tiazofurin has been researched along with Lymphoma* in 3 studies
3 other study(ies) available for tiazofurin and Lymphoma
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Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin.
The synthesis and biological activity of selenophenfurin (5-beta-D-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of alpha- and beta-anomers, and the beta-2,5-diglycosylated derivative. Deprotected ethyl 5-beta-D-ribofuranosylselenophene-3-carboxylate (12 beta) was converted into selenophenfurin by ammonolysis. The structure of 12 beta was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent decrease in GTP levels (58%). The results obtained confirm the hypothesis that the presence of heteroatoms such as S or Se in the heterocycle in position 2 with respect to the glycosidic bond is essential for both cytotoxicity and IMP dehydrogenase inhibitory activity in this type of C-nucleosides. Topics: Animals; Antineoplastic Agents; Cell Division; Computer Simulation; Crystallography, X-Ray; Enzyme Inhibitors; Guanosine Triphosphate; Humans; IMP Dehydrogenase; Inosine Monophosphate; Leukemia; Lymphoma; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Structure; Neoplasms; Organoselenium Compounds; Ribavirin; Ribonucleosides; Tumor Cells, Cultured | 1997 |
Biochemical differences among four inosinate dehydrogenase inhibitors, mycophenolic acid, ribavirin, tiazofurin, and selenazofurin, studied in mouse lymphoma cell culture.
The mechanism of the cellular toxicity of four inosinate dehydrogenase (IMP-DH) inhibitors with different antitumor and antiviral pharmacological profiles was investigated in mouse lymphoma (S-49) cell culture. Drug effects on cell growth, nucleotide pools, and DNA and RNA synthesis were measured in the presence and absence of guanine salvage supplies. Both guanine and guanosine were capable of bypassing the IMP-DH block, while they also demonstrated some growth-inhibitory effects when added alone in high concentrations. All four drugs reduced cellular guanosine triphosphate levels and caused secondary changes of the uridine, cytidine, and adenosine triphosphate pools that were similar among the four drugs. However, several drug effects in addition to IMP-DH inhibition were observed except with mycophenolic acid which may represent a pure IMP-DH inhibitor. Both tiazofurin and selenazofurin interfered with the uptake and/or metabolism of uridine and thymidine tracers; however, this effect appeared not to contribute to their cellular toxicity in vitro. Moreover, selenazofurin and tiazofurin impaired the utilization of exogenous guanine salvage supplies for DNA and RNA synthesis, and guanine was particularly ineffective in reversing the toxic effects of tiazofurin on cell growth. This finding is important in view of the available guanine salvage supplies in vivo. Since tiazofurin, selenazofurin, and their known metabolites failed to inhibit hypoxanthine-guanine-phosphoribosyl transferase, guanosine monophosphate kinase, and guanosine diphosphate kinase in cell extracts or permeabilized cells, these drugs may interfere with salvage transport across cellular membranes. The toxic effects of mycophenolic acid and ribavirin were similarly reversed by salvage supplies of up to 200 microM guanine, which suggests that ribavirin primarily acts as an IMP-DH inhibitor under these conditions. This result could explain the rather low antitumor efficacy of both mycophenolic acid and ribavirin in vivo. However, increasing the guanine salvage supply in the medium above 200 microM further reversed the toxic effects of mycophenolic acid to maximum rescue, while it increased the toxicity of ribavirin (300 microM). This finding suggests the presence of a toxic mechanism of ribavirin at higher concentrations that is dependent upon the presence of guanine supplies sufficient to fully overcome the IMP-DH inhibition. This study documents that each antimetabolite displays a unique s Topics: Adenosine Triphosphate; Animals; Cell Division; Cells, Cultured; DNA, Neoplasm; Guanine; Guanylate Kinases; Hypoxanthine Phosphoribosyltransferase; IMP Dehydrogenase; Ketone Oxidoreductases; Lymphoma; Mice; Mycophenolic Acid; Nucleoside-Diphosphate Kinase; Nucleoside-Phosphate Kinase; Organoselenium Compounds; Ribavirin; Ribonucleosides; RNA, Neoplasm; Selenium; Tritium; Uridine | 1985 |
Activity and metabolism of 2-beta-D-ribofuranosylthiazole-4-carboxamide in human lymphoid tumor cells in culture.
The antitumor activity of the C-nucleoside, 2-beta-D-ribofuranosylthiazole-4-carboxamide (TR), was investigated in four human lymphoid tumor cell lines in culture. Exposure of the cell lines CCRF-CEM (T-cell leukemia), HUT-78 (cutaneous T-cell lymphoma), NALM-1 (B-cell leukemia), and MOLT-4 (T-cell leukemia) for 72 hr to TR resulted in 50% inhibitory concentration of 30, 27, 7, and 6 microM, respectively. Maximum inhibition of DNA and RNA synthesis occurred 6 hr after drug treatment. The 50% inhibitory concentration of TR among the four cell lines varied from 5 to 8 microM for RNA synthesis and from 4 to 8 microM for DNA synthesis. Nucleotide analyses in MOLT-4 cells after 6 hr of drug exposure to 10 and 100 microM TR revealed increased inosine 5'-monophosphate concentrations which were 18- to 20-fold greater than control levels and a parallel reduction of 82 and 100% in guanosine 5'-monophosphate concentrations. Growth inhibition of MOLT-4 cells by 6 hr exposure to TR was almost fully reversible by addition of 50 microM guanosine to the medium for 18 hr. Analyses by high-pressure liquid chromatography revealed two metabolites of TR in all four cell lines, namely, thiazolecarboxamide riboside 5'-monophosphate and thiazolecarboxamide adenine dinucleotide, the latter of which is a potent inhibitor of inosine-5-'-monophosphate dehydrogenase. These results suggest that the antitumor effects of TR in human tumor cell lines may relate to guanine nucleotide depletion. Topics: Cell Division; Cell Line; DNA Replication; Guanine Nucleotides; Humans; Lymphoma; Ribavirin; Ribonucleosides; RNA; Time Factors | 1983 |