Tiazofurin is a drug which acts as an inhibitor of the enzyme IMP dehydrogenase. Tiazofurin and its analogues were under investigation for potential use in the treatment of cancer, though side effects such as pleuropericarditis and a flu-like syndrome precluded further development. They also show antiviral effects and may be reevaluated as potential options in the treatment of newly emerging viral diseases. |
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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 |
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EC 1.1.1.205 (IMP dehydrogenase) inhibitor
An EC 1.1.1.* (oxidoreductase acting on donor CH-OH group, NAD+ or NADP+ acceptor) inhibitor that interferes with the action of IMP dehydrogenase (EC 1.1.1.205), so blocking de novo biosynthesis of purine nucleotides.
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prodrug
A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug.
antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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View more via ChEBI Ontology
(1R)-1,4-anhydro-1-(4-carbamoyl-1,3-thiazol-2-yl)-D-ribitol
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tiazofurina
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WHO MedNet
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tiazofurine
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WHO MedNet
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tiazofurine
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WHO MedNet
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tiazofurinum
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WHO MedNet
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2-(β-D-ribofuranosyl)-4-thiazolecarboxamide
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ChEBI
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2-β-D-ribofuranosyl-4-thiazolecarboxamide
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ChemIDplus
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CI-909
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ChemIDplus
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riboxamide
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ChemIDplus
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TCAR
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ChEBI
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tiazofurin
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KEGG DRUG
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1084555
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Reaxys Registry Number
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Reaxys
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60084-10-8
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CAS Registry Number
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ChemIDplus
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Kusumanchi P, Zhang Y, Jani MB, Jayaram NH, Khan RA, Tang Y, Antony AC, Jayaram HN (2013) Nicotinamide mononucleotide adenylyltransferase2 overexpression enhances colorectal cancer cell-kill by Tiazofurin. Cancer gene therapy 20, 403-412 [PubMed:23764899] [show Abstract] Colorectal cancer cells exhibit limited cytotoxicity towards Tiazofurin, a pro-drug metabolized by cytosolic nicotinamide mononucleotide adenylyltransferase2 (NMNAT2) to thiazole-4-carboxamide adenine dinucleotide, a potent inhibitor of inosine 5'-monophosphate dehydrogenase required for cellular guanylate synthesis. We tested the hypothesis that colorectal cancer cells that exhibit low levels of NMNAT2 and are refractory to Tiazofurin can be rendered sensitive to Tiazofurin by overexpressing NMNAT2. Transfection of hNMNAT2 resulted in a six- and threefold cytoplasmic overexpression in Caco2 and HT29 cell lines correlating with Tiazofurin-induced enhanced cell-kill. Folate receptors expressed on the cell surface of 30-50% colorectal carcinomas were exploited for cellular targeting with Tiazofurin encapsulated in folate-tethered nanoparticles. Our results indicated that in wild-type colorectal cancer cells, free Tiazofurin-induced EC50 cell-kill was 1500-2000 μM, which was reduced to 66-156 μM in hNMNAT2-overexpressed cells treated with Tiazofurin encapsulated in non-targeted nanoparticles. This efficacy was improved threefold by encapsulating Tiazofurin in folate-tethered nanoparticles to obtain an EC(50) cell-kill of 22-59 μM, an equivalent of 100-300 mg m(-2) (one-tenth of the approved dose of Tiazofurin in humans), which will result in minimal toxicity leading to cancer cell-kill. This proof-of-principle study suggests that resistance of colorectal cancer cell-kill to Tiazofurin can be overcome by sequentially overexpressing hNMNAT2 and then facilitating the uptake of Tiazofurin by folate-tethered nanoparticles, which enter cells via folate receptors. | Grifantini M (2000) Tiazofurine ICN Pharmaceuticals. Current opinion in investigational drugs (London, England : 2000) 1, 257-262 [PubMed:11249583] [show Abstract] Tiazofurine is a nucleoside analog with oncolytic activity being developed by Ribapharm (formerly ICN Pharmaceuticals) as a potential treatment for leukemia. It is metabolized to TAD (thiazole-4-carboxamide adenine dinucleotide), an inhibitor of IMP dehydrogenase. This inhibition results in the reduction of guanylate levels and the halting of neoplastic proliferation. The compound is in phase II/III trials [215553]. It is expected that Ribapharm will file an orphan drug application for tiazofurine, as a treatment for myelogenous leukemia, following the drug's completion of phase III trials by the end of 2002. The company has reported that phase III trials will begin by the end of 2000. Preliminary studies involving 21 patients have been carried out and the results reported by the company. During these studies, seven patients with chronic myelogenous leukemia had a complete hematologic response and two patients had a partial response. Of the patients with a complete response, six had marrow and peripheral responses. Ribapharm, through a Russian subsidiary of ICN, is also planning to conduct phase II studies of tiazofurine involving patients suffering from advanced ovarian cancer or multiple myeloma which is resistant to conventional therapy. The company has reported that the multiple myeloma limited phase II study is still undergoing planning, with an intended start date in late 2000 [381453]. In March 2000, Chase Hambrecht & Quist predicted that first approval could be towards the end of 2001 [384894]. | Mitrović DM, Redzić ZB, Marković ID, Jovanović SS, Rosić MA, Rakić LM (1995) Tiazofurine uptake by the isolated guinea pig heart. Journal of chemotherapy (Florence, Italy) 7, 543-548 [PubMed:8667040] [show Abstract] Tiazofurine is a selective inhibitor of the enzyme inosine monophosphate dehydrogenase, and exhibits potent antitumor activity. Considering the potential side effects on the heart, [3H] tiazofurine uptake into the cardiomyocytes, as well as the mechanism of transport, were studied in the isolated perfused guinea pig heart, using the rapid single circulation, paired-tracer technique. The maximal cellular uptake (Umax) of [3H] tiazofurine ranged from 19% to 25% of the injected dose, with total cellular uptake (Utot) ranging 12.1-15.6%. The addition of unlabeled tiazofurine caused inhibition of [3H] tiazofurine uptake, with a Umax value of 9.06 +/- 4.6%. Therefore, the uptake of tiazofurine into cardiomyocytes could be considered a saturable process. The inhibition of [3H] tiazofurine uptake caused by adenosine and dipyridamole was of the same degree as the inhibition by unlabeled tiazofurine. Thus, it can be assumed that nucleosides' transport system(s) are involved in transport of tiazofurine into myocardial cells. | Nagy PD, Gáborjányi R, Kovács L, Farkas I (1989) Antiviral activity of tiazofurine against barley stripe mosaic virus. Antiviral research 11, 41-45 [PubMed:2712550] [show Abstract] Tiazofurine (2-beta-D-ribofuranosylthiazole-4-carboxamide) was found to inhibit replication of barley stripe mosaic virus (BSMV) in barley and wheat plants. Treatment with this nucleoside analogue delayed and inhibited symptom development and suppressed virus multiplication. The most effective concentration applied twice as a foliar spray 3 h and one day after inoculation, was 10(-3) M. Decreased virus multiplication was obtained without marked phytotoxicity. Three weeks after treatment the antiviral effect declined. |
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