Edotecarin

Identification

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Name
Edotecarin
Accession Number
DB04882
Type
Small Molecule
Groups
Investigational
Description

Edotecarin is a novel, non-camptothecin, DNA topoisomerase I inhibitor. It is member of the class of compounds called indolocarbazoles.

Structure
Thumb
Synonyms
  • E'dotecarine
  • Edotecarin
  • Edotecarina
  • Edotecarinum
External IDs
J 107088 / J-107088 / PF-804950 / PHA-782615
Categories
UNII
1V8X590XDP
CAS number
174402-32-5
Weight
Average: 608.56
Monoisotopic: 608.175457738
Chemical Formula
C29H28N4O11
InChI Key
QMVPQBFHUJZJCS-NTKFZFFISA-N
InChI
InChI=1S/C29H28N4O11/c34-7-10(8-35)31-33-27(42)20-18-13-3-1-11(37)5-15(13)30-22(18)23-19(21(20)28(33)43)14-4-2-12(38)6-16(14)32(23)29-26(41)25(40)24(39)17(9-36)44-29/h1-6,10,17,24-26,29-31,34-41H,7-9H2/t17-,24-,25+,26-,29-/m1/s1
IUPAC Name
13-[(1,3-dihydroxypropan-2-yl)amino]-6,20-dihydroxy-3-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-3,13,23-triazahexacyclo[14.7.0.0²,¹⁰.0⁴,⁹.0¹¹,¹⁵.0¹⁷,²²]tricosa-1,4(9),5,7,10,15,17(22),18,20-nonaene-12,14-dione
SMILES
OCC(CO)NN1C(=O)C2=C3C(NC4=C3C=CC(O)=C4)=C3N([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C4=C(C=CC(O)=C4)C3=C2C1=O

Pharmacology

Indication

Clinical studies with edotecarin have shown activity in subjects with colorectal cancer, esophageal cancer and other solid tumors.

Pharmacodynamics

Edotecarin, formerly J-107088 is a novel, non-camptothecin, DNA topoisomerase-1 inhibitor. It is part of the class of compounds called indolocarbazoles. It is a novel inhibitor of topoisomerase I that induces single-strand DNA cleavage more effectively than NB-506 or camptothecin (CPT) and at different DNA sequences. The DNA-topoisomerase I complexes induced by edotecarin are more stable than those occurring after exposure to CPT or NB-506. The antitumor activity of edotecarin is less cell cycle dependent than other topoisomerase I inhibitors. Being an indolocarbazole, it is structurally related to staurosporine but does not possess protein kinase inhibitory properties. The antitumor activity of edotecarin has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in breast, cervix, pharynx, lung, prostate, colon, gastric, and hepatic cancer models. Edotecarin is effective on cells that have acquired resistance related to P-glycoprotein. In vitro synergy has been demonstrated when edotecarin was tested in combination with cisplatin, 5-fluorouracil, etoposide, paclitaxel, doxorubicin, vincristine, CPT, and gemcitabine.

Mechanism of action

Edotecarin inhibits the enzyme topoisomerase I through stabilization of the DNA-enzyme complex and enhanced single-strand DNA cleavage, resulting in inhibition of DNA replication and decreased tumor cell proliferation.

TargetActionsOrganism
UDNA topoisomerase 1Not AvailableHumans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Edotecarin does not form active metabolites and is not a substrate for in vitro P450-mediated metabolism.

Route of elimination
Not Available
Half life

20 to 25 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Saif MW, Diasio RB: Edotecarin: a novel topoisomerase I inhibitor. Clin Colorectal Cancer. 2005 May;5(1):27-36. [PubMed:15929804]
  2. Yamada Y, Tamura T, Yamamoto N, Shimoyama T, Ueda Y, Murakami H, Kusaba H, Kamiya Y, Saka H, Tanigawara Y, McGovren JP, Natsumeda Y: Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors. Cancer Chemother Pharmacol. 2006 Aug;58(2):173-82. Epub 2005 Nov 25. [PubMed:16308697]
  3. Vrdoljak E, Boban M, Saratlija-Novakovic Z, Jovic J: Long-lasting partial regression of glioblastoma multiforme achieved by edotecarin: case report. Croat Med J. 2006 Apr;47(2):305-9. [PubMed:16625697]
  4. Ciomei M, Croci V, Ciavolella A, Ballinari D, Pesenti E: Antitumor efficacy of edotecarin as a single agent and in combination with chemotherapy agents in a xenograft model. Clin Cancer Res. 2006 May 1;12(9):2856-61. [PubMed:16675581]
  5. Hurwitz HI, Cohen RB, McGovren JP, Hirawat S, Petros WP, Natsumeda Y, Yoshinari T: A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2007 Jan;59(1):139-47. Epub 2006 Jul 4. [PubMed:16819636]
  6. Ciomei M, Croci V, Stellari F, Amboldi N, Giavarini R, Pesenti E: Antitumor activity of edotecarin in breast carcinoma models. Cancer Chemother Pharmacol. 2007 Jul;60(2):229-35. Epub 2006 Nov 7. [PubMed:17089166]
External Links
KEGG Drug
D03954
PubChem Compound
9808998
PubChem Substance
175426885
ChemSpider
7984757
BindingDB
50086570
ChEMBL
CHEMBL435191

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentEsophageal Cancers / Malignant Neoplasm of Stomach / Unspecified Adult Solid Tumor, Protocol Specific1
2CompletedTreatmentCancer, Breast1
2CompletedTreatmentNeoplasms Metastasis / Neoplasms, Breast1
2CompletedTreatmentStomach Neoplasms1
3CompletedTreatmentGlioblastomas1

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 Solubility1.58 mg/mLALOGPS
logP-0.11ALOGPS
logP-1.3ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)8.82ChemAxon
pKa (Strongest Basic)2.44ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count10ChemAxon
Polar Surface Area241.2 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity161.73 m3·mol-1ChemAxon
Polarizability61.93 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8545
Blood Brain Barrier-0.5252
Caco-2 permeable-0.7519
P-glycoprotein substrateSubstrate0.5195
P-glycoprotein inhibitor INon-inhibitor0.9127
P-glycoprotein inhibitor IINon-inhibitor0.9314
Renal organic cation transporterNon-inhibitor0.9176
CYP450 2C9 substrateNon-substrate0.8461
CYP450 2D6 substrateNon-substrate0.8426
CYP450 3A4 substrateSubstrate0.5352
CYP450 1A2 substrateNon-inhibitor0.8865
CYP450 2C9 inhibitorNon-inhibitor0.7748
CYP450 2D6 inhibitorNon-inhibitor0.873
CYP450 2C19 inhibitorNon-inhibitor0.893
CYP450 3A4 inhibitorNon-inhibitor0.8458
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7723
Ames testNon AMES toxic0.5481
CarcinogenicityNon-carcinogens0.7828
BiodegradationNot ready biodegradable0.9945
Rat acute toxicity2.2674 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9487
hERG inhibition (predictor II)Non-inhibitor0.5871
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 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 indolocarbazoles. These are polycyclic aromatic compounds containing an indole fused to a carbazole.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Carbazoles
Direct Parent
Indolocarbazoles
Alternative Parents
Pyrrolo[2,3-a]carbazoles / Pyrroloindoles / Glycosylamines / Phthalimides / Hydroxyindoles / N-alkylindoles / Indoles / 1-hydroxy-2-unsubstituted benzenoids / Monosaccharides / Substituted pyrroles
show 12 more
Substituents
Indolocarbazole / Pyrrolo[2,3-a]carbazole / Pyrroloindole / Glycosyl compound / Phthalimide / N-glycosyl compound / Isoindolone / N-alkylindole / Hydroxyindole / Indole
show 25 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. DNA topoisomerase 1
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
References
  1. Carvajal RD, Ilson DH, Noy A: Possible role of edotecarin, a novel topoisomerase I inhibitor, in therapy-related myelodysplastic syndrome. Leuk Lymphoma. 2007 Jan;48(1):192-4. [PubMed:17325867]
  2. Saif MW, Diasio RB: Edotecarin: a novel topoisomerase I inhibitor. Clin Colorectal Cancer. 2005 May;5(1):27-36. [PubMed:15929804]

Drug created on October 21, 2007 05:15 / Updated on June 04, 2019 06:13