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 7728		0.74 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 569 Sources: http://adisinsight.springer.com/drugs/800046928	Primary		Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
MDR1, MRP1 and MRP2 genotypes and in vitro chemosensitivity in Japanese patients with colorectal adenocarcinomas.	2004	16107775
Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38.	2004 Dec	15592324
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
A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital.	2004 Nov	15536463
Laminin-5 offsets the efficacy of gefitinib ('Iressa') in hepatocellular carcinoma cells.	2004 Nov 29	15545972
Establishment of a 7-ethyl-10-hydroxy-camptothecin-resistant small cell lung cancer cell line.	2004 Nov-Dec	15736431
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
Enhanced therapeutic efficacy of a novel liposome-based formulation of SN-38 against human tumor models in SCID mice.	2004 Sep	15494639
Gefitinib reverses breast cancer resistance protein-mediated drug resistance.	2004 Sep	15367706
The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons.	2005 Apr 8	15699047
Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics.	2005 Aug	16108826
pH-dependent association of SN-38 with lipid bilayers of a novel liposomal formulation.	2005 Aug 11	15996839
Differential UGT1A1 induction by chrysin in primary human hepatocytes and HepG2 Cells.	2005 Dec	16135700
SW-620 cells treated with topoisomerase I inhibitor SN-38: gene expression profiling.	2005 Dec 23	16375766
Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines.	2005 Feb 28	15700035
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).	2005 Feb 7	15664753
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
Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms.	2005 Mar	15608127
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
Secretory transport of irinotecan metabolite SN-38 across isolated intestinal tissue.	2005 May	15711827
Uptake of irinotecan metabolite SN-38 by the human intestinal cell line Caco-2.	2005 May	15565324
Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan.	2005 Nov 1	16278402
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
The novel UGT1A9 intronic I399 polymorphism appears as a predictor of 7-ethyl-10-hydroxycamptothecin glucuronidation levels in the liver.	2006 Jul	16595709
Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction.	2006 Jun 15	16778106
Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer.	2006 Mar	16542215
Re: Yin MB, Li Z-R, Cao S, Durrani FA, Azrak RG, Frank C, and Rustum YM (2004) Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonin-68 and down-regulation of Cdc6 expression. Mol Pharmacol 66:153-160.	2006 Mar	16535772
Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer.	2006 Mar 15	16551870
Functional SNPs of the breast cancer resistance protein-therapeutic effects and inhibitor development.	2006 Mar 8	16303243
HPLC method for determination of SN-38 content and SN-38 entrapment efficiency in a novel liposome-based formulation, LE-SN38.	2006 May 3	16386867
Radiosensitizers in cervical cancer. Cisplatin and beyond.	2006 May 8	16722549
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
Effects of green tea compounds on irinotecan metabolism.	2007 Feb	17108060
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
The contribution of intestinal UDP-glucuronosyltransferases in modulating 7-ethyl-10-hydroxy-camptothecin (SN-38)-induced gastrointestinal toxicity in rats.	2007 Jan	17003228
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 Vivo Use Guide

Unknown

Route of Administration: Unknown

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