Podofilox

Common Name

Podofilox Description

A lignan (lignans) found in podophyllin resin from the roots of podophyllum plants. It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [PubChem] Structure

Synonyms

Value Source (-)-PodophyllotoxinChEBI 9-HYDROXY-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-D][1,3]dioxol-6(5ah)-oneChEBI CondyloxChEBI Podophyllinic acid lactoneChEBI Podophyllotoxin 7ChEBI PPTChEBI Podophyllinate lactoneGenerator Ardern brand OF podophyllotoxinMeSH CondylineMeSH Hamilton brand OF podophyllotoxinMeSH Oclassen brand OF podophyllotoxinMeSH WartecMeSH CPH86MeSH EpipodophyllotoxinMeSH Fides ecopharma brand OF podophyllotoxinMeSH Paladin brand OF podophyllotoxinMeSH PODOCON-25MeSH Podophyllotoxin, (5R-(5 alpha,5a alpha,8a alpha,9 alpha))-isomerMeSH Podophyllotoxin, (5R-(5 alpha,5a beta,8a alpha,9 beta))-isomerMeSH WarticonMeSH Newport brand OF podophyllotoxinMeSH PodofilmMeSH Podophyllotoxin, (5R-(5 alpha,5a alpha,8a beta,9 alpha))-isomerMeSH Wolff brand OF podophyllotoxinMeSH Canderm brand OF podophyllotoxinMeSH Paddock brand OF podophyllotoxinMeSH PodophyllotoxinMeSH Podophyllotoxin, (5R-(5 alpha,5a alpha,8a alpha,9 beta))-isomerMeSH Stiefel brand OF podophyllotoxinMeSH Yamanouchi brand OF podophyllotoxinMeSH

Chemical Formlia

C₂₂H₂₂O₈ Average Molecliar Weight

414.4053 Monoisotopic Molecliar Weight

414.13146768 IUPAC Name

(10R,11R,15R,16R)-16-hydroxy-10-(3,4,5-trimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0³,⁷.0¹¹,¹⁵]hexadeca-1,3(7),8-trien-12-one Traditional Name

condylox CAS Registry Number

477-47-4 SMILES

InChI Identifier

InChI Key

YJGVMLPVUAXIQN-XVVDYKMHSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as podophyllotoxins. These are tetralin lignans in which the benzene moiety of the tetralin skeleton is fused to a 1,3-dioxolane and the cyclohexane is fused to a butyrolactone (pyrrolidin-2-one). Kingdom

Chemical entities Super Class

Organic compounds Class

Lignans, neolignans and related compounds Sub Class

Lignan lactones Direct Parent

Podophyllotoxins Alternative Parents

Aryltetralin lignans

Furanonaphthodioxoles

Tetralins

Benzodioxoles

Phenoxy compounds

Anisoles

Methoxybenzenes

Alkyl aryl ethers

Gamma butyrolactones

Tetrahydrofurans

Secondary alcohols

Carboxylic acid esters

Acetals

Oxacyclic compounds

Monocarboxylic acids and derivatives

Organic oxides

Hydrocarbon derivatives

Carbonyl compounds

Substituents

Podophyllotoxin

1-aryltetralin lignan

Linear furanonaphthodioxole

Naphthofuran

Tetralin

Benzodioxole

Phenoxy compound

Phenol ether

Anisole

Methoxybenzene

Alkyl aryl ether

Monocyclic benzene moiety

Benzenoid

Gamma butyrolactone

Tetrahydrofuran

Secondary alcohol

Carboxylic acid ester

Lactone

Monocarboxylic acid or derivatives

Organoheterocyclic compound

Ether

Oxacycle

Carboxylic acid derivative

Acetal

Organic oxygen compound

Carbonyl group

Organooxygen compound

Hydrocarbon derivative

Organic oxide

Alcohol

Aromatic heteropolycyclic compound

Molecliar Framework

Aromatic heteropolycyclic compounds External Descriptors

lignan (CHEBI:50305 )

furonaphthodioxole (CHEBI:50305 )

Phenylpropanoids (C10874 )

Lignans (C10874 )

Phytotoxins (C10874 )

Ontology Status

Expected but not Quantified Origin

Drug

Biofunction

Antimitotic agent

Antineoplastic Agents, Phytogenic

Keratolytic Agents

Tubliin Modliators

Application

Pharmaceutical

Cellliar locations

Cytoplasm

Membrane

Physical Properties State

Solid Experimental Properties

Property Value Reference Melting Point228 °CNot Available Boiling PointNot AvailableNot Available Water Solubility1.14e-01 g/LNot Available LogP1.5Not Available

Predicted Properties

Property Value Source Water Solubility0.11 mg/mLALOGPS logP2.37ALOGPS logP1.62ChemAxon logS-3.6ALOGPS pKa (Strongest Acidic)14.02ChemAxon pKa (Strongest Basic)-3.2ChemAxon Physiological Charge0ChemAxon Hydrogen Acceptor Count7ChemAxon Hydrogen Donor Count1ChemAxon Polar Surface Area92.68 ŲChemAxon Rotatable Bond Count4ChemAxon Refractivity103.91 m³·mol^-1ChemAxon Polarizability41.71 ųChemAxon Number of Rings5ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

Spectra Spectra

Spectrum Type Description Splash Key LC-MS/MS

LC-MS/MS Spectrum – , positivesplash10-0002-0597000000-db51a944dfa407960e8dView in MoNA LC-MS/MS

LC-MS/MS Spectrum – , positivesplash10-000j-0963000000-4476c6936a37aa211aa3View in MoNA LC-MS/MS

LC-MS/MS Spectrum – , positivesplash10-00ks-2963000000-b25b106b59de4143117bView in MoNA LC-MS/MS

LC-MS/MS Spectrum – , positivesplash10-0002-0985000000-53e98e579f100740f337View in MoNA LC-MS/MS

LC-MS/MS Spectrum – , positivesplash10-01q9-0294000000-a3c5accc0b01026c8804View in MoNA LC-MS/MS

LC-MS/MS Spectrum – , positivesplash10-0002-0986000000-0ae140ecf023e899576fView in MoNA 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

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 DB01179

21059682

details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01179

21059682

details

Abnormal Concentrations

Not Available Predicted Concentrations

Biofluid Value Original age Original sex Original condition Comments Blood0-2 uMAdlit (>18 years old)BothNormalPredicted based on drug qualities Blood0-1 umol/mmol creatinineAdlit (>18 years old)BothNormalPredicted based on drug qualities

Associated Disorders and Diseases Disease References

None Associated OMIM IDs

None External Links DrugBank ID

DB01179 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

10162 KEGG Compound ID

C10874 BioCyc ID

Not Available BiGG ID

Not Available Wikipedia Link

Podofilox NuGOwiki Link

HMDB15310 Metagene Link

HMDB15310 METLIN ID

Not Available PubChem Compound

10607 PDB ID

POD ChEBI ID

50305

Product: Bruceine A

References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References Not Available

Enzymes

General function:

Involved in monooxygenase activity

Specific function:

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.

Gene Name:

CYP3A4

Uniprot ID:

P08684

Molecular weight:

57255.585

References

1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

General function:

Involved in monooxygenase activity

Specific function:

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.

Gene Name:

CYP2C19

Uniprot ID:

P33261

Molecular weight:

55944.565

References

1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

General function:

Involved in structural molecule activity

Specific function:

Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha-chain

Gene Name:

TUBB

Uniprot ID:

P07437

Molecular weight:

49670.5

References

1. Wolff J, Knipling L, Cahnmann HJ, Palumbo G: Direct photoaffinity labeling of tubulin with colchicine. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2820-4. [PubMed:2011590 ]

General function:

Involved in structural molecule activity

Specific function:

Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha-chain

Gene Name:

TUBA4A

Uniprot ID:

P68366

Molecular weight:

49924.0

References

1. Labruere R, Gautier B, Testud M, Seguin J, Lenoir C, Desbene-Finck S, Helissey P, Garbay C, Chabot GG, Vidal M, Giorgi-Renault S: Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents. ChemMedChem. 2010 Dec 3;5(12):2016-25. doi: 10.1002/cmdc.201000305. [PubMed:20979080 ]
2. Li CM, Lu Y, Ahn S, Narayanan R, Miller DD, Dalton JT: Competitive mass spectrometry binding assay for characterization of three binding sites of tubulin. J Mass Spectrom. 2010 Oct;45(10):1160-6. doi: 10.1002/jms.1804. [PubMed:20814887 ]
3. Kim ND, Park ES, Kim YH, Moon SK, Lee SS, Ahn SK, Yu DY, No KT, Kim KH: Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents. Bioorg Med Chem. 2010 Oct 1;18(19):7092-100. doi: 10.1016/j.bmc.2010.07.072. Epub 2010 Aug 6. [PubMed:20810285 ]
4. Screpanti E, Santaguida S, Nguyen T, Silvestri R, Gussio R, Musacchio A, Hamel E, De Wulf P: A screen for kinetochore-microtubule interaction inhibitors identifies novel antitubulin compounds. PLoS One. 2010 Jul 15;5(7):e11603. doi: 10.1371/journal.pone.0011603. [PubMed:20657644 ]
5. Alam MA, Naik PK: Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity. J Mol Graph Model. 2009 Jun-Jul;27(8):930-43. doi: 10.1016/j.jmgm.2009.02.003. Epub 2009 Feb 20. [PubMed:19286405 ]
6. Clark PI: Clinical pharmacology and schedule dependency of the podophyllotoxin derivatives. Semin Oncol. 1992 Apr;19(2 Suppl 6):20-7. [PubMed:1411635 ]

General function:

Involved in sequence-specific DNA binding transcription factor activity

Specific function:

Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks

Gene Name:

TOP2A

Uniprot ID:

P11388

Molecular weight:

174383.9

References

1. Iida A, Kano M, Kubota Y, Koga K, Tomioka K: Podophyllotoxin aza-analogue, a novel DNA topoisomerase II inhibitor. Chem Pharm Bull (Tokyo). 2000 Apr;48(4):486-9. [PubMed:10783066 ]
2. Zhang YL, Shen YC, Wang ZQ, Chen HX, Guo X, Cheng YC, Lee KH: Antitumor agents, 130, Novel 4 beta-arylamino derivatives of 3,4-didemethoxy-3,4-dioxo-4-deoxypodophyllotoxin as potent inhibitors of human DNA topoisomerase II. J Nat Prod. 1992 Aug;55(8):1100-11. [PubMed:1331331 ]
3. Terada T, Fujimoto K, Nomura M, Yamashita J, Kobunai T, Takeda S, Wierzba K, Yamada Y, Yamaguchi H: Antitumor agents. I. DNA topoisomerase II inhibitory activity and the structural relationship of podophyllotoxin derivatives as antitumor agents. Chem Pharm Bull (Tokyo). 1992 Oct;40(10):2720-7. [PubMed:1334447 ]
4. Kamal A, Gayatri NL, Reddy DR, Mohan Reddy PS, Arifuddin M, Dastidar SG, Kondapi AK, Rajkumar M: Synthesis and biological evaluation of new 4beta-anilino- and 4beta-imido-substituted podophyllotoxin congeners. Bioorg Med Chem. 2005 Nov 15;13(22):6218-25. Epub 2005 Aug 2. [PubMed:16061385 ]
5. Ruckdeschel JC: Etoposide in the management of non-small cell lung cancer. Cancer. 1991 Jan 1;67(1 Suppl):250-3. [PubMed:1845848 ]
6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

PMID: 20188110

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