TRAIL-induced HCC cell engraftment is enhanced by rocaglamide. HepG2 and H-7 cell engraftment were 9% and 11%, respectively, after rocaglamide therapy alone. HepG2 and H-7 cell engraftment was 16% and 17%, respectively, after TRAIL treatment. However, it is evident that the combination of Rocaglamide and TRAIL did more than just have an additive effect because it also generated cellular tolerance in 55% of HepG2 and 57% of Huh-7 cells. Injection violet staining was used to measure cell viability, and similar results were achieved. Highly drug- and chemoresistant HepG2 and Huh-7 cells may become more susceptible to TRAIL-based therapy when exposed to rocamide [2].

Compared to the catalyst group, the tumor volume in the rocaramide-treated group was 45 ± 12%. When compared to catalyst, rocamide greatly slowed the growth of tumors. Rocamide was generally well tolerated, as evidenced by the fact that neither weight loss nor evident toxicity was seen consistently in mice during the treatment period in groups treated with the drug [2].

[1]. Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state. Science. 2013 Jul 19; 341(6143): 1238303.

[2]. Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation. Mol Med Rep.

[3]. Rocaglamide derivatives are potent inhibitors of NF-kappa B activation in T-cells. J Biol Chem. 2002 Nov 22;277(47):44791-800.

Rocaglamide is an organic heterocyclic tricyclic compound with the structure 2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]furan, substituted with hydroxyl groups at positions 1 and 8b, methoxy groups at positions 6 and 8, a 4-methoxyphenyl group at position 3a, a phenyl group at position 3, and an N,N-dimethylcarbamoyl group at position 1. It was isolated from Aglaia odorata and Aglaia duperreana and possesses antitumor activity. It is both a metabolite and an antitumor agent and an antileishmaniasis agent. It is an organic heterocyclic tricyclic compound belonging to the monomethoxybenzene and monocarboxylic acid amide class. Rocaglamide, also known as Rocaglamide-A, is a representative member of the Rocaglamide class of anticancer phytochemicals. Rocaglamide is a secondary metabolite of Aglaia plants, whose extracts have traditionally been used as insect repellents due to their natural insecticidal properties. Antitumor activity of Aglaia plants was reported as early as 1973, and rocagramidamide-A was first isolated from Aglaia elliptifolia in 1982. Rocagramid and its various derivatives (such as [didesmethylrocagramid]) are currently being investigated as chemotherapeutic agents for the treatment of various leukemias, lymphomas, and cancers, as well as as adjuvant therapy for certain chemotherapy-resistant cancers. Rocagramid has been reported to exist in Aglaia formosana, Aglaia elliptifolia, and other organisms with relevant data. Mechanism of Action: The antitumor activity of rocagramid is mainly 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 initiating protein synthesis. The rocargillamine derivative cevesol has also been observed to act directly on eIF4A, another translation initiation factor in the eIF4F complex, ultimately responsible for initiating protein synthesis. Inhibition of protein synthesis produces a series of 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, rocargillamine also promotes 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. Rocagramid's inhibitory effect on 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 TXNIP expression is a negative regulator of cellular glucose uptake, blocking glucose uptake and thus inhibiting the proliferation of malignant cells. Rocagramid also appears to induce tumor cell apoptosis by activating pro-apoptotic proteins p38 and JNK and inhibiting the anti-apoptotic protein Mcl-1. Similarly, because rocagramid inhibits the synthesis of c-FLIP and IAP/XIAP, it has 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.

C29H31NO7

505.56

505.21

84573-16-0

Aglafoline;143901-35-3;Didesmethylrocaglamide;177262-30-5

331783

White to off-white solid powder

1.3±0.1 g/cm3

667.3±55.0 °C at 760 mmHg

357.4±31.5 °C

0.0±2.1 mmHg at 25°C

1.634

3.1

2

7

6

37

810

5

CN(C)C(=O)[C@@H]1[C@H]([C@]2([C@@]([C@@H]1O)(C3=C(O2)C=C(C=C3OC)OC)O)C4=CC=C(C=C4)OC)C5=CC=CC=C5

DAPAQENNNINUPW-IDAMAFBJSA-N

InChI=1S/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

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

RocA; Rocaglamide A; Rocaglamide

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 (~197.80 mM)

Solubility in Formulation 1: ≥ 7.5 mg/mL (14.84 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 75.0 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: ≥ 7.5 mg/mL (14.84 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 75.0 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: ≥ 4.76 mg/mL (9.42 mM) (saturation unknown) in 5% DMSO + 95% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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