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Review
. 2011:94:1-58.
doi: 10.1007/978-3-7091-0748-5_1.

Chemistry and biology of rocaglamides (= flavaglines) and related derivatives from aglaia species (meliaceae)

Sherif S Ebada  1 , Neil Lajkiewicz, John A Porco Jr, Min Li-Weber, Peter Proksch
Affiliations
Review

Chemistry and biology of rocaglamides (= flavaglines) and related derivatives from aglaia species (meliaceae)

Sherif S Ebada et al. Prog Chem Org Nat Prod. 2011.
No abstract available

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Chemical structures of ziconotide, ixabepilone, retapamulin, and trabectedin (ET-743)
Fig. 2
Fig. 2
Aglaia Lour. (family Meliaceae). (a): Entire tree of Aglaia odorata, (b): leaves of A. tomentosa, (c): flowers of A. odorata, (d): fruits of A. forbesii (photos by Dr. B. W. Nugroho and from http://dps.plants.ox.ac.uk/bol/aglaia and http://www.rareflora.com/aglaiaodo.html)
Fig. 3
Fig. 3
X-ray crystal structure of rocaglamide (1) (11)
Fig. 4
Fig. 4
Rocaglamide derivatives isolated from Aglaia species
Fig. 4
Fig. 4
Rocaglamide derivatives isolated from Aglaia species
Fig. 4
Fig. 4
Rocaglamide derivatives isolated from Aglaia species
Fig. 5
Fig. 5
Plausible structures of fragment ions m/z 316 and 329 of compound 2 under EI–MS
Fig. 6
Fig. 6
Aglain derivatives isolated from Aglaia species
Fig. 6
Fig. 6
Aglain derivatives isolated from Aglaia species
Fig. 7
Fig. 7
Aglaforbesin derivatives isolated from Aglaia species
Fig. 8
Fig. 8
Forbagline derivatives isolated from Aglaia species
Fig. 9
Fig. 9
Postulated joint biosynthesis scheme of rocaglamide (= flavagline)-type compounds isolated from Aglaia species (14)
Fig. 10
Fig. 10
Proposed biosynthetic origin of isothapsakon A (47) and thapsakon (88) as bisamide-containing rocaglamide-type derivatives
Fig. 11
Fig. 11
Chemical structure of azadirachtin from Azadirachta indica (family Meliaceae)
Fig. 12
Fig. 12
Inhibition of protein synthesis by rocaglamides. The Ras-Raf-MEK-ERK and the PI3K-AKT-mTOR pathways play a central role in regulation of cap-dependent translation by activation of the eukaryotic translation initiation factor 4E (eIF4E). eIF4E binds to the 5′ cap structure and assembles eIF4G and eIF4A to initiate translation. Rocaglamide congeners 23 and 35 directly bind to and inhibit eIF4A function. Rocaglamides 1, 4, 7 and 50 block the MEK-REK pathway and inhibit eIF4E cap binding activity
Fig. 13
Fig. 13
Apoptosis pathways affected by rocaglamides. Apoptotic cell death is regulated by two main pathways: extrinsic (receptor-mediated) and intrinsic (mitochondria-mediated) pathways. The extrinsic pathway involves ligation of death receptors (e.g. CD95 and TRAIL-R) with their ligands (e.g. CD95L and TRAIL) resulting in a sequential activation of caspase-8 and -3, which cleave target proteins leading to apoptosis. This pathway is negatively regulated by the anti-apoptotic protein c-FLIP. Intrinsic stimuli (e.g. anticancer drugs) directly or indirectly activate the mitochondrial pathway by inducing release of cytochrome c and activation of caspase-9. Caspase-9, in turn, activates caspase-3. This death pathway is largely controlled by the pro-apoptotic (e.g. Bax and Bak) and anti-apoptotic (e.g. Mcl-1, Bcl-2 and Bcl-xL) proteins. Activated caspase-8 may induce cleavage of Bid, which induces translocation of Bax and/or Bak to the mitochondrial membrane and amplifies the mitochondrial apoptosis pathway. Bid cleavage can be also induced by activated p38 and JNK. Several rocaglamides can activate p38 and JNK leading to Bid cleavage. Rocaglamides can also directly inhibit protein synthesis by interfering with eIF4A (see Fig. 9) or indirectly through inhibition of the MEK-ERK-eIF4E pathway. Protein synthesis inhibition will lead to down-regulation of short-lived anti-apoptotic proteins such as c-FLIP and Mcl-1. Furthermore, rocaglamides may further increase T-cell-receptor (TCR)-mediated activation of p38 and JNK leading to down-regulation of NF-AT activity and up-regulation of AP-1 activity. This event results in up-regulation of CD95L promoter activity and suppression of c-FLIP promoter activity leading to enhancing activation-induced-cell-death
Fig. 14
Fig. 14
Taylor’s approach to the rocaglate skeleton (119)
Fig. 15
Fig. 15
Kraus’s synthesis of a rocaglamide di-epi-analogue (120)
Fig. 16
Fig. 16
Trost’s synthesis of (−)-rocaglamide (52)
Fig. 17
Fig. 17
Taylor’s racemic synthesis of rocaglamide (1) (121)
Fig. 18
Fig. 18
Watanabe’s synthesis of (±)-aglaiastatin (154) (123)
Fig. 19
Fig. 19
Dobler’s synthesis of racemic rocaglamide (1) (124)
Fig. 20
Fig. 20
Porco’s unified approach to the aglains, forbaglins, and rocaglamides (125)
Fig. 21
Fig. 21
Porco’s synthesis of (±)-methyl rocaglate (18) (125)
Fig. 22
Fig. 22
Porco’s enantioselective methodology for the synthesis of (−)-methyl rocaglate (18), (−)-rocaglaol (28), and (−)-rocaglamide (1) (126)
Fig. 23
Fig. 23
Thede and Ragot’s stereoselective synthesis of (±)-rocaglaol analogues (129)
Fig. 24
Fig. 24
Thede and Ragot’s stereoselective synthesis of (±)-rocaglaol (28) and analogues (130)
Fig. 25
Fig. 25
Magnus’s stereospecific synthesis of (±)-1,2-anhydro methyl rocaglate (180) (131)
Fig. 26
Fig. 26
Qin’s racemic synthesis of rocaglamide (1) (132)
Fig. 27
Fig. 27
Frontier’s synthesis of (±)-rocaglamide (1) via Nazarov cyclization (133)
Fig. 28
Fig. 28
Porco’s enantioselective synthesis of (−)-silvestrol (35) (134)
Fig. 29
Fig. 29
Rizzacasa’s syntheses of (−)-silvestrol (35) and (−)-epi-silvestrol (36) (136)
Fig. 30
Fig. 30
Désaubry’s synthetic rocaglaol derivatives 28 and 202–204, fluorescent probe 208, and affinity ligand 214 (138)
Fig. 31
Fig. 31
Scope of [3 + 2] photocycloaddition to produce analogues of rocaglamide (139)
Fig. 32
Fig. 32
Désaubry’s rocaglamide and rocaglaol analogues (140)
Fig. 33
Fig. 33
Désaubry’s rocaglamide and rocaglaol analogues varied at C-1 (140)
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