7-ETHYL-10-HYDROXYCAMPTOTHECIN

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H20N2O5
Molecular Weight	392.4054
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of 7-ETHYL-10-HYDROXYCAMPTOTHECIN

Structure Search

SMILES

CCc1c2cc(ccc2nc-3c1Cn4c3cc5c(COC(=O)[C@@]5(CC)O)c4=O)O

InChI

InChIKey=FJHBVJOVLFPMQE-QFIPXVFZSA-N

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

HIDE SMILES / InChI

Molecular Formula	C22H20N2O5
Molecular Weight	392.4054
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23928356 | https://www.ncbi.nlm.nih.gov/pubmed/27108266
Curator's Comment:: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/1651156

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. SN38 is formed via hydrolysis of irinotecan by carboxylesterases and metabolized via glucuronidation by UGT1A1. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. SN38 causes the strongest inhibition of DNA topoisomerase I, followed by CPT and then CPT-11. CPT-11 dose dependently shifts the position of relaxed DNA in the direction of nicked DNA, but SN38 and CPT shows no effect on the position of relaxed DNA. SN38 dose-dependently and time-dependently inhibit DNA synthesis. Respective IC50 values of SN38, in DNA synthesis is 0.077 uM.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA topoisomerase I 54 Target ID: CHEMBL1781 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1651156	Inhibitor 7701	Cancer	0.739999999999999991 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 566 Sources: http://adisinsight.springer.com/drugs/800046928	Primary	DNA topoisomerase I	Preclinical

PubMed

Title	Date	PubMed
Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan.	2001 Jan	11156563
A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4.	2001 Nov	11602529
The role of topoisomerase I inhibitor in cisplatin-resistant ovarian cancer.	2001 Sep	11774743
Induction of biphasic DNA double strand breaks and activation of multiple repair protein complexes by DNA topoisomerase I drug 7-ethyl-10-hydroxy-camptothecin.	2002 Apr	11901212
Apoptosis induced by culturing MH134 cells in the presence of porcine skin gelatin in vitro.	2002 Aug	12396702
Synergistic effects of topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin, and irradiation in a cisplatin-resistant human small cell lung cancer cell line.	2002 Jan	11801571
Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea.	2002 Jan 1	11782376
Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins.	2002 Mar	11895891
An analytical method for irinotecan (CPT-11) and its metabolites using a high-performance liquid chromatography: parallel detection with fluorescence and mass spectrometry.	2002 May	11920947
Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer--a phase II study.	2002 May 2	11988109
Combination of 5-fluorouracil and irinotecan on modulation of thymidylate synthase and topoisomerase I expression and cell cycle regulation in human colon cancer LoVo cells: clinical relevance.	2002 Nov	12482336
Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients.	2003 Aug	12730278
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).	2003 Dec	14648604
Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, and Y486D.	2003 Jan	12485959
Mouse liver and kidney carboxylesterase (M-LK) rapidly hydrolyzes antitumor prodrug irinotecan and the N-terminal three quarter sequence determines substrate selectivity.	2003 Jan	12485949
Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies.	2003 Nov	14617791
Alleviation of side effects induced by irinotecan hydrochloride (CPT-11) in rats by intravenous infusion.	2003 Nov	12904895
Characterization of inhibitors of specific carboxylesterases: development of carboxylesterase inhibitors for translational application.	2004 Aug	15299073
Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy.	2004 Dec 1	15585636
Development and characterization of a novel liposome-based formulation of SN-38.	2004 Feb 11	14726126
Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonine-68 and down-regulation of Cdc6 expression.	2004 Jul	15213307
Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3.	2004 May	15100172
Establishment of a 7-ethyl-10-hydroxy-camptothecin-resistant small cell lung cancer cell line.	2004 Nov-Dec	15736431
Identification of the cytosolic carboxylesterase catalyzing the 5'-deoxy-5-fluorocytidine formation from capecitabine in human liver.	2004 Oct	15269188
Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX.	2004 Oct 18	15467766
A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer.	2004 Oct 18	15381932
Gefitinib reverses breast cancer resistance protein-mediated drug resistance.	2004 Sep	15367706
ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition.	2004 Sep 1	15355921
SW-620 cells treated with topoisomerase I inhibitor SN-38: gene expression profiling.	2005 Dec 23	16375766
Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2.	2005 Jan 15	15695404
Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation.	2005 Jan-Feb	15816556
Differential rates of glucuronidation for 7-ethyl-10-hydroxy-camptothecin (SN-38) lactone and carboxylate in human and rat microsomes and recombinant UDP-glucuronosyltransferase isoforms.	2005 Jul	15833930
In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.	2005 Jun	15956246
The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action.	2005 Jun	15772291
Synthesis and antitumor activity of A-ring modified hexacyclic analogues of camptothecin.	2005 Mar	15952596
Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American.	2005 Mar	15572581
A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours.	2005 Mar 14	15756252
Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells.	2005 Mar 15	15788689
Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors.	2005 May	15897249
Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms.	2006 Apr	16597364
Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer.	2006 Dec 18	17133266
A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients.	2006 May 8	16622455
The thermodynamic dissociation constants of the anticancer drugs camptothecine, 7-ethyl-10-hydroxycamptothecine, 10-hydroxycamptothecine and 7-ethylcamptothecine by the least-squares nonlinear regression of multiwavelength spectrophotometric pH-titration data.	2007 Feb 19	17386633
Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial.	2007 Jan 15	17164761
Crystal structure of the Geobacillus stearothermophilus carboxylesterase Est55 and its activation of prodrug CPT-11.	2007 Mar 16	17239398
Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer.	2007 May 15	17510416
A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer.	2007 May 21	17473829
Involvement of up-regulation of hepatic breast cancer resistance protein in decreased plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38) by coadministration of S-1 in rats.	2007 Sep	17537871

Patents

Sample Use Guides

In Vitro Use Guide

Relaxation of SV40 DNA plasmids by type I DNA topoisomerase prepared from P388 murine leukemia cells was inhibited by 50% by SN-38 at approximately 1 uM of 7-ethyl-10-hydroxy camptothecin

Substance Class	Chemical Created by `admin` on `Fri Jun 25 21:42:14 UTC 2021` Edited by `admin` on `Fri Jun 25 21:42:14 UTC 2021`
Record UNII	0H43101T0J
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

7-ETHYL-10-HYDROXYCAMPTOTHECIN

Common Name

English

1H-PYRANO(3',4':6,7)INDOLIZINO(1,2-B)QUINOLINE-3,14(4H,12H)-DIONE, 4,11-DIETHYL-4,9-DIHYDROXY-, (4S)-

Systematic Name

English

IRINOTECAN RELATED COMPOUND B [USP-RS]

Common Name

English

SN-38

Code

English

SN 38 [WHO-DD]

Common Name

English

S-(+)-7-ETHYL-10-HYDROXYCAMPOTHECIN

Common Name

English

SN 38

Code

English

NK012

Code

English

NK-012

Code

English

CAMPTOTHECIN, 7-ETHYL-10-HYDROXY-

Common Name

English

IRINOTECAN RELATED COMPOUND B

Common Name

English

NK 012

Code

English

IT-141

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

513715