84573-16-0

Usage

Uses

Used in Anticancer Applications:
Rocaglamide is used as an anticancer agent for its ability to induce apoptosis in various human leukemia cell lines, including acute lymphoblastic leukemia, chronic myeloid leukemia, and acute myeloid leukemia cells. It modulates the activation of p38 MAPK/JNK and suppresses ERK, contributing to its antineoplastic properties.
Used in Anti-inflammatory Applications:
Rocaglamide is used as an anti-inflammatory agent due to its capacity to inhibit the production of IFN-γ, TNF-α, IL-2, and IL-4 in peripheral blood T cells at a concentration of 50 nM. This action helps in reducing inflammation and immune response.
Used in Insecticidal Applications:
Rocaglamide is used as an insecticide, leveraging its natural properties to control and manage insect populations, thereby providing a potential alternative to synthetic insecticides.
Used in Immunomodulation:
Rocaglamide is used to modulate the immune response by inhibiting the T cell expression of the transcription factor, nuclear factor of activated T cells. This action can be beneficial in managing immune-related conditions and diseases.

Biochem/physiol Actions

Rocaglamide is a potent anticancer agent isolated from the genus Aglaia. Rocaglamides inhibit protein synthesis without affecting DNA or RNA synthesis. Recent study shows that Rocaglamide binds to prohibitin (PHB) 1 and 2, which prevents interaction between PHB and CRaf and inhibits CRaf activation and subsequently CRaf-MEK-ERK signaling. Also, Rocaglamide is an immunosuppressant that inhibits activation of NF-kB and NF-AT.

References

1) Baumann?et al.?(2002),?Rocaglamide Derivatives Are Potent Inhibitors of NF-kB Activation in T-cells; J. Biol. Chem.?277?44791 2) Prolsch?et al.?(2005),?Rocaglamide Derivatives Are Immunosuppressive Phytochemicals That Target NF-AT Activity in T Cells; J. Immunol.?174?7075 3) Polier?et al.?(2012),?The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin1 and 2; Chem. Biol.?19?1093 4) Neumann?et al.?(2014),?The natural anticancer compound rocaglamide selectively inhibits the G1-S phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints; Int. J. Cancer?134?1991 5) Zhu?et al.?(2007),?The traditional Chinese herbal compound rocaglamide preferentially induces apoptosis in leukemia cells by modulation of mitogen-activated protein kinase activities; Int. J. Cancer?121?1839

InChI:InChI=1/C29H31NO7/c1-30(2)27(32)23-24(17-9-7-6-8-10-17)29(18-11-13-19(34-3)14-12-18)28(33,26(23)31)25-21(36-5)15-20(35-4)16-22(25)37-29/h6-16,23-24,26,31,33H,1-5H3/t23-,24?,26-,28+,29+/m1/s1

Upstream product

• 95125-08-9 4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-carboxaldehyde 
• 108-73-6 3,5-dihydroxyphenol 
• 33646-40-1 4-methoxymandelonitrile 
• 117828-32-7 4,6-dihydroxy-2-(4-methoxyphenyl)benzofuran-3(2H)-one 
• 132464-02-9 (3aS,8bR)-methyl 8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-1-oxo-3-phenyl-3a,8b-dihydro-1H-cyclopenta[b]-benzofuran-2-carboxylate 
• 132464-00-7 (2R,3S,3aR,8bR)-methyl 6,8-dimethoxy-3a-(4-methoxyphenyl)-1-oxo-3-phenyl-8b-((trimethylsilyl)oxy)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxylate 
• 117828-33-8 4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3(2H)-one 
• 123-11-5 4-methoxy-benzaldehyde 
• 117828-42-9 8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-1-oxo-3-phenyl-2,3,3a,8a-tetrahydrocyclopentabenzofuran-2(1H)-carboxamide 
• 136850-29-8 3-<4,6-dimethoxy-2-(4-methoxyphenyl)-3-oxo-2,3-dihydrobenzofuran-2-yl>-3-phenylpropanal 
• 506-59-2 N,N-dimethylammonium chloride 
• 117828-51-0 1,8b-dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-2,3,3a,8a-tetrahydrocyclopenta[b]benzofuran-2(1H)-carboxylic acid 
• 132463-97-9 (2R,3S,3aR)-6,8-Dimethoxy-3a-(4-methoxy-phenyl)-3-phenyl-3,3a-dihydro-benzo[b]cyclopenta[d]furan-2,2-dicarboxylic acid benzyl ester methyl ester 
• 132491-34-0 (3aS,8bR)-6,8-Dimethoxy-3a-(4-methoxy-phenyl)-1-oxo-3-phenyl-8b-trimethylsilanyloxy-3a,8b-dihydro-1H-benzo[b]cyclopenta[d]furan-2-carboxylic acid dimethylamide 

Relevant academic research and scientific papers

The Evolution of the Total Synthesis of Rocaglamide

The complex flavagline, (?)-rocaglamide, possesses a synthetically intriguing tricyclic scaffold with five contiguous stereocenters and also exhibits potent anticancer, anti-inflammatory and insecticidal activity. This full account details distinct approaches to (±)- and (?)-rocaglamide utilizing Br?nsted acid catalyzed and asymmetric Pd0-catalyzed Nazarov chemistry developed in our laboratory, respectively. The successful asymmetric synthesis revealed unforeseen mechanistic complexity that required adjusting our strategy to overcome an unanticipated racemization process, an unusual reversible ring-cleavage step and a very facile trialkylsilyl group migration.

Synthesis of each enantiomer of rocaglamide by means of a palladium(0)-catalyzed nazarov-type cyclization

A recently reported Pd0-catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (-)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.

Total synthesis of (±)-rocaglamide via oxidation-initiated nazarov cyclization

This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)-rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide.

Nazarov cyclization initiated by peracid oxidation: The total synthesis of (±)-rocaglamide

(Chemical Equation Presented) The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbeniumion species that undergoes cyclization. The synthesis is efficient, hig hly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.

Total synthesis and biological activity of (±)-rocaglamide and its 2,3-di-epi analogue

By introducing the strategy of intramolecular reductive coupling to construct the cyclopenta[b]benzofuran skeleton, the shortest and most efficient synthetic method hitherto was now established to rocaglamide 1 and its 2,3-di-epi analogue 3 in racemic form by Michael addition, SmI 2-promoted intramolecular keto-ester coupling, amination of the ester intermediate, and reduction of carbonyl with Me4NBH(OAc) 3. Several steps were highly stereoselective or even stereospecific. The bioassay results indicated that both 1 and 3 were much better repellents against Plutella xylostella than azadirachtin; the insecticidal activity of 1 was higher than that of azadirachtin against Pieris rapae, P. xylostella, Laphygma exigua, and Helicoverpa armigera, but that of 3 was lower. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

ASYMMETRIC SYNTHESIS OF ROCAGLAMIDES VIA ENANTIOSELECTIVE PHOTOCYCLOADDITION MEDIATED BY CHIRAL BRONSTED ACIDS

The present invention provides a new strategies for the synthesis of compounds of the rocaglamide family and related natural products. The synthetic approach generally involves photochemical generation of an oxidopyrylium species from a 3-hydroxychromone derivative followed by an enantioselective 1,3-dipolar cycloaddition of the oxidopyrylium species to a dipolarophile in the presence of a TADDOL derivative. This approach can be used for the formation of adducts containing an aglain core structure. Methods of the conversion of aglain core structures to aglain, rocaglamide and forbaglin ring systems are also provided. The present invention also relates to the use of rocaglamide/aglain/forbaglin derivatives for the manufacture of medicaments for use in the treatment of cancer or cancerous conditions, disorders associated with cellular hyperproliferation, or NF-κB-dependent conditions.

Enantioselective photocycloaddition mediated by chiral Bronsted acids: Asymmetric synthesis of the rocaglamides

Enantioselective syntheses of methyl rocaglate and the related natural products rocaglamide and rocaglaol are outlined. The approach involves enantioselective [3 + 2] photocycloaddition promoted by chiral Bronsted acids (TADDOLs) to afford an aglain precursor followed by a ketol shift/reduction sequence to the rocaglate core. Copyright

Total synthesis of (±)-rocaglamide and some aryl analogues

The insecticidal activity found for rocaglamide and its congeners, prompted us to establish a short and efficient synthesis of the natural product and some synthetic 'halo-aryl' analogues. Pd-catalysed cross-coupling reactions of the bromo analogue were then explored in order to gain a suitable access to a broad range of unnatural analogues. The key step of our approach is a keto-aldehyde acyloin ring-closure followed by a Stiles carboxylation.

Cytotoxic and antiplatelet aggregation principles from Aglaia elliptifolia

Two related 1H-2,3,3a,8b-tetrahydrocyclopenta[b]benzofurans, aglafolin (1a) and rocaglamide (2), isolated from the stems of Aglaia elliptifolia, showed significant cytotoxicity in six cancer cell lines. Aglafolin (1a) was also found to completely block platelet aggregation caused by arachidonic acid and platelet-activating factor at 100 μM and 2 ng/mL, respectively.

Synthesis of the Novel Anti-leukaemic Tetrahydrocyclopentabenzofuran, Rocaglamide and Related Synthetic Studies

Two approaches to the rocaglamide tricyclic skeleton are described.The first, which employs an unusual dithianyl anion to carbonyl addition reaction, provides access to α-phenyl rocaglamide analogues.The second route involves an intramolecular keto aldehyde pinacolic coupling in the key step and can be used for the preparation of a whole range of rocaglamide analogues possessing both α- and β-phenyl substituents.A total synthesis of rocaglamide, in racemic form, is described using this second approach.The synthetic route commences with phloroglucinol, an inexpensive and readily-available starting material, and takes only 8/9 steps giving an overall yield > 6percent.The synthesis of 1-epi-rocaglamide 29b is also described.