TRIFLURIDINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H11F3N2O5
Molecular Weight	296.1999
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC[C@H]1O[C@H](C[C@@H]1O)N2C=C(C(=O)NC2=O)C(F)(F)F

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

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 247 Target ID: CHEMBL2366042 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3a14d86-0ff2-4535-318c-ac8bc8ede42c	Inhibitor 8228

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 8360	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
Therapeutic response of herpes simplex virus-induced corneal edema to trifluridine in combination with immunosuppressive agents.	1991 Aug	1907950
Interventions for herpes simplex virus epithelial keratitis.	2001	11279774
Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections.	2001 Apr	11292644
Antiviral drugs: current state of the art.	2001 Aug	11418355
In vitro effects of antiviral agents on human keratocytes.	2001 Jan	11189008
Effects of topical unoprostone and latanoprost on acute and recurrent herpetic keratitis in the rabbit.	2001 May	11336941
Interventions for herpes simplex virus epithelial keratitis.	2003	12917935
Management of acyclovir-resistant herpes simplex virus.	2003 Apr	12757254
In vitro activity of potential anti-poxvirus agents.	2003 Jan	12615301
Recurrence of keratitis after excimer laser keratectomy.	2003 Jan	12551688
The effect of roscovitine on herpetic keratitis.	2003 Jun	12742350
Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity.	2003 Mar 24	12644837
[Trifluridine therapy in herpetic in keratitis].	2004 Apr-Jun	15688823
Management of ophthalmic zoster mucous plaque keratopathy: report of three cases.	2004 Feb	15040618
An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA.	2004 Feb	14719131
Ocular vaccinia following exposure to a smallpox vaccinee.	2004 Mar	15013881
New onset of herpes simplex virus epithelial keratitis after penetrating keratoplasty.	2004 Mar	15013862
The effect of fluoropyrimidines with or without thymidine phosphorylase inhibitor on the expression of thymidine phosphorylase.	2004 May 3	15140625
Ocular complications in the Department of Defense Smallpox Vaccination Program.	2004 Nov	15522376
Association between ocular herpes simplex virus and topical ocular hypotensive therapy.	2004 Oct	15354072
Herpes simplex keratitis misdiagnosed as rheumatoid arthritis-related peripheral ulcerative keratitis.	2005 Nov	16227854
Corneal ulceration associated with naturally occurring canine herpesvirus-1 infection in two adult dogs.	2006 Aug 1	16881829
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
Evidence-based treatment of herpes simplex virus keratitis: a systematic review.	2007 Jul	17660897
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

Name

Type

Language

TRIFLURIDINE

Official Name

English

TRIFLURIDINE [USAN]

Common Name

English

F3DTHD

Common Name

English

TRIFLURIDINE [USP-RS]

Common Name

English

TRIFLURIDINE [JAN]

Common Name

English

5-TRIFLUOROMETHYL-2'-DEOXYURIDINE

Systematic Name

English

TRIFLURIDINE [EP MONOGRAPH]

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

S-95005 COMPONENT TRIFLURIDINE

Common Name

English

NSC-75520

Code

English

TRIFLURIDINE [MART.]

Common Name

English

NSC-529182

Code

English

F3T

Common Name

English

Trifluridine [WHO-DD]

Common Name

English

VIROPTIC

Brand Name

English

TAS-102 COMPONENT TRIFLURIDINE

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175595