TRIFLURIDINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H11F3N2O5
Molecular Weight	296.2003
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C1[C@@]([H])([C@@]([H])(CO)O[C@@]1([H])n2cc(c(nc2=O)O)C(F)(F)F)O

InChI

InChIKey=VSQQQLOSPVPRAZ-RRKCRQDMSA-N

InChI=1S/C10H11F3N2O5/c11-10(12,13)4-2-15(9(19)14-8(4)18)7-1-5(17)6(3-16)20-7/h2,5-7,16-17H,1,3H2,(H,14,18,19)/t5-,6+,7+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C10H11F3N2O5
Molecular Weight	296.2003
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3a14d86-0ff2-4535-318c-ac8bc8ede42c
Curator's Comment:: description was created based on several sources, including: http://www.drugbank.ca/drugs/DB00432 http://www.drugs.com/pro/trifluridine.html

Trifluridine (also called trifluorothymidine or TFT) is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name, Viroptic, by Glaxo Wellcome, now merged into GlaxoSmithKline. It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the -CF3 group added to the uracil component blocks base pairing, thus interfering with DNA replication. It is a component of the experimental anti-cancer drug TAS-102. Trifluridine is a fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2 and vaccinia virus. Some strains of adenovirus are also inhibited in vitro. VIROPTIC is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, VIROPTIC was also effective. The mechanism of action of trifluridine has not been fully determined, but appears to involve the inhibition of viral replication. Trifluridine does this by incorporating into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 232 Target ID: CHEMBL2366042 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3a14d86-0ff2-4535-318c-ac8bc8ede42c	Inhibitor 7728

Conditions

Condition	Modality	Targets	Highest Phase	Product
Keratoconjunctivitis 7 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3a14d86-0ff2-4535-318c-ac8bc8ede42c	Curative		Approved 8043	VIROPTIC Approved Use Unknown Launch Date 3.39465601E11

C_max

Value	Dose	Co-administered	Analyte	Population
2155 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28111727	35 mg/m² single, oral dose: 35 mg/m² route of administration: Oral experiment type: SINGLE co-administered: TIPIRACIL	TIPIRACIL	TRIFLURIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
96 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28111727	35 mg/m² single, oral dose: 35 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		TRIFLURIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT

AUC

Value	Dose	Co-administered	Analyte	Population
6694 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28111727	35 mg/m² single, oral dose: 35 mg/m² route of administration: Oral experiment type: SINGLE co-administered: TIPIRACIL	TIPIRACIL	TRIFLURIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
248 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28111727	35 mg/m² single, oral dose: 35 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		TRIFLURIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT

F_unbound

Value	Dose	Co-administered	Analyte	Population
6% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207981s008lbl.pdf			TRIFLURIDINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
35 mg/m2 2 times / day multiple, oral MTD Dose: 35 mg/m2, 2 times / day Route: oral Route: multiple Dose: 35 mg/m2, 2 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/22735906 Page: p.431, 432	unhealthy, 59 n = 3 Health Status: unhealthy Condition: Cancer Age Group: 59 Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/22735906 Page: p.431, 432	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 4, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/22735906 Page: p.431, 432
80 mg/m2 3 times / day multiple, oral (total daily dose) Highest studied dose Dose: 80 mg/m2, 3 times / day Route: oral Route: multiple Dose: 80 mg/m2, 3 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	unhealthy, 60 n = 6 Health Status: unhealthy Condition: Cancer Age Group: 60 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	DLT: Granulocytopenia, Fatigue... Dose limiting toxicities: Granulocytopenia (grade 4, 33.3%) Fatigue (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797
70 mg/m2 3 times / day multiple, oral (total daily dose) MTD Dose: 70 mg/m2, 3 times / day Route: oral Route: multiple Dose: 70 mg/m2, 3 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	unhealthy, 60 n = 6 Health Status: unhealthy Condition: Cancer Age Group: 60 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	Other AEs: Granulocytopenia... Other AEs: Granulocytopenia (grade 4, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797

AEs

AE	Significance	Dose	Population
Neutropenia	grade 4, 33.3% DLT	35 mg/m2 2 times / day multiple, oral MTD Dose: 35 mg/m2, 2 times / day Route: oral Route: multiple Dose: 35 mg/m2, 2 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/22735906 Page: p.431, 432	unhealthy, 59 n = 3 Health Status: unhealthy Condition: Cancer Age Group: 59 Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/22735906 Page: p.431, 432
Fatigue	grade 3, 33.3% DLT	80 mg/m2 3 times / day multiple, oral (total daily dose) Highest studied dose Dose: 80 mg/m2, 3 times / day Route: oral Route: multiple Dose: 80 mg/m2, 3 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	unhealthy, 60 n = 6 Health Status: unhealthy Condition: Cancer Age Group: 60 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797
Granulocytopenia	grade 4, 33.3% DLT	80 mg/m2 3 times / day multiple, oral (total daily dose) Highest studied dose Dose: 80 mg/m2, 3 times / day Route: oral Route: multiple Dose: 80 mg/m2, 3 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	unhealthy, 60 n = 6 Health Status: unhealthy Condition: Cancer Age Group: 60 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797
Granulocytopenia	grade 4, 16.7%	70 mg/m2 3 times / day multiple, oral (total daily dose) MTD Dose: 70 mg/m2, 3 times / day Route: oral Route: multiple Dose: 70 mg/m2, 3 times / day Co-administed with:: thymidine phosphorylase, p.o Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797	unhealthy, 60 n = 6 Health Status: unhealthy Condition: Cancer Age Group: 60 Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/18798063 Page: p.797

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:75179	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75179
MolPort	MolPort-003-959-693	https://www.molport.com/shop/molecule-link/MolPort-003-959-693
Selleck Chemicals	Trifluridine(Viroptic)	http://www.selleckchem.com/products/Trifluridine(Viroptic).html
ZINC	ZINC000003842753	http://zinc15.docking.org/substances/ZINC000003842753
eMolecules	1971040	https://www.emolecules.com/cgi-bin/more?vid=1971040
eMolecules	594732	https://www.emolecules.com/cgi-bin/more?vid=594732

PubMed

Title	Date	PubMed
Improved synthesis and in vitro antiviral activities of 5-cyanouridine and 5-cyano-2'-deoxyuridine.	1977 Jul	195058
Therapeutic response of herpes simplex virus-induced corneal edema to trifluridine in combination with immunosuppressive agents.	1991 Aug	1907950
Intracellular immunity to HIV-1: newly defined retroviral battles inside infected cells.	2005 Apr 13	15829012
Potentiation of the antitumor activity of alpha, alpha, alpha-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo.	2005 Aug	16010427
Efficacy of topical aciclovir for the treatment of feline herpetic keratitis: results of a prospective clinical trial and data from in vitro investigations.	2005 Aug 27	16127135
Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations.	2005 Dec	16386088
Herpes simplex keratitis misdiagnosed as rheumatoid arthritis-related peripheral ulcerative keratitis.	2005 Nov	16227854
Viral infections affecting the skin in organ transplant recipients: epidemiology and current management strategies.	2006	16489840
In vitro comparison of antiviral drugs against feline herpesvirus 1.	2006 Apr 26	16640781
American Society of Clinical Oncology--42nd annual meeting. Poster presentations on leukemia and cytotoxic chemotherapy. 2-6 June 2006, Atlanta, GA, USA.	2006 Aug	16871453
Corneal ulceration associated with naturally occurring canine herpesvirus-1 infection in two adult dogs.	2006 Aug 1	16881829
Imiquimod 5% cream for the treatment of recurrent, acyclovir-resistant genital herpes.	2006 Feb 15	16421805
3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods.	2006 Feb 15	16290929
Ocular vaccinia infection in laboratory worker, Philadelphia, 2004.	2006 Jan	16494730
Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells.	2006 Jan	16010590
Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors.	2006 Sep 15	16902987
Microarray analysis distinguishes differential gene expression patterns from large and small colony Thymidine kinase mutants of L5178Y mouse lymphoma cells.	2006 Sep 6	17118152
Collisionally-induced dissociation of substituted pyrimidine antiviral agents: mechanisms of ion formation using gas phase hydrogen/deuterium exchange and electrospray ionization tandem mass spectrometry.	2007 Aug	17583534
Ganciclovir ophthalmic gel, 0.15%: a valuable tool for treating ocular herpes.	2007 Dec	19668521
Dendritic keratitis caused by an acyclovir-resistant herpes simplex virus with frameshift mutation.	2007 Jan	17198024
Irinotecan-induced cytotoxicity to colon cancer cells in vitro is stimulated by pre-incubation with trifluorothymidine.	2007 Jan	17049227
A method to distinguish between the de novo induction of thymidine kinase mutants and the selection of pre-existing thymidine kinase mutants in the mouse lymphoma assay.	2007 Jan 10	17055776
The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells.	2007 Jan 15	17179993
Therapeutic interventions for herpes simplex virus epithelial keratitis.	2007 Jan 24	17253484
Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells.	2007 Jan 29	17242697
Evidence-based treatment of herpes simplex virus keratitis: a systematic review.	2007 Jul	17660897
Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies.	2007 Jun	17441963
High level glucose increases mutagenesis in human lymphoblastoid cells.	2007 Sep 4	17848982
Collision induced dissociation studies of alkali metal adducts of tetracyclines and antiviral agents by electrospray ionization, hydrogen/deuterium exchange and multiple stage mass spectrometry.	2008	19023146
Progressive hypertrophic genital herpes in an HIV-infected woman despite immune recovery on antiretroviral therapy.	2008	18784844
Novel cell death mechanisms of trifluorothymidine.	2008	18776547
[18F]FDG and [18F]FLT uptake in human breast cancer cells in relation to the effects of chemotherapy: an in vitro study.	2008 Aug 5	18665170
Efficacy of a helicase-primase inhibitor in animal models of ocular herpes simplex virus type 1 infection.	2008 Feb	18201137
Is herpes simplex virus keratitis a different disease in children?	2008 Jan	18045258
Therapeutic interventions for herpes simplex virus epithelial keratitis.	2008 Jan 23	18254009
Ocular pharmacokinetics of acyclovir amino acid ester prodrugs in the anterior chamber: evaluation of their utility in treating ocular HSV infections.	2008 Jul 9	18472234
Trifluorothymidine induces cell death independently of p53.	2008 Jun	18600528
Synergistic interaction between trifluorothymidine and docetaxel is sequence dependent.	2008 Nov	18957056
Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors.	2008 Oct	18798063
Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.	2008 Oct	18528634
Effective treatment of ocular HSK with a human apolipoprotein E mimetic peptide in a mouse eye model.	2008 Oct	18515564
Synthesis of nucleoside-based antiviral drugs in ionic liquids.	2008 Oct 15	18796352
A human apolipoprotein E mimetic peptide effectively inhibits HSV-1 TK-positive and TK-negative acute epithelial keratitis in rabbits.	2009 Feb	19219680
Slitlamp biomicroscopy and photographic image analysis of herpes simplex virus stromal keratitis.	2009 Feb	19204233
Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2.	2010 Apr	20371715
Cellular and molecular mechanisms for the synergistic cytotoxicity elicited by oxaliplatin and pemetrexed in colon cancer cell lines.	2010 Aug	20020129
Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines.	2010 Feb	19886911
Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer.	2010 May	20372850
Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells.	2010 May 15	19816940
Prodrug activation by Cryptosporidium thymidine kinase.	2010 May 21	20231284

Patents

Sample Use Guides

In Vivo Use Guide

Instill one drop of VIROPTIC Ophthalmic Solution, 1% onto the cornea of the affected eye every 2 hours while awake for a maximum daily dosage of nine drops until the corneal ulcer has completely re-epithelialized

Route of Administration: Other

In Vitro Use Guide

HeLa cells were treated with Trifluridine (TFT) at a concentration of 1 µM (IC50 value), the concentration of TFT in the DNA was calculated as 62.2±0.9 pmol/1x106 cells for 4 h. Greater degree of incorporation of TFT into the DNA than that of 5FU or FdUrd, and that such a high degree of incorporation of TFT residues into the DNA might be related to exhibit potent cytotoxic activity to be refractory to cleavage by these DNA glycosylases; thus, the DNA-directed cytotoxic effect of the compound is quite different from that of 5FU

Substance Class	Chemical Created by `admin` on `Fri Jun 25 20:58:50 UTC 2021` Edited by `admin` on `Fri Jun 25 20:58:50 UTC 2021`
Record UNII	RMW9V5RW38
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TRIFLURIDINE

Official Name

English

TRIFLURIDINE [USAN]

Common Name

English

F3DTHD

Common Name

English

TRIFLURIDINE [USP-RS]

Common Name

English

5-TRIFLUOROMETHYL-2'-DEOXYURIDINE

Systematic Name

English

TRIFLURIDINE [EP MONOGRAPH]

Common Name

English

TRIFLURIDINE [WHO-DD]

Common Name

English

TRIFLURIDINE [ORANGE BOOK]

Common Name

English

TRIFLURIDINE [USP MONOGRAPH]

Common Name

English

TRIFLURIDINE [MI]

Common Name

English

TRIFLUOROTHYMIDINE

Systematic Name

English

TRIFLUOROMETHYLDEOXYURIDINE

Systematic Name

English

TRIFLURIDINE [INN]

Common Name

English

2'-DEOXY-5-(TRIFLUOROMETHYL)URIDINE

Systematic Name

English

THYMIDINE, .ALPHA.,.ALPHA.,.ALPHA.-TRIFLUORO-

Systematic Name

English

TRIFLURIDINE [VANDF]

Common Name

English

TRIFLURIDINE COMPONENT OF LONSURF

Brand Name

English

NSC-75520

Code

English

TRIFLURIDINE [MART.]

Common Name

English

NSC-529182

Code

English

F3T

Common Name

English

VIROPTIC

Brand Name

English

Classification Tree Code System Code

NDF-RT

N0000175595