Tmic
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Record Information
Version2.0
Creation Date2014-09-11 05:17:56 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4818
Identification
Common NameBicalutamide
ClassSmall Molecule
DescriptionBicalutamide is an oral non-steroidal anti-androgen for prostate cancer. It binds to the androgen receptor.
Compound Type
  • Drug
  • Ether
  • Metabolite
  • Nitrile
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Casodex
Chemical FormulaC18H14F4N2O4S
Average Molecular Mass430.373 g/mol
Monoisotopic Mass430.061 g/mol
CAS Registry Number90357-06-5
IUPAC NameN-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorobenzenesulfonyl)-2-hydroxy-2-methylpropanamide
Traditional Namebicalutamide
SMILESCC(O)(CS(=O)(=O)C1=CC=C(F)C=C1)C(O)=NC1=CC(=C(C=C1)C#N)C(F)(F)F
InChI IdentifierInChI=1/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25)
InChI KeyInChIKey=LKJPYSCBVHEWIU-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as trifluoromethylbenzenes. These are organofluorine compounds that contain a benzene ring substituted with one or more trifluoromethyl groups.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassTrifluoromethylbenzenes
Direct ParentTrifluoromethylbenzenes
Alternative Parents
Substituents
  • Trifluoromethylbenzene
  • Benzenesulfonyl group
  • Anilide
  • Benzonitrile
  • N-arylamide
  • Fluorobenzene
  • Halobenzene
  • Aryl fluoride
  • Aryl halide
  • Tertiary alcohol
  • Sulfonyl
  • Sulfone
  • Carboxamide group
  • Secondary carboxylic acid amide
  • Carboxylic acid derivative
  • Carbonitrile
  • Nitrile
  • Organohalogen compound
  • Alkyl halide
  • Organosulfur compound
  • Hydrocarbon derivative
  • Organic oxide
  • Alkyl fluoride
  • Alcohol
  • Carbonyl group
  • Organopnictogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Organofluoride
  • Organonitrogen compound
  • Organooxygen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point191-193°C
Boiling PointNot Available
Solubility5 mg/L
LogP2.5
Predicted Properties
PropertyValueSource
Water Solubility0.0093 g/LALOGPS
logP2.7ALOGPS
logP2.71ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)11.95ChemAxon
pKa (Strongest Basic)-4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area107.26 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity96.59 m³·mol⁻¹ChemAxon
Polarizability36.68 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-08g3-8980200000-64d743e9fc999bfbcba9View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-01p9-7953200000-a9b28d0415e04d7763bbView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-014r-2950100000-4088c17274bcf0f095d4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-014r-0980100000-89a3faa58e22068394b8View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a4r-0890000000-f2bd2727ffd1da47c463View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-014r-2950100000-4088c17274bcf0f095d4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-014r-0980100000-89a3faa58e22068394b8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0010900000-bb82a6e39969d267c6a9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00lr-0271900000-7c988dbd6f49d03a1406View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0002-2920000000-26680dccacad423296a2View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-056r-0060900000-6a1879b598e45a16fa3dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0090300000-b3a4c9df0fffd868683dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01ot-9270000000-2d4ba654071403ab6b99View in MoNA
Toxicity Profile
Route of ExposureBicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown.
Mechanism of ToxicityBicalutamide competes with androgen for the binding of androgen receptors, consequently blocking the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (1)
MetabolismBicalutamide undergoes stereo specific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Half Life: 5.9 days
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor treatment (together with surgery or LHRH analogue) of advanced prostatic cancer.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01128
HMDB IDHMDB15260
PubChem Compound ID2375
ChEMBL IDCHEMBL409
ChemSpider ID50614
KEGG IDC08160
UniProt IDNot Available
OMIM ID
ChEBI ID100717
BioCyc IDNot Available
CTD IDC053541
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkBicalutamide
References
Synthesis Reference

Nnochiri Ekwuribe, “METHODS OF SYNTHESIZING ACYLANILIDES INCLUDING BICALUTAMIDE AND DERIVATIVES THEREOF.” U.S. Patent US20020165406, issued November 07, 2002.

MSDSLink
General References
  1. Wikipedia. Cyanide poisoning. Last Updated 30 March 2009. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Zinc ion binding
Specific Function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.137 uMNVS_NR_hARNovascreen
AC504.75 uMTox21_AR_LUC_MDAKB2_AgonistTox21/NCGC
AC509.5 uMTox21_AR_LUC_MDAKB2_AntagonistTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
  2. Huang ZQ, Li J, Wong J: AR possesses an intrinsic hormone-independent transcriptional activity. Mol Endocrinol. 2002 May;16(5):924-37. [11981028 ]
  3. Chen F, Knecht K, Birzin E, Fisher J, Wilkinson H, Mojena M, Moreno CT, Schmidt A, Harada S, Freedman LP, Reszka AA: Direct agonist/antagonist functions of dehydroepiandrosterone. Endocrinology. 2005 Nov;146(11):4568-76. Epub 2005 Jun 30. [15994348 ]
  4. Hodgson MC, Astapova I, Hollenberg AN, Balk SP: Activity of androgen receptor antagonist bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors. Cancer Res. 2007 Sep 1;67(17):8388-95. [17804755 ]
  5. Teng C, Goodwin B, Shockley K, Xia M, Huang R, Norris J, Merrick BA, Jetten AM, Austin CP, Tice RR: Bisphenol A affects androgen receptor function via multiple mechanisms. Chem Biol Interact. 2013 May 25;203(3):556-64. doi: 10.1016/j.cbi.2013.03.013. Epub 2013 Apr 4. [23562765 ]
General Function:
Zinc ion binding
Specific Function:
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation.Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation.Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone.
Gene Name:
PGR
Uniprot ID:
P06401
Molecular Weight:
98979.96 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.454 uMNVS_NR_hPRNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.22 uMATG_PXR_TRANSAttagene
AC506.63 uMATG_PXRE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC503.36 uMOT_ER_ERbERb_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC506.01 uMNVS_NR_hERNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]