7-ethyl-10-hydroxycamptothecin

Identification

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Name
7-ethyl-10-hydroxycamptothecin
Accession Number
DB05482  (DB12552)
Type
Small Molecule
Groups
Investigational
Description

7-ethyl-10-hydroxycamptothecin (SN 38) is a liposomal formulation of the active metabolite of Irinotecan Irinotecan, a chemotherapeutic pro-drug approved for the treatment of advanced colorectal cancer. SN 38 has been used in trials studying the treatment of Cancer, Advanced Solid Tumors, Small Cell Lung Cancer, Metastatic Colorectal Cancer, and Triple Negative Breast Cancer, among others.

Structure
Thumb
Synonyms
Not Available
External IDs
LE-SN38 / NK 012 / NK-012 / NK012 / SN 38 / SN-38
International/Other Brands
NeoLipid Camptosar
Categories
UNII
0H43101T0J
CAS number
86639-52-3
Weight
Average: 392.4046
Monoisotopic: 392.13722176
Chemical Formula
C22H20N2O5
InChI Key
FJHBVJOVLFPMQE-QFIPXVFZSA-N
InChI
InChI=1S/C22H20N2O5/c1-3-12-13-7-11(25)5-6-17(13)23-19-14(12)9-24-18(19)8-16-15(20(24)26)10-29-21(27)22(16,28)4-2/h5-8,25,28H,3-4,9-10H2,1-2H3/t22-/m0/s1
IUPAC Name
(19S)-10,19-diethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0²,¹¹.0⁴,⁹.0¹⁵,²⁰]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-14,18-dione
SMILES
CCC1=C2C=C(O)C=CC2=NC2=C1CN1C2=CC2=C(COC(=O)[C@]2(O)CC)C1=O

Pharmacology

Indication

Investigated for use/treatment in colorectal cancer.

Pharmacodynamics

SN-38 (7-ethyl-10-hydroxycamptothecin) is the active metabolite of Irinotecan (CPT-11). Irinotecan is a topoisomerase I inhibitor commercially available as Camptosar®. SN-38 has been found to be 200–2000 times more cytotoxic than CPT-11, but has not been used as an anticancer drug due to its poor solubility in pharmaceutically acceptable solvents and low affinity to lipid membranes. SN-38 also undergoes a reversible conversion to an inactive open lactone ring structure at physiological pH. LE-SN-38 is a novel lipsome based formulation containing liposomes of uniform size distribution (<200 nm). Drug entrapment efficiency of the formulation is>95%.

Mechanism of action

The entrapment of SN-38 in lipsomes results in a more stable and more soluble form of the drug. This allows for increased affinity of SN-38 to lipid membranes and improved delivery of the drug to tumor sites. SN-38 is a highly effective cytotoxic topoisomerase I inhibitor.

TargetActionsOrganism
UDNA topoisomerase 1Not AvailableHumans
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
Toxicity
Not Available
Affected organisms
Not Available
Pathways
PathwayCategory
Irinotecan Metabolism PathwayDrug metabolism
Irinotecan Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with 7-ethyl-10-hydroxycamptothecin.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with 7-ethyl-10-hydroxycamptothecin.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with 7-ethyl-10-hydroxycamptothecin.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
AliskirenThe metabolism of Aliskiren can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
AlpelisibThe metabolism of Alpelisib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
AlprazolamThe metabolism of Alprazolam can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
AminophyllineThe metabolism of Aminophylline can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Xuan T, Zhang JA, Ahmad I: HPLC method for determination of SN-38 content and SN-38 entrapment efficiency in a novel liposome-based formulation, LE-SN38. J Pharm Biomed Anal. 2006 May 3;41(2):582-8. Epub 2006 Jan 18. [PubMed:16386867]
  2. Peikov V, Ugwu S, Parmar M, Zhang A, Ahmad I: pH-dependent association of SN-38 with lipid bilayers of a novel liposomal formulation. Int J Pharm. 2005 Aug 11;299(1-2):92-9. [PubMed:15996839]
  3. Pal A, Khan S, Wang YF, Kamath N, Sarkar AK, Ahmad A, Sheikh S, Ali S, Carbonaro D, Zhang A, Ahmad I: Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation. Anticancer Res. 2005 Jan-Feb;25(1A):331-41. [PubMed:15816556]
  4. Khan S, Ahmad A, Guo W, Wang YF, Abu-Qare A, Ahmad I: A simple and sensitive LC/MS/MS assay for 7-ethyl-10-hydroxycamptothecin (SN-38) in mouse plasma and tissues: application to pharmacokinetic study of liposome entrapped SN-38 (LE-SN38). J Pharm Biomed Anal. 2005 Feb 7;37(1):135-42. [PubMed:15664753]
  5. Lei S, Chien PY, Sheikh S, Zhang A, Ali S, Ahmad I: Enhanced therapeutic efficacy of a novel liposome-based formulation of SN-38 against human tumor models in SCID mice. Anticancer Drugs. 2004 Sep;15(8):773-8. [PubMed:15494639]
  6. Zhang JA, Xuan T, Parmar M, Ma L, Ugwu S, Ali S, Ahmad I: Development and characterization of a novel liposome-based formulation of SN-38. Int J Pharm. 2004 Feb 11;270(1-2):93-107. [PubMed:14726126]
  7. Khan S, Ahmad A, Ahmad I: A sensitive and rapid liquid chromatography tandem mass spectrometry method for quantitative determination of 7-ethyl-10-hydroxycamptothecin (SN-38) in human plasma containing liposome-based SN-38 (LE-SN38). Biomed Chromatogr. 2003 Dec;17(8):493-9. [PubMed:14648604]
  8. Guo W, Ahmad A, Khan S, Dahhani F, Wang YF, Ahmad I: Determination by liquid chromatography with fluorescence detection of total 7-ethyl-10-hydroxy-camptothecin (SN-38) in beagle dog plasma after intravenous administration of liposome-based SN-38 (LE-SN38). J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Jul 5;791(1-2):85-92. [PubMed:12798168]
External Links
Human Metabolome Database
HMDB0060510
KEGG Compound
C11173
PubChem Compound
104842
PubChem Substance
175427017
ChemSpider
94634
BindingDB
50418088
ChEBI
8988
ChEMBL
CHEMBL837

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Solid Tumors / Metastatic Colorectal Cancers1
1CompletedTreatmentAdvanced Solid Tumors / Metastatic Triple Negative Breast Cancer1
1CompletedTreatmentMalignancies1
1RecruitingTreatmentMalignancies / Neoplasms / Refractory Solid Tumors / Solid Tumor, Recurrent / Tumors1
2CompletedTreatmentLung Cancer Small Cell Lung Cancer (SCLC)1
2CompletedTreatmentTriple Negative Breast Cancer (TNBC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.29 mg/mLALOGPS
logP2.73ALOGPS
logP1.87ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)9.68ChemAxon
pKa (Strongest Basic)3.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.96 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity106.12 m3·mol-1ChemAxon
Polarizability41.43 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6456
Blood Brain Barrier-0.8359
Caco-2 permeable-0.8956
P-glycoprotein substrateSubstrate0.7357
P-glycoprotein inhibitor INon-inhibitor0.8184
P-glycoprotein inhibitor IINon-inhibitor0.9399
Renal organic cation transporterNon-inhibitor0.8729
CYP450 2C9 substrateNon-substrate0.883
CYP450 2D6 substrateNon-substrate0.8538
CYP450 3A4 substrateSubstrate0.6092
CYP450 1A2 substrateInhibitor0.7118
CYP450 2C9 inhibitorNon-inhibitor0.863
CYP450 2D6 inhibitorNon-inhibitor0.9305
CYP450 2C19 inhibitorNon-inhibitor0.8155
CYP450 3A4 inhibitorInhibitor0.6952
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5726
Ames testNon AMES toxic0.5766
CarcinogenicityNon-carcinogens0.7761
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.1600 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9953
hERG inhibition (predictor II)Non-inhibitor0.7325
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as camptothecins. These are heterocyclic compounds comprising a planar pentacyclic ring structure, that includes a pyrrolo[3,4-beta]-quinoline moiety (rings A, B and C), conjugated pyridone moiety (ring D) and one chiral center at position 20 within the alpha-hydroxy lactone ring with (S) configuration (the E-ring).
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Camptothecins
Sub Class
Not Available
Direct Parent
Camptothecins
Alternative Parents
Hydroxyquinolines / Pyranopyridines / Pyridinones / 1-hydroxy-2-unsubstituted benzenoids / Tertiary alcohols / Heteroaromatic compounds / Carboxylic acid esters / Lactams / Lactones / Azacyclic compounds
show 7 more
Substituents
Camptothecin / Hydroxyquinoline / Pyranopyridine / Quinoline / 1-hydroxy-2-unsubstituted benzenoid / Pyridinone / Pyridine / Benzenoid / Heteroaromatic compound / Tertiary alcohol
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
pyranoindolizinoquinoline (CHEBI:8988)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Poly(a) rna binding
Specific Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a singl...
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase 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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Hanioka N, Ozawa S, Jinno H, Tanaka-Kagawa T, Nishimura T, Ando M, Sawada Ji J: Interaction of irinotecan (CPT-11) and its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) with human cytochrome P450 enzymes. Drug Metab Dispos. 2002 Apr;30(4):391-6. [PubMed:11901092]
  2. Mirkov S, Komoroski BJ, Ramirez J, Graber AY, Ratain MJ, Strom SC, Innocenti F: Effects of green tea compounds on irinotecan metabolism. Drug Metab Dispos. 2007 Feb;35(2):228-33. doi: 10.1124/dmd.106.012047. Epub 2006 Nov 15. [PubMed:17108060]
  3. Camptosar FDA label [File]

Drug created on November 18, 2007 11:25 / Updated on June 04, 2019 06:17