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At least 19 recordsLinked to original sources
PubMed1984

Total synthesis of certain 2-, 6-mono- and 2,6-disubstituted-tubercidin derivatives. Synthesis of tubercidin via the sodium salt glycosylation procedure.

Direct glycosylation of the sodium salt of 4,6-dichloro- or 4,6-dibromo-2-methylthiopyrrolo[2,3-d]pyrimidine with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide gave good yield of the corresponding N7-glycosylated pyrrolo [2,3-d]pyrimidine. The intermediate 4-amino-6-chloro-2-methylthio-7-beta-D-ribofuranosylpyrrolo[2,3-d] pyrimidine provided a new synthetic route to tubercidin, via 6-chlorotubercidin. 6-Chloro-2-methoxytubercidin was also obtained from 10 via the methylsulfone. Application of this glycosylation procedure to 4,6-dichloro- or 4,6-dibromo-2-methylpyrrolo [2,3-d]-pyrimidine also furnished the corresponding N7-glycosyl derivatives with beta-configuration. Dehalogenation of gave 2-methyl-tubercidin and bromination with bromine in a buffered solution gave 5,6-dihalo-2-methyltubercidin. Several new 2,6-disubstituted tubercidin derivatives were prepared from these glycosyl intermediates. This new sodium salt glycosylation procedure was found to be superior to other procedures for the total synthesis of these halogenated 7-deazapurine nucleosides.

Chemical Phenomena↗
PubMed1975

The aqueous solution conformation of tubercidin and tubercidin 5'-phosphate.

The backbone of tubercidin and tubercidin 5'-phosphate in aqueous solution has a flexible molecular framework with preference for 2E-gg and 2E-gg-g'g' conformations, respectively. The glycosyl bond is unusually flexible and no definite preference for either anti or syn conformation could be detected. It is proposed that the incorporation of tubercidin 5'-phosphate into nucleic acids will disrupt the polymeric structure because of the high accessibility of syn conformation, and this might be related to the reported inhibition of nucleic acid and protein synthesis.

Chemical Phenomena↗
PubMed1982

Manipulation of toxicity and tissue distribution of tubercidin in mice by nitrobenzylthioinosine 5'-monophosphate.

The i.v. administration of tubercidin, an analog of adenosine, in a single dose of 45 mg/kg caused death in about 90% of B10D2F1 mice so treated. Serum and urine analysis, as well as histological examination of tissues, related the lethality of tubercidin to hepatic injury, which was markedly reduced when mice were treated with the inhibitor of nucleoside transport, nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), at i.p. doses higher than 10 mg/kg 30 min prior to tubercidin injection. With high NBMPR-P doses (100 mg/kg, i.p.) followed by tubercidin injection (45 mg/kg, i.v.), kidney damage and high mortality occurred. The tissue distribution of 3H following (( G-3H]tubercidin administration paralleled hepatic or renal injury: NBMPR-P treatment decreased the content of tubercidin-derived 3H in liver and increased that in kidney. Furthermore, the half-life of the decline in tubercidin levels in serum during the first minute after[3H]tubercidin administration was longer in NBMPR-P-treated mice (26 sec) than in untreated mice (10 sec), with the result that 3H levels in serum were more than ten times higher in the former than in the latter at an early stage during the distribution of tubercidin. Within 15 min after i.p. administration, the tissue distribution of (( 3H]tubercidin was complete. The i.p. administration of tubercidin caused ascites and the appearance of amylase in the peritoneal fluid evidently because of peritonitis and pancreatic injury. Administration of NBMPR-P by the i.p. route, but not by the i.v. route, prevented these injuries and shifted the LD50 of i.p. injected tubercidin (5 mg/kg) to markedly higher values (a 4-fold increase with NBMPR-P at 100 mg/kg). The protection of mice by NBMPR-P against lethal injuries caused by i.p. injected tubercidin was consistent with the inhibition by NBMPR-P of tubercidin accumulation in mesentery and pancreas. The tissue specificity of the NBMPR-P influence on the tissue distribution of tubercidin may reflect differences in NBMPR-P pharmacokinetics and/or in properties of the nucleoside permeation mechanism among various tissues.

Animals↗
PubMed1985

Action of tubercidin and other adenosine analogs on Schistosoma mansoni schistosomules.

The incorporation of the radiolabeled adenosine analogs tubercidin, formycin A, 9-deaza-adenosine, and adenine arabinoside into nucleotides of Schistosoma mansoni schistosomules was studied in vitro. Of the four analogs, only tubercidin and formycin A were incorporated into the nucleotide pool, at rates respectively one-tenth and one-fiftieth the rate of adenosine incorporation. Tubercidin inhibited schistosomule motility in vitro with an approximate IC50 value of 1 microM, whereas formycin A exerted no visible effect even when more of it than of tubercidin was incorporated into the nucleotides and nucleic acids. Formycin A thus acts like a nontoxic adenosine analog. 7-Deaza-adenine, the purine base of tubercidin, was not incorporated into nucleotides. 7-Deaza-adenine, 9-deaza-adenosine, and adenine arabinoside all had no effect on schistosomule motility at concentrations up to 100 microM. Formycin A blocked the incorporation of tubercidin and of adenosine with equal effectiveness, as did p-nitrobenzyl-6-mercaptopurine ribonucleoside, a specific inhibitor of nucleoside transport in many mammalian cells. Thus, formycin A, tubercidin, and adenosine appear to have a common mechanism of cellular uptake. The significant levels of adenosine phosphorylase and adenine phosphoribosyl transferase activity found in schistosomule extracts suggests that most of the transported adenosine is converted to adenine before conversion to AMP. The levels of adenosine kinase and tubercidin kinase, while low, can more than account for the rate of tubercidin incorporated into intact schistosomules. The kinase(s) may also represent a minor pathway for direct adenosine incorporation. It may have a rather unusual substrate specificity because it is able to recognize adenosine, tubercidin, and formycin A as substrates, but not 9-deaza-adenosine or adenine arabinoside.

Adenosine↗
PubMed2003

The adenosine analog tubercidin inhibits glycolysis in Trypanosoma brucei as revealed by an RNA interference library.

We used an RNA interference (RNAi) library in a forward genetic selection to study the mechanism of toxicity of tubercidin (7-deazaadenosine) to procyclic Trypanosoma brucei. Following transfection of cells with an RNAi-based genomic library, we used 5 microm tubercidin to select a drug-resistant cell line. Surprisingly, we found in these resistant cells that the hexose transporters had been silenced. We subsequently found that silencing of hexokinase, a glycolytic enzyme, also yielded tubercidin-resistant parasites. These observations suggested that glycolysis could be a target of tubercidin action and that RNAi silencing of glycolytic enzymes was gradual enough to allow the parasites to adapt to alternative sources of energy. Indeed, adaptation of procyclic trypanosomes to a glucose-independent metabolism by reduction of glucose in the culture medium caused tubercidin resistance. High pressure liquid chromatography analysis of glycolytic intermediates from parasites treated with tubercidin showed a dose-dependent increase in concentration of 1,3-bisphosphoglycerate, a substrate of phosphoglycerate kinase. Furthermore, tubercidin triphosphate inhibited recombinant T. brucei phosphoglycerate kinase activity in vitro with an IC50 of 7.5 microm. We conclude that 5 microm tubercidin kills trypanosomes by targeting glycolysis, especially by inhibition of phosphoglycerate kinase.

Adaptation, Physiological↗
PubMed1989

Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis.

Host toxicity of the dose regimen of tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis (M. H. el Kouni, D. Diop, and S. Cha, Proc. Natl. Acad. Sci. USA 80:6667-6670, 1983; M. H. el Kouni, N. J. Messier, and S. Cha, Biochem. Pharmacol. 36:3815-3821, 1987) was examined in vivo in mice and in vitro with human bone marrow progenitor cells. Four successive daily intraperitoneal injections of tubercidin at 5 mg/kg per day produced 100% mortality in mice within 3 to 5 days following the first injection, with massive peritonitis and intestinal obstruction secondary to abdominal adhesions. Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection. Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium. In vitro, tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin. At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM. Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM. NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter.

Aminoglycosides↗
PubMed1992

A comparison of the abilities of nitrobenzylthioinosine, dilazep, and dipyridamole to protect human hematopoietic cells from 7-deazaadenosine (tubercidin).

Nitrobenzylthioinosine, dilazep, and dipyridamole are potent inhibitors of equilibrative transport of nucleosides that may have pharmacological applications in modulating the therapeutic index of nucleoside antimetabolites used in cancer chemotherapy. We have compared the relative abilities of these inhibitors to reduce the toxicity of in vitro exposures to tubercidin against clonogenic progenitor cells of normal human bone marrow (CFU-GEMM, BFU-E, CFU-GM) and of two leukemic human cell lines (HL-60/C1, CCRF-CEM) that differ in their expression of transporter subtypes. Short (1-h) exposures to 1 microM tubercidin alone inhibited colony formation (a) of normal human hematopoietic progenitors (CFU-GEMM, BFU-E, CFU-GM) by 100%, and (b) of HL-60/C1 and CCRF-CEM cells by > 90%. Pretreatment (30 min) with nitrobenzylthioinosine, dilazep, or dipyridamole followed by simultaneous treatment (1 h) with these transport inhibitors during tubercidin exposures reduced toxicity against hematopoietic progenitors and cell lines. Greater reductions of toxicity were consistently seen with bone marrow progenitors and CCRF-CEM cells than with HL-60/C1 cells. For CFU-GEMM, BFU-E, and CFU-GM cells, reductions in tubercidin toxicity of 50-100% were achieved at these concentrations: > or = 0.1 microM (nitrobenzylthioinosine); > or = 0.1 microM (dilazep); and > or = 3.0 microM (dipyridamole). Pretreatment (30 min) followed by simultaneous treatment (1 h) with any of the transport inhibitors (> or = 0.1 microM) and 0.1 microM [3H]-tubercidin blocked the uptake of radioactivity completely in CCRF-CEM cells and only partially in HL-60/C1 cells. These effects, which were consistent with the nucleoside transport phenotypes of CCRF-CEM cells (inhibitor-sensitive) and HL-60/C1 cells (inhibitor-sensitive and inhibitor-resistant), suggested that protection was due to the inhibition of tubercidin uptake via equilibrative nucleoside transport system(s). Light-density mononuclear cells from human bone marrow, of which the clonogenic progenitors represented only a minor (< 0.01%) subpopulation, possessed far fewer nitrobenzylthioinosine-binding sites (2 x 10(4) sites/cell, Kd = 0.7 nM) than either HL-60/C1 cells (1.7 x 10(5) sites/cell, Kd = 0.9 nM) or CCRF-CEM cells (3.3 x 10(5) sites/cell, Kd = 0.5 nM). Initial rates of uptake of 1 microM [3H]adenosine (0-6 s, 20 degrees C) by human bone marrow mononuclear cells were reduced partially by 0.1 microM inhibitor (nitrobenzylthioinosine > dipyridamole > dilazep) and completely by 10 microM inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1984

Antiviral activity of C-5 substituted tubercidin analogues.

The pyrrolo[2,3-d]pyrimidine nucleoside antibiotics tubercidin, toyocamycin, and sangivamycin and the synthetic analogues 5-chloro-, 5,6-dichloro-, 5-bromo-, 6-bromo-, 5,6-dibromo-, 5-iodo-, 5-(1-hydroxyethyl)-, 5-(1-methoxyethyl)-, (E)-5-(2-bromoethenyl)-, (E)-5-(2-cyanoethenyl)-, 5-(2-buten-1-yl)-, 5-(3-hydroxypropyl)-, and 5-butyltubercidin were evaluated for their antiviral properties against six RNA viruses and three DNA viruses in HeLa cell, primary rabbit kidney cell, and Vero cell cultures. Most of the derivatives had substantial activity against the RNA viruses, with the least activity shown by 6-bromo-, 5,6-dichloro-, and 5,6-dibromotubercidin. The C-5 substituted derivatives were quite toxic for the host cells. 5-(1-Hydroxyethyl)-, 5-(1-methoxyethyl)-, and 5-(2-buten-1-yl)tubercidin were more selective against reovirus type 1, parainfluenza virus type 3 and Coxsackie virus B4 than tubercidin and the 5-halotubercidins. When tested for in vivo activity against Coxsackie B4 virus infection in newborn NMRI mice, 5-(1-hydroxyethyl)- and 5-(1-methoxyethyl)tubercidin caused a significant decrease in the mortality rate at a dose level of 100 micrograms per mouse. The inhibitory effects on L-1210 cell growth were also determined, and toyocamycin (ID50 = 0.006 micrograms/mL) was found to be the most active compound. This study demonstrates the significance of structural modification at C-5 and the potential of C-5 substituted analogues of tubercidin as biologically active agents.

Animals↗
PubMed1981

Treatment of mouse neoplasms with high doses of tubercidin.

Previous studies from this laboratory demonstrated that a potent inhibitor of nucleoside transport, nitrobenzylthioinosine (NBMPR), protected cultured cells against cytotoxic nucleosides (nebularine, tubercidin, and toyocamycin). NBMPR and its 5'-monophosphate (NBMPR-P) also protected mice against potentially lethal dosage of these agents. This report describes protection of mice from potentially lethal dosages of tubercidin by administration of NBMPR-P and the use of combinations of these agents in treatments of mice bearing transplanted neoplasms. Treatment of mice bearing i.p. implants of the Ehrlich ascites carcinoma, leukemia L1210/TG8, and colon carcinoma 26 with potentially lethal dosages of tubercidin administered together with host-protecting dosages of NBMPR-P resulted in substantial kill of neoplastic cells and long-term survivors. In these experiments, therapeutic effects were achieved at optimal dosages of NBMPR-P, which protected host vital tissues but did not protect neoplastic cells in ascitic fluids (Ehrlich ascites carcinoma cells and leukemia L1210/TG8 cells). However, at supraoptimal dosages of NBMPR-P, the occurrence of therapeutic failures which were neoplastic deaths indicated that NBMPR-P also protected the neoplastic ascites cells against tubercidin cytotoxicity. Thus, the selectivity of tubercidin toxicity toward cells of the Ehrlich ascites carcinoma and leukemia L1210/TG8 was modified by NBMPR-P dosage.

Animals↗
PubMed1983

Adenosine and tubercidin binding and transport in Chinese hamster ovary and Novikoff rat hepatoma cells.

The uptake of adenosine and tubercidin by control and ATP-deleted wild-type and adenosine kinase-deficient cells was measured by rapid kinetic techniques. Adenosine deamination was inhibited by pretreatment with 2-deoxycoformycin. Control wild-type cells phosphorylated adenosine so rapidly that the kinetics of transport per se could not be assessed unambiguously. ATP depletion and adenosine kinase deficiency did not abolish the conversion of adenosine to nucleotides, but reduced it to such an extent that initial velocities of uptake could be safely construed as transport velocities in both zero-trans and equilibrium exchange modes. The same was true for tubercidin, which was not phosphorylated in adenosine kinase-deficient cells. It accumulated intracellularly, however, to concentrations 50 to 120% higher than those in the extracellular space, apparently due to binding to some intracellular component(s). Binding was not saturated up to a concentration of 200 microM, but seemed to be slow relative to transport. Fits of appropriate integrated rate equations based on the simple carrier model to uptake time courses obtained under these conditions yielded Michaelis-Menten constants for adenosine and tubercidin transport of 100 to 200 microM and maximum velocities of 10 to 30 pmol/microliters cell H2O . sec, whereas the rate of intracellular phosphorylation was maximal at concentrations between 2 and 8 microM. The first-order rate constant (Vmax/Km) for adenosine phosphorylation, however, seemed to be appreciably higher than that for its transport. This indicates that at physiological concentrations, which fall in the first-order range for both processes, adenosine trapping is very efficient. Adenosine, tubercidin, tricyclic nucleoside, 2'-deoxyadenosine, and 3'-deoxyadenosine all inhibited uridine and thymidine transport to about the same extent, whereas pyrazofurin was significantly less effective.

Adenosine↗
PubMed1995

Tubercidin stabilizes microtubules against vinblastine-induced depolymerization, a taxol-like effect.

A sensitive assay for the detection of microtubule-stabilizing agents [1] was used to screen an extensive collection of cyanobacterial and microalgal extracts. The hydrophilic extract of the cyanobacterium, Plectonema radiosum (UH isolate IC-70-1), exhibited microtubule-stabilizing activity. Bioassay-directed purification of the active compound yielded tubercidin (7-deazaadenosine), a potent cytotoxic nucleoside analog. Further studies revealed that tubercidin protected a population of cellular microtubules against vinblastine-induced depolymerization, a microtubule-stabilizing, taxol-like effect. The microtubule-stabilizing effect of tubercidin is dose dependent and limited by the cytotoxicity of the agent. Tubercidin represents another natural product that interacts with microtubules and is one of the few to cause microtubule stabilization.

Animals↗
PubMed1984

Synthesis and biological activity of tubercidin analogues of ppp5'A2'p(5'A2'p)n5'A.

A series of tubercidin (7-deazaadenosine) analogues of 2-5A of the general formula p5'(c7A)2'p[5'(c7A)-2'p]n5'(c7A) (n = 0-5) were prepared by lead ion catalyzed polymerization of the 5'-phosphoroimidazolidate of tubercidin. Through the corresponding imidazolidates, these oligonucleotide 5'-monophosphates were converted to the 5'-triphosphates. All reported structures were corroborated by enzyme digestion and 1H or 31P nuclear magnetic resonance. When evaluated for its ability to bind to the 2-5 A-dependent endonuclease of mouse L cells, the tubercidin analogue of trimeric 2-5A, namely, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A), and the corresponding tetramer were bound as effectively as 2-5A itself; nonetheless, it and the corresponding tetramer, ppp5'-(c7A)2'p5'(c7A)2'p5'(c7A)2'p5'(c7A), failed to stimulate the 2-5A-dependent endonuclease as judged by its inability to inhibit translation in extracts of mouse L cells programmed with encephalomyocarditis virus RNA and to give rise to ribosomal RNA cleavage in the same cell system under conditions where 2-5A showed activity at 10(-9) M. The trimer, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A), was an antagonist of 2-5A action in the L cell extract. In the lysed rabbit reticulocyte system, both the trimeric and tetrameric tubercidin 2-5A analogues were bound to the 2-5A-dependent endonuclease as well as 2-5A, but in this case, the tetramer triphosphate, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A)2'p5'(c7A), was just as potent an inhibitor of translation as 2-5A tetramer triphosphate. Moreover, this inhibition was prevented by the established 2-5A antagonist p5'A2'p5'A2'p5'A.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1989

Synthesis, cytotoxicity, and antiviral activity of some acyclic analogues of the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics tubercidin, toyocamycin, and sangivamycin.

A number of 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3d-d]pyrimidine derivatives that are structurally related to toyocamycin and sangivamycin and the seco nucleosides of tubercidin, toyocamycin, and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]-pyrimidine with 1,3-bis(benzyloxy)-2-propoxymethyl chloride afforded compound 3, which without isolation was debrominated to obtain 4-amino-5-cyano-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine. Although catalytic hydrogenolysis failed, the benzyl ether functionalities of 4 were successfully cleaved by boron trichloride to afford 4-amino-5-cyano-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidine. Conventional functional group transformation of the cyano group of 6 provided a number of novel 5-substituted derivatives. Tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were treated separately with sodium metaperiodate and then with sodium borohydride to afford the 2',3'-seco derivatives 9a-c, respectively. The acyclic nucleoside 4-chloro-2-(methylthio)-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine was aminated, desulfurized with Raney Ni, and then debenzylated to provide the tubercidin analogue 11. Cytotoxicity evaluation against L1210 murine leukemic cells in vitro showed that although the parent compounds tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were very potent growth inhibitors, the acyclic derivatives 6, 7a-c, and 9a-c had only slight growth-inhibitory activity. Evaluation of compounds 6, 7a, 7b, 7c, 9a, 9b, 9c, 11 for cytoxicity and activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the carboxamide (7a) and the thioamide (7c) were active. Compound 7c was the more potent of the two, inhibiting HCMV but not HSV-1 at concentrations producing little cytotoxicity.

Aminoglycosides↗
PubMed1982

Comparison of the effects on cultured L1210 leukemia cells of the ribosyl, 2'-deoxyribosyl, and xylosyl homologs of tubercidin and adenosine alone or in combination with 2'-deoxycoformycin.

The biologic effects of a series of sugar-substituted analogs of tubercidin were evaluated and compared with the effects of the homologous series of adenosine analogs in combination with 2'-deoxycoformycin. The greatest cytotoxicity against cultured mouse L1210 leukemia cells was exhibited by tubercidin and by 3'-deoxyadenosine or xylosyladenine in combination with 2'-deoxycoformycin. Somewhat less active were xylotubercidin and the combination of arabinosyladenine (araA) plus 2'-deoxycoformycin. The arabinosyl and 2'- and 3'-deoxyribosyl derivatives of tubercidin were relatively ineffective in their ability to inhibit proliferation of L1210 cells. The major biochemical effects of the most active agents were inhibition of RNA synthesis (3'-deoxyadenosine and xylosyladenine) and depletion of cellular ATP plus general inhibition of macromolecular synthesis (tubercidin). The in vitro activities of xylosyladenine and 3'-deoxyadenosine (in combination with 2'-deoxycoformycin) and xylotubercidin (as a single agent) were greater than or equivalent to that of araA (in combination with 2'-deoxycoformycin).

Adenosine↗
PubMed1978

Tubercidin metabolism in mouse L5178y cells in vivo and in vitro.

Tubercidin (7-deazaadenosine) is a strong inhibitor of cell proliferation in mouse L5178y cells. Radioactive tubercidin is incorporated into DNA and RNA. Poly(A)-containing RNA shows the highest specific radioactivity. The amount of low molecular weight 4S and 5S RNA is diminished to some extent under the influence of the compound. Tubercidin triphosphate is a potent inhibitor of DNA-dependent DNA polymerases alpha and beta, and the DNA-dependent RNA polymerases I, II, and III, although the efficiency of its incorporation is lower than of dATP and ATP. Tubercidin triphosphate also seems to be a good substrate for the Mg2+-dependent poly(A) polymerase.

Animals↗
PubMed1987

Inhibition of herpes simplex virus DNA replication by ara-tubercidin.

Preliminary studies of the biochemical basis for the antiviral activity of the pyrrolo[2,3-d]pyrimidine nucleoside ara-tubercidin were conducted. Herpes simplex virus DNA synthesis was 3-fold more sensitive to inhibition by ara-tubercidin than was cellular DNA synthesis. Partially purified herpes DNA polymerases were more sensitive to inhibition by ara-tubercidin 5'-triphosphate than were cellular polymerases alpha and beta. Inhibition of viral DNA polymerase was competitive with dATP and noncompetitive with dTTP. The results suggest that the viral DNA polymerase plays a significant role in the antiviral activity of ara-tubercidin.

Antiviral Agents↗
PubMed1986

Selective protection of tubercidin toxicity by nitrobenzyl thioinosine in normal tissues but not in human neuroblastoma cells.

Tubercidin, an adenosine analogue, is toxic to human neuroblastoma cell lines, to peripheral blood mononuclear cells (PBMCs), and to myeloid colony-forming cells (CFU-C) as tested by a short-term labeled precursor uptake and by a clonogenic assay. When it was co-administered with a potent purine transport inhibitor, nitrobenzyl thioinosine (NBTI), the cytotoxic effect of tubercidin was abolished in PBMCs but not in neuroblastoma cells. Studies of nucleoside transport in neuroblastoma cells demonstrate that although [3H]NBTI binds to the plasma membrane of these cells, the transport of thymidine into the cells is only partially inhibited in the presence of excess NBTI. These data imply that neuroblastoma cells contain a nucleoside transport mechanism which is insensitive to NBTI. "Host protection" with a nucleoside transport inhibitor such as NBTI, may allow effective therapy with otherwise toxic dosages of tubercidin and other cytotoxic nucleosides in patients with neuroblastoma.

Biological Transport↗