Didesmethylrocaglamide

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

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
Thumb
Weight
Average: 477.513
Monoisotopic: 477.178752213
Chemical Formula
C27H27NO7
Synonyms
  • RocB

Pharmacology

Indication

Not Available

Pharmacology
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Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AProhibitin
inhibitor
Humans
AProhibitin-2
inhibitor
Humans
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
Adverseeffects
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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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
ChemSpider
352511
ChEMBL
CHEMBL583207
ZINC
ZINC000006009986

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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
PropertyValueSource
Water Solubility0.0179 mg/mLALOGPS
logP2.98ALOGPS
logP1.94ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)11.63ChemAxon
pKa (Strongest Basic)-2.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area120.47 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity126.47 m3·mol-1ChemAxon
Polarizability49.24 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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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
  1. 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
  1. 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 on September 26, 2019 16:17 / Updated on June 12, 2020 16:53