ECHINOMYCIN

Investigational

Details

Stereochemistry	UNKNOWN
Molecular Formula	C51H64N12O12S2
Molecular Weight	1101.257
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 9
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CSC1SC[C@@H]2N(C)C(=O)[C@H](C)NC(=O)[C@@H](COC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]1N(C)C(=O)[C@H](C)NC(=O)[C@@H](COC(=O)[C@H](C(C)C)N(C)C2=O)NC(=O)C3=CN=C4C=CC=CC4=N3)NC(=O)C5=CN=C6C=CC=CC6=N5

InChI

InChIKey=AUJXLBOHYWTPFV-VITLIGDRSA-N

InChI=1S/C51H64N12O12S2/c1-25(2)38-49(72)74-22-36(59-42(65)34-21-53-30-17-13-15-19-32(30)57-34)44(67)55-28(6)46(69)63(10)40-48(71)62(9)39(26(3)4)50(73)75-23-35(58-41(64)33-20-52-29-16-12-14-18-31(29)56-33)43(66)54-27(5)45(68)60(7)37(47(70)61(38)8)24-77-51(40)76-11/h12-21,25-28,35-40,51H,22-24H2,1-11H3,(H,54,66)(H,55,67)(H,58,64)(H,59,65)/t27-,28-,35+,36+,37-,38-,39-,40+,51?/m0/s1

HIDE SMILES / InChI

Description
Sources: DOI: 10.1007/s13273-017-0025-6 | https://www.ncbi.nlm.nih.gov/pubmed/6089341 | https://www.ncbi.nlm.nih.gov/pubmed/16204079 | https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=39587

Echinomycin is a cyclic peptide of the family of quinoxaline antibiotics that was originally isolated from Streptomyces echinatus. It is thought to act as a bifunctional DNA intercalator. Echinomycin has a binding site size of four base pairs. The strong binding sites for echinomycin contain the central two-base-pair sequence 5'-CG-3'. Echinomycin interferes with HIF-1 DNA binding in a sequence-specific fashion. It was brought into clinical trials by the NCI 20 years ago based on its antitumor activity. It has been extensively tested in phase I-II clinical trials. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. However, minimal or no antitumor activity was found in phase II clinical trials.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hypoxia-inducible factor 1 alpha 17 Target ID: CHEMBL4261 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16204079	Inhibitor 8504
Aryl hydrocarbon receptor nuclear translocator 1 Target ID: CHEMBL5618 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16204079	Inhibitor 8504
DNA 282 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6089341	Binding Agent 1076

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 211 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9445185	Primary	Phase II 1147	Unknown Approved Use Unknown
Sarcoma 14 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8617582	Primary	Phase II 1147	Unknown Approved Use Unknown
Renal cell carcinoma 33 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7860234 https://www.ncbi.nlm.nih.gov/pubmed/8262733 http://adisinsight.springer.com/drugs/800004274	Primary	Phase II 1147	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
GLUT1 20	supressor 160 Sources: https://www.sciencedirect.com/science/article/pii/S2405844020308306	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY557633	https://www.001chemical.com/chem/512-64-1
AA Blocks	AA00D7U8	https://www.aablocks.com/goods/Goods/detail?id=AA00D7U8
abcr GmbH	AB259479	http://www.abcr.com/shop/en/AB259479
AK Scientific, Inc. (AKSCI)	2677AH	http://www.aksci.com/item_detail.php?cat=2677AH
Alfa Chemistry	AP512641	https://reagents.alfa-chemistry.com/product/echinomycin-cas-512-64-1-12287.html
Ambinter	Amb16182781	http://www.ambinter.com/reference/16182781
Ambinter	Amb19930583	http://www.ambinter.com/reference/19930583
Ambinter	Amb22352704	http://www.ambinter.com/reference/22352704
Aurora Fine Chemicals LLC	A24.087.937	http://online.aurorafinechemicals.com/info?ID=A24.087.937
AvaChem Scientific	6302	https://www.avachem.com/productSearch.asp?6302
BioChemPartner	BCP23887	http://www.biochempartner.com/512-64-1-BCP23887
BOC Sciences	512-64-1	https://www.bocsci.com/quinomycin-a-cas-512-64-1-item-120819.html
Chem Scene	CS-0024860	http://www.chemscene.com/512-64-1.html
ChemMol	99097812	http://www.chemmol.com/chemmol/99097812.html
DC Chemicals	DC32277	http://www.dcchemicals.com//product_show-Echinomycin.html
eNovation Chemicals	D670246	https://www.enovationchem.com/ProductDetails.asp?ProductID=D670246
Glentham Life Sciences	GA8422	http://www.glentham.com/products/product/GA8422/
Hello Bio	HB3882	https://www.hellobio.com/echinosporin.html
iChemical	EBD541059	http://www.ichemical.com/products/512-64-1.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs
Lab Network	LN01319202	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01319202
MedChem Express	HY-106101	https://www.medchemexpress.com/echinomycin.html
Molcore	MC557633	https://www.molcore.com/product/512-64-1
MolPort	MolPort-003-933-120	https://www.molport.com/shop/molecule-link/MolPort-003-933-120
MolPort	MolPort-019-939-218	https://www.molport.com/shop/molecule-link/MolPort-019-939-218
MolPort	MolPort-046-162-822	https://www.molport.com/shop/molecule-link/MolPort-046-162-822
Nextpeptide	NP182327	http://www.nextpeptide.com/512-64-1.html
Smolecule	S526852	http://www.smolecule.com/products/s526852
Smolecule	S532977	http://www.smolecule.com/products/s532977
Smolecule	S701871	https://www.smolecule.com/products/s701871
THE BioTek	bt-267032	https://www.thebiotek.com/product/inhibitors/bt-267032
THE BioTek	bt-272650	https://www.thebiotek.com/product/inhibitors/bt-272650
Tocris	5520	https://www.tocris.com/products/echinomycin_5520

PubMed

Title	Date	PubMed
Recent developments in bisintercalator natural products.	2010-09	20578002
3-Methyl-1-(prop-2-en-1-yl)quinoxalin-2(1H)-one.	2010-06-23	21587981
Pharmacological and genetic accumulation of hypoxia-inducible factor-1alpha enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor.	2010-04-28	20427666
Capture of a Transition State Using Molecular Dynamics: Creation of an Intercalation Site in dsDNA with Ethidium Cation.	2010-03-31	20798766
Insulin induces REDD1 expression through hypoxia-inducible factor 1 activation in adipocytes.	2010-02-19	19996311
Identification of cyclooxygenase-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia: effect on angiogenesis and metastases.	2010-01-15	20068092
A ferrocene-quinoxaline derivative as a highly selective probe for colorimetric and redox sensing of toxic mercury(II) cations.	2010	22163528
Drug release from a chemically-anchored PEG/phospholipid monolayer onto polymer-coated metallic stents.	2010	20482985
Control of oocyte release by progesterone receptor-regulated gene expression.	2009-12-31	20087433
Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity.	2009-09-16	19758437
Rationally engineered total biosynthesis of a synthetic analogue of a natural quinomycin depsipeptide in Escherichia coli.	2009-08-17	19588480
Gallium (III) triflate-catalyzed synthesis of heterocycles: quinoxalines, 1,5-benzodiazepines and their fluorinated derivatives.	2009-08	21426089
Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan.	2009-08	19671732
Escherichia coli allows efficient modular incorporation of newly isolated quinomycin biosynthetic enzyme into echinomycin biosynthetic pathway for rational design and synthesis of potent antibiotic unnatural natural product.	2009-07-08	19514719
Interaction of an echinomycin-DNA complex with manganese ions.	2009-07-01	19574634
Signaling by hypoxia-inducible factors is critical for ovulation in mice.	2009-07	19325003
Automated genome mining for natural products.	2009-06-16	19531248
Antitumor compounds from marine actinomycetes.	2009-06-11	19597582
Recepteur d'origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1alpha-mediated invasion of breast carcinoma cells.	2009-05-22	19307182
Indicator-based and indicator-free magnetic assays connected with disposable electrochemical nucleic acid sensor system.	2009-04-15	19174223
Diversification of echinomycin molecular structure by way of chemoenzymatic synthesis and heterologous expression of the engineered echinomycin biosynthetic pathway.	2009-04	19278894
Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: implication in manganese-induced pulmonary inflammation.	2009-03-15	19263519
Structure-activity studies of echinomycin antibiotics against drug-resistant and biofilm-forming Staphylococcus aureus and Enterococcus faecalis.	2009-03-01	19185486
TioS T-TE--a prototypical thioesterase responsible for cyclodimerization of the quinoline- and quinoxaline-type class of chromodepsipeptides.	2009-03	19220461
Complete sequence of biosynthetic gene cluster responsible for producing triostin A and evaluation of quinomycin-type antibiotics from Streptomyces triostinicus.	2009-02-06	19194935
Hypoxia decreases insulin signaling pathways in adipocytes.	2009-01	18984735
Hypoxia-inducible factor-1alpha protects cultured cortical neurons from lipopolysaccharide-induced cell death via regulation of NR1 expression.	2008-12-24	19109507
A dialogue between the hypoxia-inducible factor and the tumor microenvironment.	2008-12	19308685
Exploring the biosynthesis of natural products and their inherent suitability for the rational design of desirable compounds through genetic engineering.	2008-10	18838806
NF-kappaB-dependency and consequent regulation of IL-8 in echinomycin-induced apoptosis of HT-29 colon cancer cells.	2008-10	18675368
Enzymatic macrolactonization in the presence of DNA leading to triostin A analogs.	2008-08-25	18721753
The effects of local DNA sequence on the interaction of ligands with their preferred binding sites.	2008-07	18226601
[Recent progress in the study on antitumor drugs targeting hypoxia-inducible factor-1].	2008-06	18822956
Selective and potent in vitro antitrypanosomal activities of ten microbial metabolites.	2008-06	18667785
Improved production of triostin A in engineered Escherichia coli with furnished quinoxaline chromophore by design of experiments in small-scale culture.	2008-01-05	18173279
In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus.	2008-01	17967852
Relative and absolute configuration of antitumor agent SW-163D.	2007-12	18071270
Dual effect of echinomycin on hypoxia-inducible factor-1 activity under normoxic and hypoxic conditions.	2007-11	17916190
[Biosynthesis of natural products from microbes].	2007-10	18051407
Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface.	2007-08-17	17708671
Probing ligand binding to duplex DNA using KMnO4 reactions and electrospray ionization tandem mass spectrometry.	2007-06-15	17508717
The short-term effects on restenosis and thrombosis of echinomycin-eluting stents topcoated with a hydrophobic heparin-containing polymer.	2007-03	17157376
Robust platform for de novo production of heterologous polyketides and nonribosomal peptides in Escherichia coli.	2007-02-21	17285165
Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies.	2007-02	17268609
Biochemistry. Directing biosynthesis.	2006-10-27	17068249
Identification and stereochemical assignment of the beta-hydroxytryptophan intermediate in the echinomycin biosynthetic pathway.	2006-10-12	17020286
Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli.	2006-08	16799553
[Echinomycin production by Actinomadura sp. INA 654].	2006	18030784
Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation.	2005-01	17191924
Interaction of DNA with echinomycin at the mercury electrode surface as detected by impedance and chronopotentiometric measurements.	2002-04-01	18968569

Patents

Sample Use Guides

In Vivo Use Guide

1200 ug/m2 over 30-60 minutes once a week for 4 weeks, repeated every 6 weeks

Route of Administration: Intravenous

In Vitro Use Guide

Echinomycin very potently inhibited hypoxic induction of luciferase expression in U251-HRE in a dose-dependent fashion with an EC50 of 1.2 nmol/L. U251-HRE cells were treated with Echinomycin at 5, 10, and 20 nmol/L for 4 hours and then washed and incubated under normoxic or hypoxic conditions for 36 hours. 94%, 80%, and 42% of hypoxiainduced luciferase expression was restored in cells in which Echinomycin was washed out after 4-hour treatment at 5, 10, and 20 nmol/L, respectively, indicating that the DNA-binding activity of Echinomycin is in fact reversible.

Name

Type

Language

ECHINOMYCIN

Common Name

English

ANTIBIOTIC A-654I

Preferred Name

English

NSC-13502

Code

English

LEVOMYCIN

Common Name

English

N-(2-QUINOXALINYLCARBONYL)-O-(N-(2-QUINOXALINYLCARBONYL)-D-SERYL-L-ALANYL-3-MERCAPTO-N,S-DIMETHYLCYSTEINYL-N-METHYL-L-VALYL)-D-SERYL-L-ALANYL-N-METHYLCYSTEINYL-N-METHYL L-VALINE (8->1)-LACTONE CYCLIC (3->7)-THIOESTER

Systematic Name

English

QUINOMYCIN A

Common Name

English

NSC-526417

Code

English

SK-302B

Code

English

ECHINOMYCIN [MI]

Common Name

English

L-VALINE, N-(2-QUINOXALINYLCARBONYL)-O-(N-(2-QUINOXALINYLCARBONYL)-D-SERYL-L-ALANYL-3-MERCAPTO-N,S-DIMETHYLCYSTEINYL-N-METHYL-L-VALYL)-D-SERYL-L-ALANYL-N-METHYLCYSTEINYL-N-METHYL-, (8->1)-LACTONE, CYCLIC (3->7)-THIOETHER

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

479815