Chemistry and Biological Activity of Rocaglamide Derivatives and Related Compounds in Aglaia Species (Meliaceae)

Current Organic Chemistry, 2001, 5, 923-938 923

Chemistry and Biological Activity of Rocaglamide Derivatives and RelatedCompounds in Aglaia Species (Meliaceae)

Peter Proksch*, RuAngelie Edrada, Rainer Ebel, Frank I. Bohnenstengel# andBambang W. Nugroho§

Institute of Pharmaceutical Biology, Heinrich Heine University of Düsseldorf, Universitätsstr.1, D-40225 Düsseldorf, Germany

#Permanent address: Clinical Research & Development, Novartis Pharma GmbH, Roonstr.25, D-90429 Nürnberg, Germany

§Permanent address: Department of Plant Pests and Diseases, Faculty of Agriculture, BogorAgricultural University, Jl. Raya Pajajaran-Bogor 16144, Indonesia

Abstract: The genus Aglaia is the source of a unique group of natural products featuring acyclopenta[b]tetrahydrobenzofuran skeleton. Commonly these compounds, which until now include more than50 naturally occurring derivatives, are named after the parent compound, rocaglamide, which was described forthe first time almost twenty years ago. This review highlights the chemical diversity of rocaglamide derivativesand of biogenetically similar compounds from the genus Aglaia and their remarkable biological activity in thefields of insecticides and cytostatic agents. With a few exceptions, all naturally occurring rocaglamidederivatives exhibit striking insecticidal activity against various pest insects. In addition, they displaypronounced cytostatic activity against human cancer cell lines in vitro. Furthermore, it was shown recentlythat rocaglamide and several of its congeners inhibit NF-κB induced gene activation in human T cells and areable to elicit apoptosis in resistant tumor cells. Taken together, these data make rocaglamide derivativesinteresting candidates for possible therapeutic agents primarily in the field of cancer chemotherapy. In someAglaia species, rocaglamide derivatives co-occur with biogenetically similar natural products of the aglain,aglaforbesin or forbaglin type. These latter compounds differ from rocaglamide and its congeners mainly by thenature of their heterocycle. Furthermore, they seem to be devoid of significant biological activity at least in theareas mentioned above, thereby pointing to the cyclopenta[b]tetrahydrobenzofuran core of the rocaglamideskeleton as one essential structural requirement for the pronounced biological activity of the rocaglamides.

INTRODUCTION of secondary metabolites in the last couple of years. Thegenus Aglaia consists of approximately 130 species that arefound in the Indo-Malaysian region, in South China and onthe Pacific Islands [4,5]. Species of Aglaia often form animportant element of the moist tropical forests in the Indo-Malaysian region [6]. Several species of this genus such asA. odorata are traditionally used in folk medicine forexample as heart stimulant, febrifuge and for the treatment ofcoughs, inflammations and injuries [7]. The fragrant flowersof Aglaia species are furthermore used to scent tea (e.g. inVietnam) or are kept in cupboards to protect clothing frommoths.

The family Meliaceae (order Rutales) is the source ofnumerous bioactive secondary products with several of themexhibiting significant insecticidal activity. Azadirachtin fromthe neem tree Azadirachta indica is the most famousexample being even marketed as a botanical insecticide inthe USA as well as in other countries like India [1,2].Whereas limonoids from the Meliaceae includingazadirachtin have constantly attracted wide attention over thelast decades thanks to their remarkable insecticidalproperties, phytochemical interest in the natural constituentsof the genus Aglaia is of far more recent origin. It can betraced back to the discovery of the first cyclopenta[b]tetra-hydrobenzofuran derivative, rocaglamide, from Aglaiaelliptifolia [3], though these compounds have only receivedbroader attention over the last decade as indicated by therising number of papers published on this fascinating group

The traditional use of flowers for example from A.odorata in parts of South East Asia (e.g. in Indonesia) asinsect repellent is another striking example for the empiricalknowledge on the use of plants that can still be encounteredin many parts of the world. In the last ten years or so thetruly remarkable insecticidal properties of many Aglaiaspecies could be unequivocally traced to a unique group ofnatural products characterized by a cyclopenta[b]tetrahydro-benzofuran skeleton which up to now have only beenisolated from members of this particular genus. Most of thesecompounds (but not all) feature a more or less complexamide substituent at position C-2 and can hence also be

*Address correspondence to this author at the Institute of PharmaceuticalBiology, Heinrich Heine University of Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany; Tel: 0049 211 81 14 166; Fax: 0049 211 8111 923;E-mail: [email protected]

1385-2728/01 $20.00+.00 © 2001 Bentham Science Publishers Ltd.

924 Current Organic Chemistry, 2001, Vol. 5, No. 9 Proksch et al.

considered as alkaloids sensu lato. For the sake ofconvenience these unusual benzofuran derivatives are mostlynamed after the parent compound rocaglamide originallyisolated in 1982 [3] even though this nomenclature is notused consistently among all scientists who are active in thisfield. In addition to the 50 or so different rocaglamidecongeners isolated from Aglaia spp. up to now (see Fig.(2)), members of this genus have also yielded structurallyrelated heterocyclic compounds called aglain (see Fig. (3)),aglaforbesin (see Fig. (4)) or forbaglin (see Fig. (5))derivatives, respectively [8], which are obviously derivedfrom the same biogenetic pathway (see Fig. (6)) asrocaglamide and its numerous analogues [9]. In comparisonto the well documented bioactivity of rocaglamidederivatives (see below), the structurally more complexaglain, aglaforbesin and forbaglin congeners seem to bedevoid of any noteworthy biological activity based on theinformation available up to date [9-12]. The present reviewdescribes the group of rocaglamide derivatives and relatedcompounds from the genus Aglaia with emphasis on theirchemical diversity and structure elucidation and focuses ontheir significant insecticidal and antiproliferative propertieswhich are the reason for attracting more and more attentionfrom natural product chemists and from cell biologists tothis remarkable group of natural products.

Spectral data of rocaglamide and its analogues:desmethylrocaglamide (7), methyl rocaglate (18) androcaglaol (28) were first established in 1993 by Ishibashi etal. through MS and 1D and 2D NMR [14]. Its congenersdiffer basically with regards to their substituents at C-1, C-2,C-8b, and C-3’ at ring B. Major variations in thesubstitution pattern occur at C-2 while the hydroxylsubstituents at C-1 or C-8b can either be acetylated,methylated, or ethylated (e.g. congeners 4, 5, and 6). Theposition C-3’ is either hydroxylated or methoxylated (e.g.congeners 2 and 3). However, in more recent papers,esterification [15] and oxidation [12] of the hydroxyl groupat C-1 have also been reported. The structures ofrocaglamides known so far are summarized in Fig. (2).

The mass spectra of rocaglamide and its derivatives oftenshow characteristic pairs of fragments at m/z 300 and 313dependent on the substitution pattern. Plausible structuresfor the ions m/z 300 and 313 arising from fragmentation ofrocaglamide type compounds under EI conditions have beendescribed [16], see Fig. (1). Changes in the fragmentationpattern in the range m/z 300 - 343 proved to be indicative ofthe type of substitution at ring B and C-8b of the furan ring.For example, the presence of a hydroxyl substituent at C-3’shifted the characteristic pair of fragments at m/z 300 and 313(as in rocaglamide) to m/z 316 and 329 while a methoxylsubstituent at the same position gave rise to fragments at m/z330 and 343 in the EI mass spectrum of the respectivederivative [17]. Modification of the hydroxyl substituent atC-8b (e.g. methylation) can also be initially determined bycomparison of its diagnostic fragments to those of the morecommon structural analogues featuring a hydroxy group atthat position [18].

CHEMISTRY OF ROCAGLAMIDES AND RELATEDCOMPOUNDS

Rocaglamide Derivatives

Rocaglamide, a 1H-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran, was first structurally elucidated in 1982 by Kinget al. through single-crystal X-ray analysis [3]. Its absolutestereochemistry was unequivocally determined byenantioselective synthesis in 1990 by Trost et al. [13].

Rocaglamide analogues exhibited 1H and 13C NMRsignals for aromatic protons and aromatic methoxy groupstypical for those of substituted phenols. Investigation of the

Fig. (1). Plausible structures for fragment ions m/z 316 and m/z 329 of compound 2 under EI–MS.

Chemistry and Biological Activity of Rocaglamide Current Organic Chemistry, 2001, Vol. 5, No. 9 925

1H NMR spectra of several rocaglamide derivatives showedempirically that hydroxylation at C-3’ causes a deshieldingeffect on the aromatic protons at ring B in the followingorder: H-2’>H-6’>H-5’. Consequently, methylation of thehydroxyl group at C-3’ causes a deshielding of the aromaticprotons accordingly: H-6’>H-5’>H-2’. Substitution at C-3’,furthermore, changes the symmetrical 1H NMR resonancepattern for the AA’BB’ system for the para-substituted ringB to an ABC pattern of methines as for a 3-way substitutedphenyl ring system. Assignment of the relative configurationat C-2 was also deduced by inspection of their 1H NMRspectra. The vicinal coupling constant values of the methineprotons at C-1, C-2, and C-3 positions (J1,2 ca. 5-7 Hz andJ2,3 ca. 13-14 Hz) indicated the 1α, 2α, 3β configuration aswell as cis- BC ring junction [14]. NOESY experimentshave been used to confirm the stereochemical relationship ofthe substituents from different carbon ring junctions. TheNOESY spectrum showed NOE correlation peaks betweenH-2’ and both H-1α and H-2α but not between H-2’ and H-3β [14].

our group [12] comes to the same conclusion as the earlierdescribed procedures.

Considering rocaglamide (1) as the parent compound,major modifications in substitution patterns occur at C-2which is essentially a dimethylamino substituentcharacterized by two NMe 1H NMR resonance signals at ca2.90 - 3.40 ppm. Derivatives 2, 5, and 6 with a hydroxylfunction at C-3’ of ring B were isolated from the twigs [17]and flowers [18] of the Vietnamese species A. duppereanawhile its methoxylated form known as aglaroxin E (3) wasisolated from the bark of the Sri Lankan species A.roxburghiana [21]. Compounds with an acetoxy function atC-1 (4 and 5) [17, 22] and ethoxylated substituent at C-8b(6) [18] were obtained from the same A. duppereana sample.

N-desmethylrocaglamide congeners (7 – 11) arecharacterized by a –CONHMe group at C-2. N-desmethylrocaglamide (7) was isolated from twigs and leavesof A. odorata [9, 14]. Its EI mass spectrum showed acharacteristic fragment ion peak at m/z 162 corresponding to[PhCH=CHCONMeH2]+. Only one -NMe 1H NMRresonance signal was observed in the expected region.Congeners with an acetylated hydroxy function at C-1 havebeen isolated from flowers of A. odorata [23] and from rootsof A. duppereana [22] collected from Vietnam. An ethylatedform of substitution at C-8b occurred in compound 11 whichwas obtained from the flowers of the same collection [18].This unusual substituent at C-8b was indicated by the EIfragmentation pattern as described above. Derivatives with anamino acyl substituent at C-2 as in congeners 12 and 13were isolated from A. harmsiana [16]. From the samespecies, the cyclized form of the amino acyl chain yieldingthe tetrahydrofuran ring, which is present in congener 14,was isolated in its two stereoisomeric configurations. The N-didesmethylrocaglamide derivatives (15 – 17) are widelydistributed among various Aglaia species from differentgeographical origins, e.g. A. odorata from Indonesia [23],A.argentea from Malaysia [8] and A. duppereana fromVietman [18].

The CD spectra of the rocaglamides show prominentnegative Cotton effects between 217 and 220 nm as the mostcharacteristic features [16]. Their CD-spectra are dominatedby the nature of the cyclopenta[b]tetrahydrobenzofuranmoiety forming the backbone of the rocaglamide derivativeswith stereocentres at C-1, C-2, C-3, C-3a, and C-8b andthus by the 3D array of the main molecular chromophores,the three aromatic rings. The asymmetric carbon C-2,however, has apparently no influence on the CD spectra ofthe rocaglamide congeners as exemplified by the α-sugar-substituted derivative (30) [16], which shows virtually thesame CD spectrum as 1, even though it lacks thestereocentre at C-2.

Quantum chemical CD calculations combined withmolecular dynamics (MD) simulation were used to establishthe absolute stereochemistry for rocaglamides [12],particularly on compound 34. The structure of rocaglamidesis quite flexible due to the numerous substituents withrotatable bonds connected to the rigid framework.Investigation of their chiroptical properties showed thatconformational changes of the two aromatic functions willgive drastic changes on the corresponding CD spectrum andin this case, assigning the absolute configuration by meansof Boltzmann weighing based conformational analysis willnot be feasible [19]. Calculating the CD spectrum was thencombined with MD simulation [20]. Through MDsimulation, 1000 possible structures were determined andtheir single CD spectra were calculated resulting to a MD-based theoretical overall CD spectrum. The experimentalspectrum is in excellent agreement with that of the calculatedoverall spectrum for the (1R,2R,3S,3aR,8bS)-configuredenantiomer thus permitting an unequivocal conclusion aboutthe absolute configuration of compound 34 [12]. CDcalculation by MD simulation provided a secondindependent stereochemical standard in unambiguouslyestablishing the absolute configuration of the rocaglamides,since – unlike all other reports giving absoluteconfigurations of rocaglamides so far – it does not rely on acomparison with the CD behaviour or optical rotation ofrocaglamide (1), or its synthetically obtained enantiomer[13], respectively. Note that the new method introduced by

The methyl rocaglate congeners, compounds 18 to 26,were identified by their methyl ester function at C-2 which isindicated by a 13C NMR signal at ca. 170 ppm as well asby a three-proton singlet at ca. 3.70 ppm in the 1H NMRspectrum. The first rocaglate derivative (18) was isolatedfrom A. odorata [14], then later from A. forbesii [8] andfrom A. elaeagnoidea [24]. Methyl rocaglate was also namedaglafolin [25]. Compounds with ethylated substituents at C-1 (21 and 22) were isolated from A. duppereana [18], andalso from A. odorata [23] while esterified congeners (23 and24) were obtained from the bark of A. spectabilis collectedfrom Vietnam [15]. An unusual C-1 oxime (25) derivative ofrocaglate was isolated from the leaves of A. odorata [9]which was exemplified by a large downfield shift of 153.0ppm as compared to the C-1 resonance for methylrocaglate at80.6 ppm and consequently by the loss of the H-1 resonanceat 4.90 ppm. The H-2 resonance in congener 25 wasobserved as a doublet which couples only with H-3, insteadof a double doublet as observed in methylrocaglate (18).

Rocagloic acid (27) is the demethylated derivative ofmethyl rocaglate or the acid congener of this series of


cyclopenta[b]tetrahydrobenzofuran compounds. Thecompound was obtained from the leaves of the Taiwanesespecies A. elliptifolia [26] and also from the leaves of A.dasyclada [27] collected in Yunan (P.R. China). The 1HNMR and 13C NMR spectra of 27 are comparable to that ofmethyl rocaglate (18), with the exception of the loss of themethyl ester resonance signals.

multiplets splitting as a ddd due to coupling with thevicinal methine protons, H-1 and H-3. Modification of thesubstitution pattern for compounds 28 to 32, occurred eitherat C-3’ or C-8b. Methoxylation (29) and glycosidation (30)at C-3’ have been reported for compounds isolated from theflowers of A. odorata [23] and leaves of A. harmsiana [16],respectively. Inspection of the 1H NMR spectrum of theglycoside congener (30) revealed an α-linked modifiedrhamnose unit with a methoxy group at the C-3” position asconfirmed by NOE [16]. This sugar-substituted rocaglaolderivative (30) was the first rocaglamide glycoside isolatedfrom nature. From the leaf extract of the Malaysian species A.laxiflora, a similar rocaglaol rhamnoside (31) was isolated,which was reported to contain an additional acetyl group atthe C-2” position of the modified rhamnose unit asconfirmed by HMBC [30]. Methylation (32) and ethylation(33) of the hydroxyl group at C-8b were described to occurin compounds isolated from roots of A. duppereana [22] andbark of A. forbesii [8], respectively.

The rocaglaol derivatives, compounds 28 to 32, areunsubstituted at C-2. Rocaglaol (28) was first isolated fromthe leaves of A. odorata [14] and later proved identical toferrugin which was reported from A. ferruginaea [28] butinitially assigned a different structure [29]. Their 13C NMRspectra exhibited no signal indicative of a carbonyl group(usually in the range of 171 –175 ppm), whereas they exhibitan aliphatic methylene signal at ca. 38 ppm for C-2 asdetected from the DEPT-135 spectrum [16]. In their 1HNMR spectra, the resonance for the methylene protons at ca.2.15 and 2.80 ppm appeared as a pair of geminally coupled

Dr. Mansoor Alam


(Fig. 2). contd.....

compound trivial name R1 R2 R3 R4 ref.

1 rocaglamide OH CON(CH3)2 H OH 3,8,33

2 OH CON(CH3)2 OH OH 17

3 (aglaroxin E) OH CON(CH3)2 OCH3 OH 17,21

4 OCOCH3 CON(CH3)2 H OH 22

5 OCOCH3 CON(CH3)2 OH OH 17

6 OH CON(CH3)2 OH OC2H5 18

7 desmethyl-rocaglamide OH CONHCH3 H OH 8,14

8 OH CONHCH3 OH OH 9

9 OCOCH3 CONHCH3 H OH 22

10 OCOCH3 CONHCH3 OH OH 23

11 OH CONHCH3 OH OC2H5 18

12 OH CONH(CH2)4OH H OH 16

13 OCOCH3 CONH(CH2)4OH H OH 16

14 OH ring1 H OH 16

15 didesmethyl-rocaglamide OH CONH2 H OH 8

16 OH CONH2 OH OH 23

17 OCOCH3 CONH2 H OH 18

18 methyrocaglate OH COOCH3 H OH 8,14,24

19 OH COOCH3 OH OH 9

20 OH COOCH3 OCH3 OH 15

21 OCOCH3 COOCH3 H OH 18

22 OCOCH3 COOCH3 OH OH 23

23 OCHO COOCH3 H OH 15

24 OCHO COOCH3 OH OH 15

25 =NOH COOCH3 OCH3 OH 9

26 OH COOCH3 H OCH3 22

27 rocagloic acid OH COOH H OH 26

28 rocaglaol OH H H OH 8,14,28

29 OH H OCH3 OH 23

30 OH H sugar2 OH 16

31 OH H sugar3 OH 30

32 OH H H OC2H5 8

33 OH H H OCH3 22

34 aglaroxin A OH CON(CH3)2 H H 12,21

35 aglaroxin B OH CON(CH3)2 OCH3 H 12,21

36 aglaroxin F OH CON(CH3)2 OCH3 OH 21

37 pannellin OH COOCH3 H H 12,34


(Fig. (2). contd.....

compound trivial name R1 R2 R3 R4 ref.

38 pannellin-1-O-acetate OCOCH3 COOCH3 H H 34

39 3‘-methoxy pannellin OH COOCH3 OCH3 H 34

40 =O chain4 H H 12

41 OH COOCH3 - - 35

42 OH H - - 35

43 =O H - - 35

44 OCHO COOCH3 - - 35

45 OCOCH3 COOCH3 - - 15

46 ∆9,10 H - 36

47 ∆9,10 OH - 18

48 (aglaroxin D) H H H - 16,21,32

49 aglaroxin C ∆9,10 H - 21

50 aglaroxin G ∆9,10 OCH3 - 21

51 aglaroxin H H H OCH3 - 21

52 aglaroxin I H H H - 21

Fig. (2). Rocaglamide derivatives isolated from Aglaia species.

A group of 6,7-methylenedioxy rocaglamide analogues(34 – 36) were isolated from the stem bark of the Sri Lankanspecies A. roxburghiana [21] and were named as aglaroxinsA, B, and F, respectively. Their UV data, molecular massesand 13C NMR data were listed in a 1996 patent for the saidcollection [31]. Compared to the fundamental structure of therocaglamides, the 1H resonances for the OMe-6 and H-7 wereabsent and instead replaced by a methylenedioxy singlet atca. 5.9 ppm. The meta doublet for H-5 at ca. 6.3 ppm in a1H NMR spectra of a rocaglamide was replaced by a singlet[34]. The resonance for OMe-8 was also shifted downfieldfrom δ 3.85 to δ 4.10 due to the deshielding effect of the

adjacent methylenedioxy function. The presence of amethylenedioxy function was also evident from a tripletresonance at ca. 103 ppm as observed in its DEPT spectra[12]. Consequently, the 4a,6,7,8–tetraoxygenated-substitution at ring A caused a shielding effect on themethine proton at C-5, resulting in an extreme upfield shift(δ ca. 88 ppm). Further proof of the methylenedioxy functionat ring A was provided by HMBC [34, 12]. The absoluteconfiguration of aglaroxin A (35) was first determined byBringmann and Proksch by calculation of its CD spectrumusing molecular dynamics simulations [12] as describedabove. Variations for the analogues occur at ring B in which


aglaroxin B (35) was methoxylated at C-3’ while aglaroxinF (36) was both methoxylated and hydroxylated at C-3’ andC-4’, respectively [21].

H-10 to C-5, C-5a; H-4 to C-11, C-5, C-5a; and H-3 to C-2”/6”, C-2, C-5 [8].

Aglains, aglaforbesins as well as forbaglins containbisamide side chains that are derived from cinnamic acidbisamides. These low molecular weight precursors, namelyodorine [37, 38], odorinol [37, 39], and piriferine [40], arecomposed of cinnamic acid, the bifunctional amine 2-aminopyrrolidine, and 2-methylbutanoic acid (in the case ofodorinol), or 2-hydroxy-2-methylbutanoic acid (in odorinol),or 2-methylpropanoic acid (in piriferine). In 22 of the total of24 aglain derivatives isolated so far, the bisamide side chainis directly analogous to the naturally occurring cinnamic acidbisamides, odorine, odorinol or piriferine, respectively. Thetwo remaining compounds 63 and 76 can formally beobtained by dehydration of the hydroxy group at C-19resulting in a double bond between C-19 and C-20. Aglainsdiffer with regard to their configuration at C-19 which caneither be R or S, but more often remains uncertain. Thisfinding parallels the situation of the cinnamic acid bisamideswhich also occur as diastereomers at the respective position.Similarly, the configuration at C-13 can either be R or Swhich again is consistent with the occurrence of both (+)- or(-)-forms of odorine, odorinol, and piriferine in nature,respectively. It is noteworthy that this aminal position isprone to epimerization in low molecular weight precursors[38], and frequently, aglains are isolated as diastereomericmixtures [46].

The pannellins (37 – 39) were isolated from A.elaeagnoidea collected from Thailand [34]. For this group ofanalogues, the amide function at C-2 in aglaroxins A, B andF was replaced by a methyl ester. Pannellin 1-O-acetate (38)is the acetylated product of 37 while 3’-methoxypannellin(39) is characterized by an additional –OCH3 function in ringB. A recent paper from our laboratory [12] described theisolation of a similar group of congeners from the twigs of aVietnamese collection of A. oligophylla, includingcompound 40, a C-1-oxo derivative of aglaroxin A, bearing abisamide side chain at C-2 which is derived from piriferine.The ketone substituent at C-1 was identified by the carbonresonance at 206 ppm consequently resulting in a downfieldshift of H-2 which appeared as a doublet coupling only withH-3. The piriferine-like substituent at C-2 has beenpreviously reported to occur in aglain type derivatives [21]as will be described below.

From A. elliptica [35] collected in Thailand and theVietnamese species A. spectabilis, derivatives (41 - 45) witha 3', 4'-methylenedioxy substitution in the B ring have beenreported. These are the first derivatives with themethylenedioxy function in ring B whereas in congeners 34– 40, this substituent is positioned in ring A.

The last group of rocaglamide congeners (46 - 52) ischaracterized by a pyrimidinone subunit fused at C-1 and C-2. The resulting pentacyclic skeleton can conceptually beconsidered as a rocaglamide with a 2-aminopyrrolidineamide substituent at C-2 linked to C-1 via the primaryamino group. This pyrimidinone type rocaglamide (46) wasfirst isolated from the roots of A. odorata collected inThailand and was elucidated by X-ray crystallography [36].The same compound was isolated from the leaves and twigs[17] of the Vietnamese species A. duperreana while itsflowers [18] yielded the C-3’-hydroxy derivative (47).Compound 48 (aglaroxin D), the dihydro derivative of 46,has been isolated from the leaves of A. duperreana [17] andA. odorata [32] and from the stem bark of the Sri Lankanspecies A. roxburghiana [21]. The latter collection yieldedfour further pyrimidinone analogues with an additional 6,7-methylenedioxy substituent in ring A, known as aglaroxin C(49), G (50), H (51), and I (52) [21].

In the cyclic core, aglains display structural variability atthe following positions: The bridging carbon atom, C-10,nearly always carries one proton as well as one oxygencontaining substituent, the latter being either a hydroxyl oran acetoxyl group. The substituents can be oriented bothendo or exo with regard to ring A. Only two derivatives, 74and 75, are known to be featuring a carbonyl group at C-10.In the oxepine ring, H-3 and H-4 are always trans-oriented,but both possible diastereomeric forms, i.e. H-3α, H-4β aswell as H-3β, H-4α, occur more or less evenly distributed innature.

As in the case of rocaglamides, ring A is usuallysubstituted by two m-oriented methoxyl goups at C-6 andC-8, but can also carry a 7,8-methylenedioxy substituent,mostly in addition to the methoxyl group at C-6. The latteris lacking in only two derivatives, 67 and 68. Ring Balways carries a 4‘-methoxy substituent, in some casesaccompanied by a hydroxyl or methoxyl group at C-3‘,while ring C is always unsubstituted. These substitutionpatterns are again parallel to those of rocaglamides, whereasmethylenedioxy substituents in ring B have not beenencountered in aglains so far. In general, spectroscopicidentification of the said substituents follows the sameprinciples as discussed above for rocaglamides.

Aglain Derivatives

Aglains (see Fig. (3)) are characterized by acyclopenta[bc]benzopyran (2,5-methano-1-benzoxepin)skeleton thought to be biogenetically derived from additionof a flavonoid precursor and a bisamide such as odorine,odorinol or piriferine, respectively [8, 9, see also biogeneticscheme below]. Formally, rocaglamides can also be derivedfrom aglains by cleaving the C-C bond between C-10 and C-5a, while linking C-5 and C-5a (note the different numberingscheme used for rocaglamides and aglains). Unequivocalproof of the nature of the ring system in aglains was affordedby X-ray crystallography of the first derivative, aglain A(53), thus also revealing the relative stereochemistry [8]. KeyHMBC correlations indicative of the aglain skeleton include

Despite the numerous structural analogies betweenrocaglamides and aglains, and the speculated similarbiogenetic pathways leading to both classes of compounds(see below), it is interesting to note that bisamide-derivedside chains mainly occur in aglains (and in aglaforbesins aswell as in forbaglins, see below), but are very rarelyencountered in rocaglamides. It is tempting to speculate thatbulky substituents such as those present in odorine,odorinol, or piriferine, cannot be easily incorporated into


rocaglamides, and thus are usually replaced by simpleramide or nitrogen-free side chains.

with opposite configurations at C-10, NOEs of H-3 or H-4are observed to 10-OH [8, 46] (in aprotic solvents) or 10-OCOCH3 [46], respectively. In addition, 3J(H-3,H-4)amounts to 5-6 Hz in the case of H-3β,H-4α configuration,while the vicinal coupling constant is 9-10 Hz when H-4 isβ and H-3 is α [46]. In thapsakones A (74) and B (75)which lack a proton at C-10, the stereochemistries of H-3and H-4 were deduced in an elegant manner by observing astronger lanthanide induced shift (LIS) to the respective β-proton (4 in 74, 3 in 75) [46]. The configuration of theaminal proton H-13 is assigned to be (13S) by observingNOEs between H-4 and H-13 as well as between the terminalmethyl group(s) H-21 (and H-20 in the case of piriferine-derived side chains) and H-2''/6'', while no such NOEs aredetected with (13R)-derivatives, as was confirmed by closeinspection of Dreiding models [8, 46].

Assignment of the relative stereochemistry in aglains ismainly derived from one or two-dimensional NOE data,while the absolute configuration until now has only beendeduced on grounds of biogenetical considerations incomparison with rocaglamide [46], whose absolutestereochemistry is known by asymmetric synthesis [13].According to Bacher et al. [46], formal conversion ofrocaglamides into aglains would leave the absoluteconfiguration at C-2 (C-4 in rocaglamides) unchanged, aswas deduced by inspecting Dreiding models. This is also inagreement with the common biogenetic origin ofrocaglamides proposed by our group [9]. Thus, in thecommonly chosen representation of aglains, the methylenebridge, i.e. C-10, points upwards, while ring B as well 5-OH point downwards [46]. The relative stereochemistry ofH-3 and H-4, which are trans in all aglains (and also inaglaforbesins as well as in forbaglins) isolated so far, and H-10 at the methylene bridge can be deduced by an NOEbetween the respective β-proton H-3 or H-4, and H-10, if thelatter is oriented endo with respect to the former. In aglains

Aglaforbesin Derivatives

Aglaforbesins are closely related to aglains, but with thecinnamic acid bisamide-derived side chain at C-3 and theunsubstituted phenyl ring C at C-4 mutually interchanged.


(Fig. 3). contd.....

compound trivial name R1 R2 R3 R4 R5 H-3, H-4 13 19 ref.

53 aglain A OAc H H H - β,α S nd 8

54 aglain B H OH H H - β,α S nd 8

55 aglain C H OH H H - α,β S nd 8

56 H OH H OH - α,β S nd 9

57 H OH OH OH - α,β S nd 9

58 H OH OH OCH3 - α,β S nd 9

59 H OH H OH - β,α S nd 9

60 aglaxiflorin A OAc H OH H - β,α S R 30

61 aglaxiflorin B OAc H OH H - α,β S R 30

62 aglaxiflorin D H OH OH H - α,β S R 30

63 elliptifoline H OH ∆19,20 H - α,β S - 26

64 aglaroxin J H OAc H H - α,β nd nd 21

65 aglaroxin L H OH OH H - α,β nd nd 21

66 H OH OH H - β,α nd nd 21

67 H OH OH C2H5 H β,α nd nd 21

68 H OAc H C2H5 H β,α nd nd 21

69 (13S)-thapsakin B H OH H CH3 OCH3 β,α S - 46

70 (13R)-thapsakin B H OH H CH3 OCH3 β,α R - 46

71 isothapsakin B OH H H CH3 OCH3 β,α S - 46

72 homothapsakin A H OH H C2H5 OCH3 α,β S nd 46

73 thapsakin A 10-OAc H OAc H CH3 OCH3 α,β S - 46

74 thapsakon A =O H CH3 OCH3 α,β S - 46

75 thapsakon B =O H CH3 OCH3 β,α S - 46

76 grandiamide A OAc H ∆19,20 H - α,β - - 41

Fig. (3). Aglain derivatives isolated from Aglaia species.

This structural feature was evidenced by HMBC correlationsfrom H-3 to C-11 as well as H-4 to C2”/6” [8]. Until nowonly four aglaforbesin derivatives (see Fig. (4)) have beendescribed from nature that differ with regard to thesubstitution pattern of ring A as well as to thestereochemistry at C-3, C-4, and C-13, respectively. Unlikeaglains, no structural variants from the 4’-methoxysubstituted ring B are known. Side chains are derived fromodorine (in 77 and 78) [8], odorinol (in 79) [30], andpiriferine (in 80) [12].

pronounced upfield shift of 6-OCH3 (δ approx. 3.1 ppm),since in this case the methoxy group is placed inside theshielding zone of the unsubstituted benzene ring at C-4α [8,30], while a normal chemical shift (δ approx. 4.1 ppm) isobserved in case of reversed stereochemistry at C-3 and C-4,respectively [12]. In analogy to the aglains, configurations atthe respective positions are also reflected by the magnitude ofthe vicinal coupling constants: 3J(H-3,H-4) amounts to 10-11Hz when H-3 is α and H-4 is β [8, 30], and to 6-7 Hz in theopposite case [12].

Assignment of the stereochemistry of aglaforbesins isbased on the same principles as described above for aglains.Consequently, the configuration of the aminal proton H-13was deduced to be (R) in aglaforbesin A (77) and B (78) dueto NOEs between H-3 and H-13 as well as H-21 and H-2''/6''[8]. Interestingly, H-3α/H-4β configuration leads to a

Forbagline derivatives

Forbaglines are benzo[b]oxepines that are formallyobtained from aglains by oxidative cleavage at the methylenebridge between C-5 and C-10 [8]. The structure of the first


Compound trivial name R1 R2 R3 R4 R5 R6 H-3, H-4 13 19 ref.

77 aglaforbesin A OH H OCH3 H C2H5 H α,β R nd 8

78 aglaforbesin B H OH OCH3 H C2H5 H α,β R nd 8

79 aglaxiflorin C H OAc OCH3 H C2H5 OH α,β S R 30

80 H OH -OCH2O- CH3 H β,α nd - 12

Fig. (4). Aglaforbesin derivatives isolated from Aglaia species.

derivative, forbaglin A (81), was established by X-raycrystallographic analysis, thus revealing the relativestereochemistry [8]. So far, seven derivatives (see Fig. (5))have been isolated that show a similar structural diversity toaglaforbesins, i.e. substitution pattern of ring A as well asstereochemistry at C-3, C-4, and C-13, respectively. Unlikeaglains, ring B is always 4'-methoxylated, while side chainsare derived from odorine and piriferine. No odorinol derivedsubstituents have been isolated so far.

Since forbaglines are probably biogenetically closelyrelated to aglains, aglaforbesins, and rocaglamides, it seemsjustified to assume the identical absolute configuration at C-2 as compared to the latter [8, 46]. (13R)-configuration wasdeduced for forbaglin A (81) [8] as well as the minor isomers84 and 87 [46] by an NOE between the methyl group H3-19(and H-20 in the case of the piriferine-derived side chain in87) and H-2''/6'', which was consistent with a close spatialproximity of the respective positions observed in the X-ray

Compound trivial name R1 R2 R3 H-3, H-4 13 19 ref.

81 forbaglin A OCH3 H C2H5 α,β R S 8

82 forbaglin B OCH3 H C2H5 α,β S nd 8

83 (13S)-thapoxepine A -OCH2O- CH3 α,β S - 46

84 (13R)-thapoxepine A -OCH2O- CH3 α,β R - 46

85 homothapoxepine A -OCH2O- C2H5 α,β S nd 46

86 (13S)-thapoxepine B -OCH2O- CH3 β,α S - 46

87 (13R)-thapoxepine B -OCH2O- CH3 β,α R - 46

Fig. (5). Forbagline derivatives isolated from Aglaia species.


structure of 81 [8]. Bacher et al. [46] were also able toestablish confirmation of the stereochemistry at C-13 byinspection of chemical shifts for C-14 and C-15, respectively.

related precursors that include cinnamic amides andflavonoids. Our biosynthetic rationale is depicted in Fig. (6).According to this hypothesis, the initial C,C-connectingstep (step A) between C-2 of the flavonoid of I and C-3 ofthe cinnamic amide II is a Michael-type 1,4-addition of theenolate subunit of I to the α,β-unsaturated amide II. The C-2 atom of the resulting amide enolate of III can now attackC-4 of the previous flavonoid, which has now become astrongly activated carbonyl group, to yield a 5-memberedring, giving rise to IV (step B). According to our concept,

A rationale for the Biogenesis of Rocaglamides andAglains

It is tempting to assume that rocaglamides and aglainderivatives arise biosynthethically from common structurally

Fig (6). Proposed joint biosynthetic origin of aglain derivatives V' and rocaglamide derivatives VII.


IV constitutes the biosynthetic key intermediate andprecursor both to aglain und rocaglamide derivatives. IV canalready be considered as a dehydroaglain derivative, and asimple reduction step (e.g. with ‘H-’ possibly beingNADPH or a related H-nucleophile), will yield thecorresponding aglain derivative V’ (step C’).

understanding of their pronounced insecticidal propertiescommenced which up to now has led to the isolation ofmore than 50 naturally occurring rocaglamide congeners aswell as numerous other biogenetically related compoundsisolated from over 15 different Aglaia species collectedmainly in Indonesia, China, Thailand and Vietnam.

This reduction to give V stabilizes the strained moleculeIV, which, as the key intermediate, may otherwise undergo arearrangement by an intramolecular migration of the electron-rich substituted (phloroglucinol-type) aromatic ring from theprevious C-4 to C-3 of the flavonoid. Mechanistically, thiscan be considered as an electrophyllic aromatic ipso-substitution via the cyclopropyl derivative V as the σ-complex (steps C and D), thus ultimately transforming thehydroxyketone IV into the isomeric hydroxyketone VI,which is already a dehydrorocaglamide derivative. Again,this possibly reversible process becomes definite by astabilizing final reduction step (step E), to give rise torocaglamide derivatives VII.

The majority of the 52 naturally occurring rocaglamidederivatives known up to date were analysed for theirinsecticidal activity employing various Lepidopteran larvaeincluding Ostrinia nubilalis [43], Peridroma saucia [14] orSpodoptera littoralis as experimental insects. Most of thesestudies, however, have been performed with larvae of thepolyphagous pest insect Spodoptera littoralis [9, 12, 15,16, 17, 18, 22, 23] thereby allowing to draw up structureactivity relationships based on a larger set of data obtainedwith the same insect species. In the studies with S.littoralis, different rocaglamide derivatives were usuallyadded at a range of concentrations to artificial diet which wassubsequently offered to newly hatched larvae in no choicechronic feeding bioassay. From the larval survival, LC50values can be calculated for the various rocaglamidecongeners and compared to other insecticides of naturalorigin such as azadirachtin from Azadirachta indica. Withonly a few exceptions all naturally occurring rocaglamidecongeners analysed exhibited strong insecticidal activitytowards larvae of S. littoralis. The most active compoundsincluding the parent compound rocaglamide (1) itself or itsdidesmethyl analogue (15) exhibited LC50 values rangingbetween 1 – 2 ppm and are thus comparable with regard totheir insecticidal activity to azadirachtin [9, 16, 17, 23].

Although not depicted in Fig. (6), aglaforbesinderivatives also fit into the proposed biogenetic scheme, butdiffer in comparison to aglains by opposite orientation of thecinnamic amide II with respect to flavonoid I. Apparently,the addition of the cinnamic amide II to the flavonoid I isneither regioselective nor stereoselective, since all fourpossible stereoisomers do exist in nature, i.e. in both aglainsand aglaforbesines, (H-3α, H-4β)− as well as (H-3β, H-4α)−derivatives have been encountered.

From these considerations, the search for the probablyunstable, possibly interconverting intermediates IV and VIof our postulated biosynthesis of dehydroaglain androcaglamide derivatives, seems rewarding.

Acylation of the OH group at C-1 (e. g. with formic oracetic acid) caused always a reduction of insecticidal activityas exemplified by comparison of the LC50 values ofcompound 2 (1.5 ± 0.7 ppm) and the acetyl derivative 5 (8.0± 1.4 ppm) or of compound 12 (1.1 ± 0.6 ppm) and theacetyl derivative 13 (14.7 ± 2.8 ppm) [9, 16, 17].BIOLOGICAL ACTIVITY OF ROCAGLAMIDE

DERIVATIVESThe nature of the amide substituent present at C-2 on the

other hand, had little or no influence on the insecticidalactivity of the resulting rocaglamide congeners even whendimethylamine as present in the parent compoundrocaglamide (LC50 of 0.9 ± 0.4 ppm) was exchanged for arather bulky group as for example in compound 14 (LC50 of1.6 ± 0.6 ppm). The same holds true for an exchange of theamide group to an ester substituent which likewise had nosignificant effect on the insecticidal activity of the respectivecompounds. However, a drop of insecticidal activity by thefactor of 5 or 6 was usually observed for rocaglamidederivatives featuring an unsubstituted C-2 when compared toanalogues with an amide or carboxylic ester substituent atthis particular carbon [9, 16, 17, 23].

Insecticidal Activity

The first report on the remarkable insecticidal activity ofextracts from Aglaia spp. in the scientific literature originatesfrom 1985 when Chiu et al. [42] described the antifeedantproperties of a crude extract derived from A. odorata towardslarvae of the cabbage worm Pieris rapae. The activeprinciples of A. odorata responsible for the strong antifeedantproperties of the respective crude extracts against P. rapaeand against other insects, however, were only identified in1993 when Ishibashi et al. [14] reported on the bioassayguided isolation of rocaglamide and three of its congenersusing larvae of the polyphagous noctuid Peridroma sauciaas experimental insects. Interestingly, rocaglamide hadalready previously been isolated in 1982 from A. elliptifoliaand described as having anti-leukemic properties againstmurine cell lines in vitro [3], thereby providing an early hintto the parallelism between insecticidal and antiproliferativeproperties of rocaglamide and its analogues that became evenmore obvious in subsequent studies [10, 11].

Additional oxygen substituents in ring A or B (comparedto the substitution pattern of the parent compoundrocaglamide) were shown to have only marginal influenceson the insecticidal activity of the respective products [16].

However, a dramatic effect with regard to structureactivity relationships of rocaglamide derivatives wasobserved for analogues with a substituted OH group at C-8b.Compounds featuring for example a methoxyl group at C-8b

Sparked by these findings, a more directed search for newrocaglamide derivatives from nature aiming also at a better


that were isolated from roots of A. duppereana proved to becompletely inactive with regard to insecticidal activity evenwhen tested at concentrations of 100 ppm and higher, thus,pointing to the presence of a free OH group at C-8b as themost important structural prerequisite for insecticidal activityof rocaglamide analogues so far elucidated [18, 22].

the antitumor activity of an extract from A. odoratissimatoward P388 lymphocytic leukemia-infected mice. This earlystudy was followed by further investigations on theantitumor activity of crude extracts from various Aglaiaspecies including for example A. elaegnoidea [49], A.elliptifolia [50], A. formosana [51] or A. odorata [39]mostly in mice. Whereas these studies uniformlydemonstrated the remarkable effects of Aglaia derived extractsagainst cancer cell lines in vitro or even in tumor bearingmice, it was not until 1982 that the group of King [3]described rocaglamide for the first time as being responsiblefor the antitumor activity in mice provoked by treatmentwith an extract of A. elliptifolia. When rocaglamide wastested in P388 lymphocytic leukemia-infected mice, itshowed an optimal T/C value of 156% at a non-toxic dose of1.0 mg/kg [3]. When tested in vitro rocaglamide exhibitedan IC50 of 1.0 ng/mL against the human carcinoma cell lineKB and an IC50 of 2.1 ng/mL against P388 cells,respectively [3]. Eventually these findings led to the filing ofa US patent [52].

It is difficult to decide whether the mortality of the S.littoralis larvae observed in chronic feeding bioassaysdescribed above is mainly caused by starvation due tofeeding deterrency or by a direct toxicity of the analysedrocaglamide derivatives or by a combination of both. Whenneonate larvae of S. littoralis were given the choice betweenartificial diet treated with rocaglamide and control diet theyavoided the former and showed a clear preference for the latter(the IC50 in these experiments varied between 0.2 – 0.25ppm) indicating that rocaglamide and its congeners havestrong antifeedant properties [44]. Toxicity of rocaglamidewas proven by injecting known amounts of thisdihydrobenzofuran derivative into the haemolymph of lastinstar larvae of S. littoralis. In these experiments the LC50 ofrocaglamide varied between 5.6 – 7.5 ppm [44]. Furtherproof for the effects of rocaglamide on a cellular level wasobtained using in vitro cultures of Spodoptera frugiperdacells. Addition of rocaglamide to the in vitro culturesresulted in an arrest of cellular division as indicated by theseverely reduced incorporation of [3H]-thymidine. The IC50of rocaglamide amounted to 1.9 µg/mL [45].

Rather surprisingly research on the antitumor propertiesof rocaglamide and its congeners more or less came to acomplete stop following the findings of King et al. [3] andwas only resumed in the nineties when didesmethylroca-glamide (15) was reported to have the strongest cytotoxicactivity out of six derivatives tested against KB cells with anIC50 of 6.0 ng/mL [8]. In the same year rocaglamide andmethylrocaglate were shown to have strong cytotoxicactivity against a panel of human cancer cell lines includingA-549 (human lung carcinoma), HCT-8 (human coloncarcinoma), RPMI-7951 (human melanoma), TE-671(human rhabdomyosarcoma) and KB cells (human cervixcarcinoma) [26]. The IC50 values of both compounds rangedfrom 1.0 – 6.0 ng/mL depending on the cell lineinvestigated. In the same year five rocaglamide derivativeswere isolated from A. elliptica and tested against a panel ofhuman cancer cell lines in vitro with IC50 values rangingfrom 8.0 – 300.0 ng/mL depending on the compoundanalysed [35]. In a following publication by the same groupthe authors suggested the mode of action of rocaglamidederivatives to be due to cytostatic rather than to cytotoxiceffects [52] thereby providing the first information about thepossible mode of action of these natural products. Thesefindings were corroborated by a recent study on the effect ofdidesmethylrocaglamide on the survival of MONO-MAC-6(human monocytic leukemia) cells [10]. After cultivation inthe presence of didesmethylrocaglamide (20 – 100 ng/mL)for 48 h, MONO-MAC-6 cells were washed and furtherincubated in rocaglamide free control medium for anadditional period of 48 h. Whereas treatment withdidesmethylrocaglamide caused a complete stop of celldivision even after washing and transfer of the cells intocontrol medium only an insignificant number of cells died(as shown by staining of the cells with trypan blue dye).This indicates that didesmetyhlrocaglamide (and most likelyalso other rocaglamide derivatives) inhibits cell proliferationand has only marginal cytotoxic effects at least againstMONO-MAC-6 cells [10]. Using flow cytometry we couldshow that didesmethylrocaglamide arrests the leukemia cellsmainly in G1/G0 phase with an additional arrest in theG2/M phase of the cell cycle [11].

These experiments as well as those conducted by othergroups [14, 33, 43, 46, 47] prove that rocaglamide and itscongeners are active against herbivorous insects asantifeedants but are also toxic to insects as evidenced by thehaemolymph injection experiments with larvae of S.littoralis [44]. Even though the molecular target ofrocaglamide and its congeners in insects is still unknown theinsecticidal activity of these compounds can be linked todistinct structural features such as the OH group at positionC-8b which is an indispensable prerequisite for bioactivity.Interestingly, rocaglamide derivatives often co-occur inAglaia species with biogenetically closely relatedcompounds of the aglain, aglaforbesin or forbaglin type [8, 9,12]. In these latter compounds, the oxygen heterocycle of thedihydrobenzofuran nucleus in rocaglamides is replaced eitherby a bridged pyran (as in aglain or aglaforbesin derivatives)or by a oxepine ring (as in forbaglin derivatives). Thesestructural differences lead to a complete loss of insecticidalactivity for aglain, aglaforbesin or forbaglin derivatives [9,12]. The putative biogenetic precursors of rocaglamides aswell as aglains, aglaforbesins, and forbaglins – methylatedflavonoids and 2-aminopyrrolidines such as odorine – arelikewise devoid of any significant insecticidal activity [44]indicating that the integrity of thecyclopenta[b]tetrahydrobenzofuran moiety of the rocaglamideskeleton is essential for the insecticidal activity of thisunique group of natural products.

Antiproliferative Activity Against Human Cancer CellLines

The first report on the effect of a crude Aglaia extract oncancer cells was already published in 1973 [48] describing


In addition to inhibiting [3H]-thymidine incorporationinto MONO-MAC-6 cells, didesmethylrocaglamide as wellas other rocaglamide derivatives were also able to inhibitprotein synthesis as measured by incorporation of [3H]-leucine. Protein synthesis was reduced by roughly 50% atconcentrations of didesmethylrocaglamide varying from 50 –100 ng/mL which compares favourably to other inhibitors ofprotein synthesis such as cycloheximide which was used as apositive control in this experiment [11].

CONCLUSION

Taken together, rocaglamide type compounds constitutea fascinating group of bioactive plant constituents thatcontinue to provide challenges both to natural productchemists as well as to cell biologists and pharmacologistsinterested in new lead structures from nature and their modeof action. Whereas, it seems unlikely at the moment thatrocaglamide or its congeners may be developed into newcommercially available insecticides, their pronouncedcytostatic activity against human cancer cells in vitro as welltheir apoptosis promoting effects in resistant acute T cellleukemia cells make them interesting candidates fortherapeutic agents especially in the field of cancer.

Structure activity relationships of 13 naturally occurringrocaglamide congeners and of one aglain derivative inMONO-MAC-6 cells yielded results very similar to thoseobtained previously with larvae of S. littoralis [10, 11]. Allrocaglamide derivatives analysed except those with amethoxy instead of a hydroxy substituent at position C-8bproved to be highly active with IC50 values in the range of 6– 30 ng/mL for most derivatives [11]. The IC50 ofdidesmethylrocaglamide (15) as the most active compoundencountered in this comparative study was even comparableto that of the well known anticancer drug vinblastine sulfate.Since similar structure activity relationships of rocaglamidederivatives and of biogenetically related compounds (aglains)are revealed in human cancer cells and in insects it isconceivable that the molecular targets of rocaglamidederivatives are similar in cancer cells and in insects.Recently, it was shown that rocaglamide and most of itscongeners (except those with a substituted OH-group at C-8b) represent highly potent and specific inhibitors of TNF-αor PMA-induced NF-κB activity in different mouse andhuman T cell lines [45]. The IC50 values observed were inthe nM range whereas aglain derivatives proved to beinactive. Rocaglamide and several of its derivatives areamong the strongest inhibitors of NF-κB induced geneactivation known so far [45]. Interestingly, the structureactivity relations more or less resembled those elucidatedpreviously with human cancer cell lines [11] or with insects[10]. The molecular basis of NF-κB inhibition byrocaglamide derivatives is apparently localizedpredominantly upstream of the IKK complex anddownstream of the TRAF protein [53].

ACKNOWLEDGEMENTS

We are indebted to several colleagues who made valuablecontributions to our ongoing research on rocaglamidederivatives including Dr. V. Wray (GBF, Braunschweig,Germany), Dr. K. Steube (DSMZ, Braunschweig, Germany),Prof. Dr. G. Bringmann (University of Würzburg, Germany),Prof. Dr. T. Wirth (University of Ulm, Germany), Prof Dr.P.D. Hung, Prof. Dr. L.C. Kiet (University of Saigon,Vietnam), and Prof. Dr. W.H. Lin (University of Beijing,P.R. China). Furthermore, we would like to thank past andpresent members of our group who were involved in thisproject at various times including Dr. B. Güssregen, Mr.Chaidir, Mr. M. Dreyer, Ms. M. Fuhr, Mr. J. Hiort and Ms.C. Schneider. Last not least we would like to thank theBMBF/Bayer AG and the „Fonds der ChemischenIndustrie“ for continued financial support.

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