1998, 47, 1631.[84] B. S. Siddiqui, Ghiasuddin, S. Faizi, M. Rasheed, J. Nat. Prod. 1999, 62, 1006.[85] C. Y. Ragasa, Z. D. Nacpil, G. M. Natividad, M. Tada, J. C. Coll, J. A. Rideout, Phytochemistry 1997,

46, 555.[86] B. S. Siddiqui, M. Rasheed, Ghiasuddin, S. Faizi, S. N. H. Naqvi, R. M. Tariq, Tetrahedron 2000, 56,

3547.[87] B. S. Siddiqui, F. Afshan, T. Gulzar, M. Hanif, Phytochemistry 2004, 65, 2363.[88] M. Nakatani, R. C. Huang, H. Okamura, T. Iwagawa, K. Tadera, Phytochemistry 1998, 49, 1773.[89] P. Suhag, Bharati, M. Mahla, R. Singh, S. B. Kalidhar, J. Indian Chem. Soc. 2002, 79, 548.[90] P. Sengupta, S. N. Choudhuri, H. N. Khastgir, Tetrahedron 1960, 10, 45.[91] T. Nakanishi, M. Konishi, H. Murata, A. Inada, A. Fujii, N. Tanaka, T. Fujiwara, Chem. Pharm. Bull.

1991, 39, 2529.[92] L. L. Rogers, L. Zeng, J. L. McLaughlin, J. Org. Chem. 1998, 63, 3781.[93] T. Nakanishi, M. Kobayashi, H. Murata, A. Inada, Chem. Pharm. Bull. 1988, 36, 4148.[94] A. Inada, M. Kobayashi, T. Nakanishi, Chem. Pharm. Bull. 1988, 36, 609.[95] M. Nakatani, H. Takao, I. Miura, T. Hase, Phytochemistry 1985, 24, 1945.[96] R. Banerji, G. Misra, S. K. Nigam, Fitoterapia 1977, 48, 166.[97] B. G. Lee, S. H. Kim, O. P. Zee, K. R. Lee, H. Y. Lee, J. W. Han, H. W. Lee, Eur. J. Pharmacol. 2000,

406, 301.[98] M. Mishra, S. K. Srivastava, Curr. Sci. 1984, 53, 694.[99] G. Yang, Y. Chen, S. Zhang, Z. Zhu, Nat. Prod. Res. Dev. 1998, 10, 45.

[100] S. K. Srivastava, M. Mishra, Indian J. Chem., Sect. B 1985, 24, 793.[101] M. C. Carpinella, C. G. Ferrayoli, S. M. Palacios, J. Agric. Food Chem. 2005, 53, 2922.[102] M. C. Carpinella, L. M. Giorda, C. G. Ferrayoli, S. M. Palacios, J. Agric. Food Chem. 2003, 51, 2506.[103] J. Han, W. H. Lin, R. S. Xu, W. L. Wang, S. H. Zhao, Acta Pharm. Sin. 1991, 26, 426.[104] V. Sharma, A. Bali, M. Singh, Phytochemistry 1998, 49, 2121.[105] H. Okamura, K. Yamauchi, K. Miyawaki, T. Iwagawa, M. Nakatani, Tetrahedron Lett. 1997, 38, 263.[106] B. Zhang, Z.-F. Wang, M.-Z. Tang, Y.-L. Shi, Invest. New Drugs 2005, 23, 547.[107] M.-F. Li, Y.-L. Shi, Eur. J. Pharmacol. 2004, 501, 71.

Received February 22, 2009


chemical constituents of plants from the genus melia

Documents