TIAZOFURIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C9H12N2O5S
Molecular Weight	260.267
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=O)C1=CSC(=N1)[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O

InChI

InChIKey=FVRDYQYEVDDKCR-DBRKOABJSA-N

InChI=1S/C9H12N2O5S/c10-8(15)3-2-17-9(11-3)7-6(14)5(13)4(1-12)16-7/h2,4-7,12-14H,1H2,(H2,10,15)/t4-,5-,6-,7-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/1358769
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/11249583

Tiazofurin (NSC-286193; 2-beta-D-ribofuranosylthiazole-4-carboxamide) an approved chronic myeloid leukemia (CML) drug, is converted by cellular enzymes into tiazofurin adenine dinucleotide, TAD, which inhibits the enzyme as a cofactor mimic. Resistance to tiazofurin is quickly developed due to diminished ability of resistant cells to synthesize TAD and increased enzymatic degradation of TAD. It is a nucleoside analog with oncolytic activity being developed by Ribapharm (formerly ICN Pharmaceuticals) as a potential treatment for leukemia. Ribapharm, through a Russian subsidiary of ICN, is planned to conduct phase II studies of tiazofurine involving patients suffering from advanced ovarian cancer or multiple myeloma which is resistant to conventional therapy.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Inosine-5'-monophosphate dehydrogenase (IMPDH) 11 Target ID: CHEMBL2111369 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1358769	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Chronic myeloid leukemia 25 Sources: http://cdmrp.army.mil/search.aspx?LOG_NO=CM043020	Primary	Approved 8429	Unknown Approved Use Unknown
Head and neck squamous cell carcinoma 32 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3548960	Primary	Phase II 1132	Unknown Approved Use Unknown
Advanced ovarian cancer 5 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11249583	Primary	Phase II 1132	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent.	1983 Sep	6615611
Synergistic antiviral effects of ribavirin and the C-nucleoside analogs tiazofurin and selenazofurin against togaviruses, bunyaviruses, and arenaviruses.	1984 Oct	6151377
Phase I trial of tiazofurin administered by i.v. bolus daily for 5 days, with pharmacokinetic evaluation.	1987 Feb	3802111
Reversible cerebral lesions associated with tiazofurin usage: MR demonstration.	1988 Nov-Dec	3183120
Clinical toxicity associated with tiazofurin.	1990 May	2200759
Antiviral and immunomodulating inhibitors of experimentally-induced Punta Toro virus infections.	1994 Oct	7847873
Tiazofurin: molecular and clinical action.	1996 Nov-Dec	9042306
Sir Hans A. Krebs Centenary Lecture: cancer and clinical targeting.	2001	11417529
A new C-nucleoside analogue of tiazofurin: synthesis and biological evaluation of 2-beta-D-ribofuranosylimidazole-4-carboxamide (imidazofurin).	2001 Jan 8	11140736
[Application of tiazofurin in the study of regulation of AMP deaminase in intact malignant cells].	2002	16078449
The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside.	2002 Apr	11966436
Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia.	2002 Jan 31	11806722
Down-regulation of experimental allergic encephalomyelitis in DA rats by tiazofurin.	2002 Sep	12225889
Anticancer therapeutic potential of soy isoflavone, genistein.	2004	15584372
Inhibition of B16 mouse melanoma cell growth and induction of apoptotic cell death with 8-chloroadenosine-3',5'-monophosphate and tiazofurin.	2004 Dec	15659821
Differentiation of human prostate cancer PC-3 cells induced by inhibitors of inosine 5'-monophosphate dehydrogenase.	2004 Dec 15	15604271
Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part II. In vitro studies.	2004 Nov	15380336
Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part I. In vivo studies.	2004 Nov	15380335
Synthesis of 3'-deoxy-3'-C-hydroxymethyl analogues of tiazofurin and ribavirin.	2005	16248075
Down-regulation of increased signal transduction capacity in human cancer cells.	2005	16054198
Metabolism and antiviral activity of ribavirin.	2005 Feb	15649562
Sensitization of human erythroleukemia K562 cells resistant to methotrexate by inhibiting IMPDH.	2005 Jan	15614187
Role of human nucleoside transporters in the cellular uptake of two inhibitors of IMP dehydrogenase, tiazofurin and benzamide riboside.	2005 Jan	15486050
Combination of nucleoside analogues tiazofurin and ribavirin downregulates experimental autoimmune encephalomyelitis.	2005 Jun	16154960
IMP dehydrogenase from the protozoan parasite Toxoplasma gondii.	2005 Jun	15917510
Synergistic action of resveratrol, an ingredient of wine, with Ara-C and tiazofurin in HL-60 human promyelocytic leukemia cells.	2005 Mar	15730856
Zinc(II) triflate-controlled 1,3-dipolar cycloadditions of C-(2-thiazolyl)nitrones: application to the synthesis of a novel isoxazolidinyl analogue of tiazofurin.	2005 Oct 28	16238338
Efficient route to C2 symmetric heterocyclic backbone modified cyclic peptides.	2005 Sep 29	16178569
Resveratrol, an ingredient of wine, acts synergistically with Ara-C and tiazofurin in HL-60 human promyelocytic leukemia cells.	2006	17065057
Modulation of cancer pathways by inhibitors of guanylate metabolism.	2006	16857242
Metabolic regulation and chemotherapy.	2006	16814369
Synthesis and biological activity of some new 5'-O-acyl tiazofurin derivatives.	2006 Apr	16519966
Synthesis and antiproliferative activity of two new tiazofurin analogues with 2'-amido functionalities.	2006 May 15	16495053
2-(3-Amino-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide: a new tiazofurin analogue with potent antitumour activity.	2006 Oct 15	16908146
Organosilicon-containing thiazole derivatives as potential lipoxygenase inhibitors and anti-inflammatory agents.	2007	18256725
Crystal structure of human nicotinamide riboside kinase.	2007 Aug	17698003
Synthesis and antitumour activity of new tiazofurin analogues bearing a 2,3-anhydro functionality in the furanose ring.	2007 Aug 1	17543526
Recent development of IMP dehydrogenase inhibitors for the treatment of cancer.	2007 Jul	17659481
Antiviral activity of tiazofurin and mycophenolic acid against Grapevine leafroll-associated virus 3 in Vitis vinifera explants.	2007 Mar	17125850
Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.	2007 Nov 15	17958343
Nicotinamide riboside kinase structures reveal new pathways to NAD+.	2007 Oct 2	17914902
Treatment of yellow fever.	2008 Apr	18061688
Therapeutic effects of combined treatment with ribavirin and tiazofurin on experimental autoimmune encephalomyelitis development: clinical and histopathological evaluation.	2008 Apr 15	17996253
A kinetic alignment of orthologous inosine-5'-monophosphate dehydrogenases.	2008 Aug 19	18642884
Ribavirin targets eIF4E dependent Akt survival signaling.	2008 Oct 24	18706892
Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues.	2009 Aug 1	19596199
Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro.	2010 Apr 27	20424615
Overexpression of inosine 5'-monophosphate dehydrogenase type II mediates chemoresistance to human osteosarcoma cells.	2010 Aug 16	20808934
New trends in nucleoside biotechnology.	2010 Jul	22649640
A comparative profile of methanol extracts of Allium cepa and Allium sativum in diabetic neuropathy in mice.	2010 Nov	21713142

Patents

Sample Use Guides

In Vivo Use Guide

Tiazofurin was given by IV infusion (2200-2700 mg/m2 per day) for up to 10 days. Leukemia blasts rapidly disappeared from the circulation of patients during treatment, while mature myeloid cells in the marrow increased in number. Although these hematologic responses were transient, persisting less than 3-4 weeks, our findings confirm that Tiazofurin has anti-leukemia activity.

Route of Administration: Intravenous

In Vitro Use Guide

Concentration of tiazofurin required to reduce the number of cells in a culture by 50% with respect to control cultures was 0.51 uM for Lewis lung carcinoma cell lines (LLAK), 2.6 uM for in vitro cell line (LLTC), and greater than 10 uM for a range of human cancer cell lines. In cytotoxicity assays involving a 2-hour drug exposure followed by clonogenic assay, tiazofurin was more toxic to LLAK cells than to LLTC cells or L1210 murine leukemia cells, consistent with its high in vivo activity against LL. MM-96 human melanoma cells were highly resistant.

Name

Type

Language

TIAZOFURIN

Official Name

English

CI-909

Code

English

tiazofurine [INN]

Common Name

English

Tiazofurine [WHO-DD]

Common Name

English

TCAR

Common Name

English

TIAZOFURIN [USAN]

Common Name

English

TIAZOFURINE

Official Name

English

2-.BETA.-D-RIBOFURANOSYL-4-THIAZOLECARBOXAMIDE

Common Name

English

RIBOXAMIDE

Common Name

English

NSC-286193

Code

English

TIAZOFURIN [MI]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1556