Eukaryotic initiation factor 4A (eIF4A)

Didesmethylrocaglamide (5 nM and 10 nM; 72 hours; MPNST cells) treatment arrests MPNST cells at G2-M, increases the sub-G1 population, induces caspase and PARP cleavage, and elevates DNA-damage response marker γH2A.X levels while lowering the expression of AKT and ERK1/2[1].
Didesmethylrocaglamide causes cell cycle arrest at G2/M, which leads to cell death, and thereby reduces MPNST cell proliferation. 697-R cells treated with didesmethylrocaglamide display IC50 values that are remarkably similar to those of parental 697 cells (4 vs. 3nM, respectively)[1].
Didesmethylrocaglamide triggers apoptosis in MPNST cells with and without neurofibromatosis type 1 (NF1), possibly as a result of the DNA damage response. Insulin-like growth factor-1 receptor is just one of the oncogenic kinases that are reduced in didesmethylrocaglamide-treated sarcoma cells[1].

[1]. Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas. Mol Cancer Ther. 2020 Mar;19(3):731-741.

[2]. Abstract 1950: The eIF4A inhibitors didesmethylrocaglamide and rocaglamide as effective treatments for pediatric bone and soft-tissue sarcomas. Cancer Res 2020;80(16 Suppl):Abstract nr 1950.

Didesmethylrocaglamide is a naturally-occurring derivative of [rocaglamide] and belongs to a class of anti-cancer phytochemicals referred to as "rocaglamides" derived from plants of the genus Aglaia. While traditionally used for their insecticidal benefits, this class of compounds is now being studied for use as chemotherapeutic agents in the treatment of various leukemias, lymphomas, and carcinomas. Of the known derivatives of rocaglamide, didesmethylrocaglamide appears to carry the most potent anti-tumour activity.
Didesmethylrocaglamide has been reported in Aglaia argentea, Aglaia perviridis, and other organisms with data available.

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Mechanism of Action
Little research has been conducted specifically regarding didesmethylrocaglamide, but its mechanism of action is likely to be congruent with the rest of the rocaglamide class. Didesmethylrocaglamide’s anti-tumor activity, similar to other rocaglamide derivatives, is driven primarily via inhibition of protein synthesis in tumor cells. Inhibition of protein synthesis is accomplished via inhibition of prohibitin 1 (PHB1) and prohibitin 2 (PHB2) - these proteins are necessary in the proliferation of cancer cells and are implicated in the Ras-mediated CRaf-MEK-ERK signaling pathway responsible for phosphorylating eIF4E, a key factor in the initiation of protein synthesis. There is also some evidence that rocaglamides can act directly on eIF4A, another translation initiation factor of the eIF4F complex ultimately responsible for initiation of protein synthesis. Inhibition of protein synthesis has a number of downstream effects. Many of the proteins that are down-regulated in response to protein synthesis inhibition in tumor cells are short-lived proteins responsible for regulation of the cell cycle, such as Cdc25A. Cdc25A is an oncogene that can become overexpressed in certain cancers and lead to unchecked cell growth. In addition to inhibiting its synthesis via the mechanism described above, rocaglamides promote degradation of Cdc25A via activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway. This pathway is normally activated in response to DNA damage and serves to reduce the expression of proteins responsible for cell cycle progression, thereby inhibiting proliferation of damaged (i.e. tumour) cells. Inhibition of protein synthesis also appears to prevent the actions of the transcription factor heat shock factor 1 (HSF1), leading to an increased expression of thioredoxin-interacting protein (TXNIP) which is negatively regulated by HSF1. TXNIP is a negative regulator of cell glucose uptake, and its increased expression blocks glucose uptake and consequently impairs the proliferation of malignant cells. Rocaglamides also appear to induce apoptosis in tumor cells via activation of the pro-apoptotic proteins p38 and JNK and inhibition of the anti-apoptotic Mcl-1 protein. Similarly, they have been studied as an adjuvant in TRAIL-resistant cancers due to their ability to inhibit the synthesis of c-FLIP and IAP/XIAP - these anti-apoptotic proteins can become elevated in certain cancers, preventing the induction of apoptosis and resulting in resistance to TRAIL-based therapies.

C27H27NO7

477.505788087845

477.18

C, 67.91; H, 5.70; N, 2.93; O, 23.45

177262-30-5

Rocaglamide;84573-16-0

397614

White to off-white solid powder

2.2

3

7

6

35

767

5

COC1=CC=C(C=C1)[C@]23[C@@H]([C@H]([C@H]([C@]2(C4=C(O3)C=C(C=C4OC)OC)O)O)C(=O)N)C5=CC=CC=C5

RMNPQEWLGQURNX-PXIJUOARSA-N

InChI=1S/C27H27NO7/c1-32-17-11-9-16(10-12-17)27-22(15-7-5-4-6-8-15)21(25(28)30)24(29)26(27,31)23-19(34-3)13-18(33-2)14-20(23)35-27/h4-14,21-22,24,29,31H,1-3H3,(H2,28,30)/t21-,22-,24-,26+,27+/m1/s1

(1R,2R,3S,3aR,8bS)-1,8b-dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide

Didesmethylrocaglamide; rocaglamide-derivative; DDR

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~209.4 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)