NAV

Rocaglamide

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

Identification

Generic Name
Rocaglamide
DrugBank Accession Number
DB15495
Background

Rocaglamide, also referred to as rocaglamide-A, is the eponymous member of a class of anti-cancer phytochemicals known as rocaglamides.1 Rocaglamides are secondary metabolites of the plant genus Aglaia, and extracts of the plant have traditionally been used as a form of insect repellant due to its natural insecticidal properties.9 Reports of Aglaia anti-tumor activity date back as far as 1973, and rocaglamide-A was first isolated in 1982 from the species A. elliptifolia.1 Rocaglamide and a number of its derivatives (e.g. didesmethylrocaglamide) are currently being studied for use as chemotherapeutic agents in the treatment of various leukemias, lymphomas, and carcinomas, as well as adjuvant therapy in the treatment of certain chemotherapy-resistant cancers.7,8,10,3

Type
Small Molecule
Groups
Experimental
Structure
3D
Similar Structures
Weight
Average: 505.567
Monoisotopic: 505.210052342
Chemical Formula
C29H31NO7
Synonyms
Not Available

Pharmacology

Indication

Not Available

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Pharmacodynamics

Not Available

Mechanism of action

Rocaglamide’s anti-tumor activity 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)2 - 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.2,1 The rocaglamide derivative silvestrol has also been observed to act directly on eIF4A, another translation initiation factor of the eIF4F complex ultimately responsible for initiation of protein synthesis.3

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.4 In addition to inhibiting its synthesis via the mechanism described above, rocaglamide promotes degradation of Cdc25A via activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway5. 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. Rocaglamide’s 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 HSF1.6 TXNIP is a negative regulator of cell glucose uptake, and its increased expression blocks glucose uptake and consequently impairs the proliferation of malignant cells.6

Rocaglamide also appears 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, it has been studied as an adjuvant in TRAIL-resistant cancers due to its 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.7,8

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
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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
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as flavaglines. These are heterocyclic compounds with a structure characterized by a cyclopenta[b]benzofuran skeleton.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzofurans
Sub Class
Flavaglines
Direct Parent
Flavaglines
Alternative Parents
Stilbenes / Coumarans / Anisoles / Methoxybenzenes / Phenoxy compounds / Alkyl aryl ethers / Tertiary carboxylic acid amides / Tertiary alcohols / Cyclic alcohols and derivatives / 1,2-diols
show 7 more
Substituents
1,2-diol / Alcohol / Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Coumaran
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid amide, organic heterotricyclic compound, monomethoxybenzene (CHEBI:66309)
Affected organisms
Not Available

Chemical Identifiers

UNII
FRG4N852F7
CAS number
84573-16-0
InChI Key
DAPAQENNNINUPW-IDAMAFBJSA-N
InChI
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
IUPAC Name
(2S,3R,4R,5S,6R)-2,3-dihydroxy-10,12-dimethoxy-6-(4-methoxyphenyl)-N,N-dimethyl-5-phenyl-7-oxatricyclo[6.4.0.0^{2,6}]dodeca-1(8),9,11-triene-4-carboxamide
SMILES
COC1=CC=C(C=C1)[C@@]12OC3=C(C(OC)=CC(OC)=C3)[C@]1(O)[C@H](O)[C@@H]([C@H]2C1=CC=CC=C1)C(=O)N(C)C

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. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. Hausott B, Greger H, Marian B: Flavaglines: a group of efficient growth inhibitors block cell cycle progression and induce apoptosis in colorectal cancer cells. Int J Cancer. 2004 May 10;109(6):933-40. doi: 10.1002/ijc.20033. [Article]
ChemSpider
293974
BindingDB
50196926
ChEBI
66309
ChEMBL
CHEMBL438139
ZINC
ZINC000005664046
PDBe Ligand
RCG
Wikipedia
Rocaglamide
PDB Entries
5zc9

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 Solubility0.0176 mg/mLALOGPS
logP3.53ALOGPS
logP2.39Chemaxon
logS-4.5ALOGPS
pKa (Strongest Acidic)11.63Chemaxon
pKa (Strongest Basic)-1.7Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area97.69 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity136.26 m3·mol-1Chemaxon
Polarizability53.71 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Details1. Prohibitin
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. 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. 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]
Details2. Prohibitin-2
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. 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. 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 16:14 / Updated at June 12, 2020 16:53