TETRAHYDROURIDINE

Investigational

Details

Stereochemistry	EPIMERIC
Molecular Formula	C9H16N2O6
Molecular Weight	248.2331
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N2CCC(O)NC2=O

InChI

InChIKey=UCKYOOZPSJFJIZ-XVKVHKPRSA-N

InChI=1S/C9H16N2O6/c12-3-4-6(14)7(15)8(17-4)11-2-1-5(13)10-9(11)16/h4-8,12-15H,1-3H2,(H,10,16)/t4-,5?,6-,7-,8-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28880867
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT03233724 | https://www.ncbi.nlm.nih.gov/pubmed/24520856 | https://clinicaltrials.gov/ct2/show/NCT02839694 | https://www.ncbi.nlm.nih.gov/pubmed/25567350 | https://www.ncbi.nlm.nih.gov/pubmed/26518542

Tetrahydrouridine is a potent competitive reversible inhibitor of cytidine deaminase. Tetrahydrouridine can inhibit cell proliferation by regulation of the cell cycle independent of cytidine deaminase (CDA) expression levels. Tetrahydrouridine may be useful for researching potential treatments for high CDA-expressing tumors. Tetrahydrouridine use, alone or in combination with the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine, is being evaluated in animal models and clinical trials for diseases, including cancer and mitochondrial DNA depletion syndrome.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cytidine deaminase 5 Target ID: CHEMBL4502 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24520856	Inhibitor 8297		0.34 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT03233724	Primary	Phase II 1132	Unknown Approved Use Unknown
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT02839694	Primary	Phase I 428	Unknown Approved Use Unknown
Sickle cell disease 3 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28880867	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
29.9 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Macaca fascicularis population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1428 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	1750 mg/m² single, oral dose: 1750 mg/m² route of administration: Oral experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
16452 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	350 mg/m² single, intravenous dose: 350 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7.31 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	500 mg/kg single, oral dose: 500 mg/kg route of administration: Oral experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Macaca fascicularis population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
8969 mg × min/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Macaca fascicularis population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1606 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	1750 mg/m² single, oral dose: 1750 mg/m² route of administration: Oral experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7969 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	350 mg/m² single, intravenous dose: 350 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4017 mg × min/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	500 mg/kg single, oral dose: 500 mg/kg route of administration: Oral experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Macaca fascicularis population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.85 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Macaca fascicularis population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.99 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26321472	500 mg/kg single, oral dose: 500 mg/kg route of administration: Oral experiment type: SINGLE co-administered: 5-FLUORO-2'-DEOXYCYTIDINE5-FLUORO-2'-DEOXYCYTIDINE	5-FLUORO-2'-DEOXYCYTIDINE5-FLUORO-2'-DEOXYCYTIDINE	TETRAHYDROURIDINE plasma	Macaca fascicularis population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA0038TU	https://www.aablocks.com/goods/Goods/detail?id=AA0038TU
Aaron Chemicals	AR0039LM	http://www.aaronchem.com/18771-50-1
Achemtek	0102-013862	http://www.achemtek.com/18771-50-1
Ambeed	A549104	https://www.ambeed.com/products/18771-50-1.html
Angene	AGN-PC-0WH4BZ	http://www.angenechemical.com/productshow/AGN-PC-0WH4BZ.html
BLD Pharm	BD601005	http://www.bldpharm.com/products/18771-50-1.html
BOC Sciences	18771-50-1	https://www.bocsci.com/tetrahydrouridine-cas-18771-50-1-item-61747.html
BioChemPartner	BCP31863	http://www.biochempartner.com/18771-50-1-BCP31863
BioSynth	J-012078	https://www.biosynth.com/en/products/all-products/products/J-012078.html
ChemMol	99117211	http://www.chemmol.com/chemmol/99117211.html
Chemspace	CSSB00102580075	https://chem-space.com/CSSB00102580075
Clearsynth	CS-O-05908	https://www.clearsynth.com/en/CSO05908.html
DC Chemicals	DC31388	http://www.dcchemicals.com//product_show-Tetrahydrouridine.html
EMD Biosciences	584222	http://www.emdbiosciences.com/products/EMD_BIO-584222
EMD Millipore	584222	http://www.emdbiosciences.com/products/EMD_BIO-584222
Lab Network	LN01331037	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01331037
MolPort	MolPort-044-561-340	https://www.molport.com/shop/molecule-link/MolPort-044-561-340
MuseChem	R021023	https://www.musechem.com/product/R021023.html
Smolecule	S545040	http://www.smolecule.com/products/s545040
THE BioTek	bt-284038	https://www.thebiotek.com/product/inhibitors/bt-284038
eNovation Chemicals	D395048	https://www.enovationchem.com/ProductDetails.asp?ProductID=D395048

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

Tetrahydrouridine 10 mg/kg was administered 60 minutes before oral decitabine at 0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg. Repeat dose administration 2X/week for 8 weeks

Route of Administration: Oral

In Vitro Use Guide

Panc-1, MIAPaCa-2, BxPC-3, H322, H441, and H1299 cells were seeded in 96-well plates at 2,500-5,000 cells/well in triplicate. After incubating for 12 hrs, cell viability was determined by treating cells with stepwise 4-fold serial dilutions of gemcitabine (from 100 mkM), and incubating at 37uC for 96 hrs with or without Tetrahydrouridine (THU). To evaluate cell viability, all cells were fixed with 25% glutaraldehyde for 30 min at room temperature and then stained with 200 mkl of 0.05% methylene blue for 20 min. The dye was eluted with 0.33 M HCl for 20 min with agitation. Absorbance was measured in a microplate reader (model 3550, Bio-Rad, Tokyo, Japan) at 598 nm.

Name

Type

Language

TETRAHYDROURIDINE

Common Name

English

2(1H)-PYRIMIDINONE, TETRAHYDRO-4-HYDROXY-1-.BETA.-D-RIBOFURANOSYL-

Systematic Name

English

URIDINE, 3,4,5,6-TETRAHYDRO-

Systematic Name

English

3,4,5,6-TETRAHYDROURIDINE

Systematic Name

English

NSC-112907

Code

English

U-23284

Code

English

1-(.BETA.-D-RIBOFURANOSYL)-4-HYDROXYTETRAHYDRO-1(1H)-PYRIMIDINONE

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

555916