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Trilostane

July 24, 2017
Common Name

Trilostane Description

Trilostane is only found in individuals that have used or taken this drug. It is an inhibitor of 3 beta-hydroxysteroid dehydrogenase used in the treatment of Cushings syndrome. It was withdrawn from the United States market in April 1994. [Wikipedia]Trilostane produces suppression of the adrenal cortex by inhibiting enzymatic conversion of steroids by 3-beta-hydroxysteroid dehydrogenase/delta 5,4 ketosteroid isomerase, thus blocking synthesis of adrenal steroids. Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source TrilostanoChEBI TrilostanumChEBI 4alpha,5-Epoxy-17beta-hydroxy-3-oxoandrostane-2-carbonitrileMeSH ModrenalMeSH

Chemical Formlia

C20H27NO3 Average Molecliar Weight

329.4333 Monoisotopic Molecliar Weight

329.199093735 IUPAC Name

(1S,2R,6R,8S,11S,12S,15S,16S)-5,15-dihydroxy-2,16-dimethyl-7-oxapentacyclo[9.7.0.0²,⁸.0⁶,⁸.0¹²,¹⁶]octadec-4-ene-4-carbonitrile Traditional Name

trilostane CAS Registry Number

13647-35-3 SMILES

[H][C@]12O[C@]11CC[C@@]3([H])[C@]4([H])CC[C@H](O)[C@@]4(C)CC[C@]3([H])[C@@]1(C)CC(C#N)=C2O

InChI Identifier

InChI=1S/C20H27NO3/c1-18-7-6-14-12(13(18)3-4-15(18)22)5-8-20-17(24-20)16(23)11(10-21)9-19(14,20)2/h12-15,17,22-23H,3-9H2,1-2H3/t12-,13-,14-,15-,17+,18-,19+,20+/m0/s1

InChI Key

KVJXBPDAXMEYOA-CXANFOAXSA-N Chemical Taxonomy Description

This compound belongs to the class of organic compounds known as estrane steroids. These are steroids with a structure based on the estrane skeleton. Kingdom

Organic compounds Super Class

Lipids and lipid-like moleclies Class

Steroids and steroid derivatives Sub Class

Estrane steroids Direct Parent

Estrane steroids Alternative Parents

  • Secondary alcohols
  • Cyclic alcohols and derivatives
  • Oxacyclic compounds
  • Nitriles
  • Epoxides
  • Enols
  • Dialkyl ethers
  • Organopnictogen compounds
  • Hydrocarbon derivatives

    • Substituents

  • Estrane-skeleton
  • Cyclic alcohol
  • Secondary alcohol
  • Dialkyl ether
  • Enol
  • Oxirane
  • Ether
  • Carbonitrile
  • Nitrile
  • Organoheterocyclic compound
  • Oxacycle
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Organopnictogen compound
  • Organic oxygen compound
  • Alcohol
  • Hydrocarbon derivative
  • Aliphatic heteropolycyclic compound

    • Molecliar Framework

    Aliphatic heteropolycyclic compounds External Descriptors

  • 17beta-hydroxy steroid (CHEBI:32260 )
  • androstanoid (CHEBI:32260 )
  • 3-hydroxy steroid (CHEBI:32260 )

    • Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Antiadrenal
  • Anticorticosteroids
  • Cell signaling
  • Fuel and energy storage
  • Fuel or energy source
  • Membrane integrity/stability

    • Application

  • Nutrients
  • Pharmaceutical
  • Stabilizers
  • Surfactants and Emlisifiers

    • Cellliar locations

  • Cytoplasm
  • Extracellliar
  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting Point264 °CNot Available Boiling PointNot AvailableNot Available Water Solubility5.93e-02 g/LNot Available LogP3Not Available

    Predicted Properties

    Property Value Source Water Solubility0.059 mg/mLALOGPS logP2.41ALOGPS logP2.3ChemAxon logS-3.8ALOGPS pKa (Strongest Acidic)5.23ChemAxon pKa (Strongest Basic)-0.88ChemAxon Physiological Charge-1ChemAxon Hydrogen Acceptor Count4ChemAxon Hydrogen Donor Count2ChemAxon Polar Surface Area76.78 Å2ChemAxon Rotatable Bond Count0ChemAxon Refractivity90.17 m3·mol-1ChemAxon Polarizability36.96 Å3ChemAxon Number of Rings5ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

    Biological Properties Cellliar Locations

  • Cytoplasm
  • Extracellliar
  • Membrane

    • Biofluid Locations

  • Blood
  • Urine

    • Tissue Location

    Not Available Pathways

    Not Available Normal Concentrations

    Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01108

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01108

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB01108 DrugBank Metabolite ID

    Not Available Phenol Explorer Compound ID

    Not Available Phenol Explorer Metabolite ID

    Not Available FoodDB ID

    Not Available KNApSAcK ID

    Not Available Chemspider ID

    570949 KEGG Compound ID

    C12580 BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Trilostane NuGOwiki Link

    HMDB15240 Metagene Link

    HMDB15240 METLIN ID

    Not Available PubChem Compound

    656583 PDB ID

    Not Available ChEBI ID

    32260

    Product: RTA-409

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References
    1. Komanicky P, Spark RF, Melby JC: Treatment of Cushings syndrome with trilostane (WIN 24,540), an inhibitor of adrenal steroid biosynthesis. J Clin Endocrinol Metab. 1978 Nov;47(5):1042-51. [PubMed:233687 ]

    Enzymes

    General function:
    Involved in sequence-specific DNA binding transcription factor activity
    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. 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:
    59215.8
    References
    1. Puddefoot JR, Barker S, Vinson GP: Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. [PubMed:17109615 ]
    2. Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP: Non-competitive steroid inhibition of oestrogen receptor functions. Int J Cancer. 2002 Sep 1;101(1):17-22. [PubMed:12209583 ]
    3. Barker S, Malouitre SD, Glover HR, Puddefoot JR, Vinson GP: Comparison of effects of 4-hydroxy tamoxifen and trilostane on oestrogen-regulated gene expression in MCF-7 cells: up-regulation of oestrogen receptor beta. J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):141-51. Epub 2006 Jun 27. [PubMed:16806905 ]
    General function:
    Involved in sequence-specific DNA binding transcription factor activity
    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. Can activate the transcriptional activity of TFF1
    Gene Name:
    ESR1
    Uniprot ID:
    P03372
    Molecular weight:
    66215.4
    References
    1. Puddefoot JR, Barker S, Vinson GP: Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. [PubMed:17109615 ]
    2. Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP: Non-competitive steroid inhibition of oestrogen receptor functions. Int J Cancer. 2002 Sep 1;101(1):17-22. [PubMed:12209583 ]
    3. Barker S, Malouitre SD, Glover HR, Puddefoot JR, Vinson GP: Comparison of effects of 4-hydroxy tamoxifen and trilostane on oestrogen-regulated gene expression in MCF-7 cells: up-regulation of oestrogen receptor beta. J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):141-51. Epub 2006 Jun 27. [PubMed:16806905 ]
    General function:
    Involved in 3-beta-hydroxy-delta5-steroid dehydrogenase activity
    Specific function:
    3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids. Efficiently catalyzes the transformation of pregnenolone to progesterone, 17-alpha-hydroxypregnenolone to 17-alpha-hydroxyprogesterone, DHEA to 4-androstenedione, dihydrotestosterone to 5-alpha-androstane-3 beta,17 beta-diol, dehydroepiandrosterone to androstenedione and 5-alpha-androstan-3 beta,17 beta-diol to 5-alpha-dihydrotestosterone.
    Gene Name:
    HSD3B1
    Uniprot ID:
    P14060
    Molecular weight:
    42251.25
    References
    1. Naville D, Keeney DS, Jenkin G, Murry BA, Head JR, Mason JI: Regulation of expression of male-specific rat liver microsomal 3 beta-hydroxysteroid dehydrogenase. Mol Endocrinol. 1991 Aug;5(8):1090-100. [PubMed:1944305 ]
    2. Takahashi M, Luu-The V, Labrie F: Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5—-4-ene-isomerase activity. J Steroid Biochem Mol Biol. 1990 Oct;37(2):231-6. [PubMed:2268554 ]
    3. Suzuki S, Endo Y, Tanaka S, Iizuka R: Indirect immunofluorescence studies on the steroid-producing activity of hamster ova. Am J Obstet Gynecol. 1984 Jan 1;148(1):76-85. [PubMed:6362415 ]
    4. Duffy DM, Hess DL, Stouffer RL: Acute administration of a 3 beta-hydroxysteroid dehydrogenase inhibitor to rhesus monkeys at the midluteal phase of the menstrual cycle: evidence for possible autocrine regulation of the primate corpus luteum by progesterone. J Clin Endocrinol Metab. 1994 Dec;79(6):1587-94. [PubMed:7989460 ]
    5. Mensah-Nyagan AG, Feuilloley M, Dupont E, Do-Rego JL, Leboulenger F, Pelletier G, Vaudry H: Immunocytochemical localization and biological activity of 3 beta-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci. 1994 Dec;14(12):7306-18. [PubMed:7996177 ]
    6. Cooke GM: Differential effects of trilostane and cyanoketone on the 3 beta-hydroxysteroid dehydrogenase-isomerase reactions in androgen and 16-androstene biosynthetic pathways in the pig testis. J Steroid Biochem Mol Biol. 1996 Apr;58(1):95-101. [PubMed:8809191 ]
    7. Igaz P, Tombol Z, Szabo PM, Liko I, Racz K: Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice. Curr Med Chem. 2008;15(26):2734-47. [PubMed:18991633 ]
    General function:
    Involved in 3-beta-hydroxy-delta5-steroid dehydrogenase activity
    Specific function:
    3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids.
    Gene Name:
    HSD3B2
    Uniprot ID:
    P26439
    Molecular weight:
    42051.845
    References
    1. Naville D, Keeney DS, Jenkin G, Murry BA, Head JR, Mason JI: Regulation of expression of male-specific rat liver microsomal 3 beta-hydroxysteroid dehydrogenase. Mol Endocrinol. 1991 Aug;5(8):1090-100. [PubMed:1944305 ]
    2. Cooke GM: Differential effects of trilostane and cyanoketone on the 3 beta-hydroxysteroid dehydrogenase-isomerase reactions in androgen and 16-androstene biosynthetic pathways in the pig testis. J Steroid Biochem Mol Biol. 1996 Apr;58(1):95-101. [PubMed:8809191 ]
    3. Takahashi M, Luu-The V, Labrie F: Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5—-4-ene-isomerase activity. J Steroid Biochem Mol Biol. 1990 Oct;37(2):231-6. [PubMed:2268554 ]
    4. Suzuki S, Endo Y, Tanaka S, Iizuka R: Indirect immunofluorescence studies on the steroid-producing activity of hamster ova. Am J Obstet Gynecol. 1984 Jan 1;148(1):76-85. [PubMed:6362415 ]
    5. Duffy DM, Hess DL, Stouffer RL: Acute administration of a 3 beta-hydroxysteroid dehydrogenase inhibitor to rhesus monkeys at the midluteal phase of the menstrual cycle: evidence for possible autocrine regulation of the primate corpus luteum by progesterone. J Clin Endocrinol Metab. 1994 Dec;79(6):1587-94. [PubMed:7989460 ]
    6. Mensah-Nyagan AG, Feuilloley M, Dupont E, Do-Rego JL, Leboulenger F, Pelletier G, Vaudry H: Immunocytochemical localization and biological activity of 3 beta-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci. 1994 Dec;14(12):7306-18. [PubMed:7996177 ]
    7. Igaz P, Tombol Z, Szabo PM, Liko I, Racz K: Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice. Curr Med Chem. 2008;15(26):2734-47. [PubMed:18991633 ]

    PMID: 19477412

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