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.

Di-desmethylrocargranamide is a natural derivative of rocargranamide, belonging to a class of anticancer phytochemicals known as "rocargranamides," derived from plants in the genus Aglaia. While these compounds have traditionally been used for their insecticidal properties, they are currently being investigated as chemotherapy agents for various leukemias, lymphomas, and cancers. Among known rocargranamide derivatives, di-desmethylrocargranamide appears to possess the strongest antitumor activity. It has been reported in Aglaia argentea, Aglaia perviridis, and other organisms with relevant data. Mechanism of Action: While specific studies on di-desmethylrocargranamide are limited, its mechanism of action is likely consistent with other rocargranamide compounds. Similar to other rocargranamide derivatives, the antitumor activity of desmethylrocargranamide is primarily achieved by inhibiting protein synthesis in tumor cells. Inhibition of protein synthesis is achieved by suppressing prohibitin 1 (PHB1) and prohibitin 2 (PHB2)—proteins essential for cancer cell proliferation and involved in the Ras-mediated CRaf-MEK-ERK signaling pathway, which phosphorylates eIF4E, a key factor in the initiation of protein synthesis. There is also evidence that rocarbidopaamides can directly act on eIF4A, another translation initiation factor of the eIF4F complex, ultimately responsible for initiating protein synthesis. Inhibition of protein synthesis has numerous downstream effects. In tumor cells, many proteins downregulated in response to inhibition of protein synthesis are short-lived proteins responsible for cell cycle regulation, such as Cdc25A. Cdc25A is an oncogene that is overexpressed in some cancers, leading to uncontrolled cell growth. In addition to inhibiting its synthesis through the mechanisms described above, rocarbidopaamides can also promote the degradation of Cdc25A by activating the ATM/ATR-Chk1/Chk2 checkpoint pathway. This pathway is typically activated after DNA damage, whereby it reduces the expression of proteins responsible for cell cycle progression, thereby inhibiting the proliferation of damaged (i.e., tumor) cells. Inhibition of protein synthesis also appears to block the activity of the transcription factor heat shock factor 1 (HSF1), leading to increased expression of thioredoxin-interacting protein (TXNIP), which is negatively regulated by HSF1. Increased expression of TXNIP, a negative regulator of cellular glucose uptake, blocks glucose uptake, thus inhibiting the proliferation of malignant cells. Rocargoramines also appear to induce tumor cell apoptosis by activating pro-apoptotic proteins p38 and JNK and inhibiting the anti-apoptotic protein Mcl-1. Similarly, due to their ability to inhibit the synthesis of c-FLIP and IAP/XIAP, rocargoramines have been investigated as adjuvant therapy for TRAIL-resistant cancers—these anti-apoptotic proteins are elevated in some cancers, preventing the induction of apoptosis and leading to 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.

---

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.

---

View More

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.

---

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