Didesmethylrocaglamide
Identification
- Generic Name
- Didesmethylrocaglamide
- DrugBank Accession Number
- DB15496
- Background
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.1 While traditionally used for their insecticidal benefits,7 this class of compounds is now being studied for use as chemotherapeutic agents in the treatment of various leukemias, lymphomas, and carcinomas.2,4,5,6 Of the known derivatives of rocaglamide, didesmethylrocaglamide appears to carry the most potent anti-tumour activity.2,3
- Type
- Small Molecule
- Groups
- Experimental
- Structure
- Weight
- Average: 477.513
Monoisotopic: 477.178752213 - Chemical Formula
- C27H27NO7
- Synonyms
- RocB
Pharmacology
- Indication
Not Available
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- Pharmacodynamics
Not Available
- 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.1 Inhibition of protein synthesis is accomplished via inhibition of prohibitin 1 (PHB1) and prohibitin 2 (PHB2)4 - 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.4,1 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.8
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.1 Cdc25A is an oncogene that can become overexpressed in certain cancers and lead to unchecked cell growth.9 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 pathway10. 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 HSF1.11 TXNIP is a negative regulator of cell glucose uptake, and its increased expression blocks glucose uptake and consequently impairs the proliferation of malignant cells.11
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.1 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.5,6
Target Actions Organism AProhibitin inhibitorHumans AProhibitin-2 inhibitorHumans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Not Available
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- Not Available
- CAS number
- Not Available
- InChI Key
- RMNPQEWLGQURNX-PXIJUOARSA-N
- InChI
- 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
- IUPAC Name
- (2S,3R,4R,5S,6R)-2,3-dihydroxy-10,12-dimethoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxatricyclo[6.4.0.0^{2,6}]dodeca-1(12),8,10-triene-4-carboxamide
- SMILES
- COC1=CC=C(C=C1)[C@@]12OC3=CC(OC)=CC(OC)=C3[C@]1(O)[C@H](O)[C@@H]([C@H]2C1=CC=CC=C1)C(N)=O
References
- General References
- Li-Weber M: Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer. 2015 Oct 15;137(8):1791-9. doi: 10.1002/ijc.29013. Epub 2014 Jun 11. [Article]
- Bohnenstengel FI, Steube KG, Meyer C, Quentmeier H, Nugroho BW, Proksch P: 1H-cyclopenta[b]benzofuran lignans from Aglaia species inhibit cell proliferation and alter cell cycle distribution in human monocytic leukemia cell lines. Z Naturforsch C. 1999 Dec;54(12):1075-83. doi: 10.1515/znc-1999-1212. [Article]
- Bohnenstengel FI, Steube KG, Meyer C, Nugroho BW, Hung PD, Kiet LC, Proksch P: Structure activity relationships of antiproliferative rocaglamide derivatives from Aglaia species (Meliaceae). Z Naturforsch C. 1999 Jan-Feb;54(1-2):55-60. [Article]
- Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012. [Article]
- Zhu JY, Giaisi M, Kohler R, Muller WW, Muhleisen A, Proksch P, Krammer PH, Li-Weber M: Rocaglamide sensitizes leukemic T cells to activation-induced cell death by differential regulation of CD95L and c-FLIP expression. Cell Death Differ. 2009 Sep;16(9):1289-99. doi: 10.1038/cdd.2009.42. Epub 2009 Apr 17. [Article]
- Giaisi M, Kohler R, Fulda S, Krammer PH, Li-Weber M: Rocaglamide and a XIAP inhibitor cooperatively sensitize TRAIL-mediated apoptosis in Hodgkin's lymphomas. Int J Cancer. 2012 Aug 15;131(4):1003-8. doi: 10.1002/ijc.26458. Epub 2011 Nov 8. [Article]
- Schneider C, Bohnenstengel FI, Nugroho BW, Wray V, Witte L, Hung PD, Kiet LC, Proksch P: Insecticidal rocaglamide derivatives from Aglaia spectabilis (Meliaceae). Phytochemistry. 2000 Aug;54(8):731-6. doi: 10.1016/s0031-9422(00)00205-3. [Article]
- Cencic R, Carrier M, Galicia-Vazquez G, Bordeleau ME, Sukarieh R, Bourdeau A, Brem B, Teodoro JG, Greger H, Tremblay ML, Porco JA Jr, Pelletier J: Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS One. 2009;4(4):e5223. doi: 10.1371/journal.pone.0005223. Epub 2009 Apr 29. [Article]
- Kristjansdottir K, Rudolph J: Cdc25 phosphatases and cancer. Chem Biol. 2004 Aug;11(8):1043-51. doi: 10.1016/j.chembiol.2004.07.007. [Article]
- Neumann J, Boerries M, Kohler R, Giaisi M, Krammer PH, Busch H, Li-Weber M: 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. 2014 Apr 15;134(8):1991-2002. doi: 10.1002/ijc.28521. Epub 2013 Oct 21. [Article]
- Santagata S, Mendillo ML, Tang YC, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr, Whitesell L, Lindquist S: Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science. 2013 Jul 19;341(6143):1238303. doi: 10.1126/science.1238303. [Article]
- External Links
- ChemSpider
- 352511
- ChEMBL
- CHEMBL583207
- ZINC
- ZINC000006009986
Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0179 mg/mL ALOGPS logP 2.98 ALOGPS logP 1.94 Chemaxon logS -4.4 ALOGPS pKa (Strongest Acidic) 11.63 Chemaxon pKa (Strongest Basic) -2.2 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 120.47 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 126.47 m3·mol-1 Chemaxon Polarizability 49.24 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-0000900000-2e01cf927989975f7b21 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-1a4463ba133567912afa Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-02w9-0001900000-089f0250566ec1d4c868 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0fc4-0002900000-cf526d80c7fc4924b93e Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00c1-0002900000-d3bcf44d97fb02fc4034 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-7309800000-7ffe35e663d1e35aa0ba Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 227.0396654 predictedDarkChem Lite v0.1.0 [M+H]+ 227.5886654 predictedDarkChem Lite v0.1.0 [M+Na]+ 226.3696654 predictedDarkChem Lite v0.1.0
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Prohibitin inhibits DNA synthesis. It has a role in regulating proliferation. As yet it is unclear if the protein or the mRNA exhibits this effect. May play a role in regulating mitochondrial respiration activity and in aging.
- Specific Function
- Complement component c3a binding
- Gene Name
- PHB
- Uniprot ID
- P35232
- Uniprot Name
- Prohibitin
- Molecular Weight
- 29803.775 Da
References
- Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases (By similarity). Functions as an estrogen receptor (ER)-selective coregulator that potentiates the inhibitory activities of antiestrogens and represses the activity of estrogens. Competes with NCOA1 for modulation of ER transcriptional activity. Probably involved in regulating mitochondrial respiration activity and in aging.
- Specific Function
- Amide binding
- Gene Name
- PHB2
- Uniprot ID
- Q99623
- Uniprot Name
- Prohibitin-2
- Molecular Weight
- 33296.06 Da
References
- Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012. [Article]
Drug created at September 26, 2019 16:17 / Updated at June 12, 2020 16:53