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PubMed1979

High frequency of mutation to tubercidin resistance in CHO cells.

The acquisition of high-level resistance to tubercidin (an adenosine analog) in CHO cells occurs in a single step at high frequency (10(-3) to 10(-4)) without mutagenesis. Analysis of a large number of independent mutants by a fluctuation test (Luria and Delbruk, 1943) indicates that they arise independently of the selection medium and all fall into the same complementation group. All mutants tested lack detectable adenosine kinase activity. An analysis of hybrids between mutant and wild-type cells indicates that resistance to tubercidin is a recessive marker which segregates as would be expected if it were a haploid locus in the parental CHO cell. Resistance to tubercidin is not linked to the X chromosome in CHO cells and appears to occur at much lower frequency in primary Chinese hamster cells and other cultured cell lines.

Animals↗

PubMed1984

Genetic and biochemical studies on mutants of CHO cells resistant to 7-deazapurine nucleosides: differences in the mechanisms of action of toyocamycin and tubercidin.

From mutants of Chinese hamster ovary cells which are resistant to toyocamycin and tubercidin, second-step mutants which exhibit a further 8- to 9-fold increase in resistance to toyocamycin (ToyrII mutants) but no change in resistance to tubercidin have been isolated. The ToyrII mutants are similar to the first-step mutants in their levels of adenosine kinase activity (congruent to 1%), as well as cellular uptake and phosphorylation of adenosine and its analogs. The increased resistance of the ToyrII mutants to toyocamycin but not to tubercidin provides strong evidence that the mechanism of cellular toxicity of these two analogs is different from each other and suggests that these mutants may be affected in a cellular component which is specifically involved in the toxicity of toyocamycin. The ToyrII mutants also exhibit increased resistance to sangivamycin and the tricyclic nucleoside pentaaza-acenaphthylene riboside (TCN, NSC 154020) indicating that the mechanisms of cellular toxicity of these two analogs may be similar to that of toyocamycin.

Animals↗

PubMed1985

Combination therapy of Schistosoma japonicum by tubercidin and nitrobenzylthioinosine 5'-monophosphate.

Coadministration of nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) with high doses of tubercidin by i.p. injection into Schistosoma japonicum infected mice beginning 5 weeks post-infection was highly toxic to the parasite but not the hose. Combination therapy resulted in a striking reduction in the number of worms, and the few worms that could be found were stunted. Combination therapy also caused a drastic reduction in the number of eggs in the livers (from 86,500 to 2,800 eggs/liver) and intestines (from 2,200 to 74 eggs/cm2), and 95% of eggs that were found were dead, indicating the termination of oviposition. Mice receiving the combination of tubercidin plus NBMPR-P appeared healthy and had normal size livers and spleens. These results demonstrate that by combining NBMPR-P with tubercidin high selective toxicity against S. japonicum can be achieved, as was shown previously with S. mansoni.

Animals↗

PubMed1988

Nucleoside uptake in Trypanosoma cruzi: analysis of a mutant resistant to tubercidin.

Nucleoside salvage pathways are vital to the parasitic protozoan Trypanosoma cruzi, and have become important targets in the development of new chemotherapeutic agents against this organism. We produced a mutant T. cruzi clone with a defect in the uptake of the adenosine analogue tubercidin which allowed us to hypothesize that there are at least two distinct nucleoside transport pathways in this parasite. The mutant shows a marked defect in the uptake of tubercidin and thymidine, whereas the uptake of adenosine and inosine are normal. Inhibition and metabolic studies suggest that the defect is related to transport and that there are two transport processes relatively specific for purines and pyrimidines, respectively, although tubercidin is transported via the latter. This is similar to the reported dual nucleoside transport pathways in Leishmania donovani and may be a common system in the Trypanosomatidae. These transport processes are markedly different from those which have been described for mammalian cells and may play an important role in the design of strategies for the chemotherapy of human infection with these pathogenic parasites.

Adenosine↗

PubMed2002

Study on the synthesis and PKA-I binding activities of 5-alkynyl tubercidin analogues.

5-alkynyl tubercidin analogues were synthesized and their biological activities were evaluated. It was found that protein kinase A could be activated by 5-alkynyl tubercidin (9a) and cAMP-binding ability to PKA-I was selectively inhibited by it. Molecular modeling showed that the interaction of 9a and PKA-I was associated with the existence of hydrophobic alkynyl group. During the synthesis of tubercidin analogues, a pair of 2'-carbonyl participating abnormal coupling products (11a, 11b) was obtained, the structure was identified by X-ray crystalline diffraction.

Alkynes↗

PubMed1981

Favored incorporation of tubercidin in poly(adenylic, 7-deazadenylic acids) and their function as messenger ribonucleic acids in protein synthesis.

The following polynucleotides containing the antibiotic tubercidin (Tu; 4-amino-7-beta-D-ribofuranosylpyrrolo-[2,3-d]pyrimidine) were enzymatically synthesized by polymerization of adenosine 5'-diphosphate-tubercidin 5'-diphosphate mixtures with polynucleotide phosphorylase: poly(A2,Tu), poly(A,Tu2), and poly(Tu). The incorporation of the antibiotic was favored by the enzyme. The polymers are compared to poly(adenylic acid) [poly(A)] with respect to their structure, conformation, and ability to direct polylysine synthesis in a ribosome-dependent protein synthesis system. From physical data (thermal melting, NMR, and circular dichroism) it is concluded that tubercidin destabilizes the structure of the polynucleotide chain and that this may be due to an altered polarization of the nucleobases and their enhanced rotation around the N-glycosylic bond. Since there is an apparent correlation between thermal unfolding of the polymers and their ability to mediate polylysine synthesis, it is suggested that partial destacking of the messenger ribonucleic acid favors its binding to the ribosome and/or its ability to enhance codon-anticodon-specific protein synthesis.

Circular Dichroism↗

PubMed1995

Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.

Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.

Animals↗

PubMed1983

Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5'-monophosphate.

Nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) inhibits the transport of nucleosides, including tubercidin, in mammalian systems but not in Schistosoma mansoni. Administration of NBMPR-P with high doses of tubercidin (lethal doses if injected alone) by intraperitoneal injection into S. mansoni-infected mice was highly toxic to the parasite but not to the host. Combination therapy resulted in a striking decrease in the number and copulation of worms. The few worms that could be found were so stunted that it was difficult to identify their sex. Mice receiving the combination of tubercidin plus NBMPR-P appeared healthy and had normal-sized livers and spleens. Combination therapy also caused a drastic decrease in the number of eggs in the liver (from 32,500 to 1,800 eggs per liver) and in the intestine (from 1,295 to 2 eggs per cm2). All eggs found were dead, indicating the termination of oviposition. Very few granulomas were detected in livers of treated animals. Sections of these livers showed lesions containing dead worms and what appeared to be a process of regeneration of normal tissue around old granulomas. Thus, combination therapy reduced the number and the progress of the primary pathological lesions associated with schistosomiasis. These results demonstrate that through combination therapy, highly selective toxicity against a parasite can be achieved. The effectiveness, simplicity, and practicality of host protection afforded by this method may yield a promising chemotherapeutic approach for the treatment of schistosomiasis and other parasitic diseases.

Animals↗

PubMed1981

Growth inhibition of axenic Entamoeba histolytica by tubercidin and ara-A.

Several analogs of nucleic acid components including 7-deazaadenosine (tubercidin), adenine 9-beta-D-arabinofuranoside (ara-A), 8-azaguanine, 6-azathymine, 6-mercaptopurine, 6-mercaptopurine arabinoside, 6-mercaptopurine riboside and 1,3-dideazapurine (benzimidazole) were tested for inhibition of growth of an axenic strain of Entamoeba histolytica in 72 hour experiments. Metronidazole and emetine were included in the experiments for comparison. Tubercidin and ara-A, analogs of adenosine, were the most potent of the tested growth inhibitors with amebistatic concentrations of about 0.6 and 3.0 microM, respectively. The other analogs did not significantly inhibit amebal growth below 100 microM. In the present study metronidazole and emetine had amebistatic concentrations, respectively, 17- and 60-fold higher than tubercidin.

Animals↗

PubMed1975

A study on the reactions of tubercidin triphosphate with myosin and actomyosin.

The triphosphate ester of tubercidin (tubercidin triphosphate, TuTP) was synthesized. This is an analog of ATP in which a CH group replaces the N-7 of the adenine ring. The rate of TuTP hydrolysis by myosin in the presence of Mg2+ was the same as that of ATP in the 10(-7)-10(-3) M range, whereas the increment in the optical density of myosin ihe 290mmu region caused by TuTP was twice that caused by ATP. TuTP is hydrolyzed by actomyosin faster than ATP, the value of Vmax being about 4 times larger while the Km values were of the same order of magnitude. The rate of superprecipitation induced by TuTP was 50% of that caused by ATP at nucleotide concentrations of 3-60 muM. A similar difference was observed with respect to the rate of tension development by glycerol-extracted rabbit psoas fibers upon addition of these two substances. Substitution of ADP by tubercidin diphosphate (TuDP) in F-actin did not affect the rate of superprecipitation or enzymic activity of actomyosin.

Actomyosin↗

PubMed1982

Initial rate kinetics of the transport of adenosine and 4-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (tubercidin) in cultured cells.

A procedure is described for determining early time courses of nucleoside uptake by cultured cells in suspension. Replicate samples of cell suspensions were exposed to medium containing 3H-nucleosides for brief intervals (sec) ended by addition of nitrobenzylthioinosine, a potent inhibitor of nucleoside transport that terminated nucleoside uptake virtually instantaneously. Time courses of nucleoside uptake were constructed from the cellular content of nucleoside acquired by the replicate samples during graded intervals of exposure to the labeled permeant. Such time courses were definitive of cellular uptake of nucleosides during the first few sec of exposure to permeant and yielded initial rates of uptake of adenosine and 4-amino-7-(beta-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (tubercidin). Defining initial rates of nucleoside uptake as rates of inward transport, relationships between transport rates and extracellular concentrations of these permeants were evaluated in HeLa cells and in two cultured lines of mouse lymphoma L5178Y cells that differ in their abilities to phosphorylate adenosine and tubercidin. Transport rates for these permeants were similar in the two L5178Y cell types and were saturable in the 3 cell lines with Km values between 14 and 38 microM. Adenosine and tubercidin were mutually competitive permeants in L5178Y cells, indicating that they are substrates for the same transport mechanism.

Adenosine↗

PubMed1980

Introduction of substituents to the 7(8)-position of 7-deazaadenosine (tubercidin): conversion to toyocamycin.

Treatment of 2',3',5'-tri-O-acetyl-7-deazaadenosine with C1SCN gave the 7-thiocyanato derivative, which was converted to 7-methylthio and 7-methyl-sulfone derivatives. The thio-Claisen rearrangement and desulfurization of 7-allylthio derivative afforded 7-propyl-7-deazaadenosine. The 7-methylsulfone derivative gave the 8-cyano compound by treatment with NaCN. The action of nitrating agent on triacetyltubercidin gave a mixture of the 7- and 8-nitro derivatives. The Mannich reaction of tubercidin gave the 7-morpholinomethyl derivative which was converted to the methyl, formyl, hydroxymethyl, or cyano derivatives in good yield. The conversion of tubercidin to toyocamycin was thus accomplished. Some physical and biological properties of these substituted tubercidins were presented.

Indicators and Reagents↗

PubMed1978

Genetic and biochemical studies with the adenosine analogs toyocamycin and tubercidin: mutation at the adenosine kinase locus in Chinese hamster cells.

The pyrrolopyrimidine nucleosides toyocamycin and tubercidin show several unique features of growth inhibition in Chinese hamster ovary (CHO) cells. Stable mutants which are more than 600-fold resistant to these drugs are obtained in CHO cells at a strikingly high frequency of approximately 10(-3), in the absence of mutagenesis. The mutants resistant to toyocamycin (Toyr) and tubercidin (Tubr) exhibit similar cross-resistance patterns to the two selective drugs as well as to adenosine and 6-methyl mercaptopurine riboside, indicating that the same lesion is probably involved in all cases. The mutants examined were found to be deficient in the enzyme adenosine kinase (AK), indicating that the phosphorylation of these analogs is an essential first step in their toxic action. The above mutants (AK-) behaved recessively in cell hybrids, and segregation studies indicate that the AK locus is not linked to the X chromosome. The frequencies of similar Toyr mutants in other Chinese hamster lines, e.g., V79, CHW, M3-1, GM7, and CHO-K1, varied from similar to more than three logs less than that observed for CHO cells, indicating that various cell lines probably differ in the number of functional gene copies for this locus.

Adenosine Kinase↗

PubMed1991

Efficacy of combination therapy with tubercidin and nitrobenzylthioinosine 5'-monophosphate against chronic and advanced stages of schistosomiasis.

The efficacy of the highly selective antischistosomal combination chemotherapy with tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), [el Kouni et al., Proc Natl Acad Sci USA 80: 6667-6670, 1983; el Kouni et al., Biochem Pharmacol 36: 3815-3821, 1987] was examined against chronic and advanced stages of schistosomiasis in mice. Administration of four successive daily doses of tubercidin (5 mg/kg/day) plus NBMPR-P (25 mg/kg/day) to Schistosoma mansoni-infected mice beginning 5, 6, 7 and 8 weeks post-infection and monitored for 22 weeks was very effective against the parasite. It resulted in a marked increase in survivorship of treated mice. Repetition of the dose-regimen after a 10-day rest period was even more effective. However, survivorship of infected animals decreased with the delay of therapy. Early treatment (5 weeks post-infection) resulted in 100% survival compared to 13% only for untreated animals. If therapy was instituted at 8 weeks post-infection, only 70% of the treated mice survived. Treated animals appeared healthy and were found to have less splenomegaly and hepatomegaly. Combination therapy also caused a significant reduction in the number of worms as well as the number of eggs in the liver and small intestine. However, these differences diminished as the treatment was delayed. The number of eggs in the liver was reduced from an average of 120,000 eggs per liver in untreated animals to approximately 16,000 eggs per liver when treated at 5 weeks post-infection. When treatment was delayed to 8 weeks post-infection, the reduction in liver egg count was not as dramatic (88,000 eggs per liver). Similarly, the number of eggs was reduced in the intestine from 1,759 to an average of 58 and 860 eggs per cm2 of the intestine when the mice were treated at 5 and 8 weeks post-infection respectively. However, some worms survived and resumed egg production after an extended period of recuperation. Histological examination indicated that combination therapy was effective in preventing the formation of new egg granulomas but not on pre-existing granulomas.

Animals↗

PubMed1994

2'-Deoxy-2'-methylene derivatives of adenosine, guanosine, tubercidin, cytidine and uridine as inhibitors of L1210 cell growth in culture.

The 2'-deoxy-2'-methylene derivatives of adenosine (MdAdo), guanosine (MdGuo), tubercidin (MdTu), cytidine (MdCyd) and uridine (MdUrd) were synthesized as mechanism-based inhibitors directed at ribonucleotide reductase. It was shown that MdCyd 5'-diphosphate irreversibly inactivated ribonucleotide reductase from Escherichia coli (Baker et al., J Med Chem 34: 1879-1884, 1991). In studies reported here, MdAdo/EHNA, MdGuo and MdCyd inhibited L1210 cell growth with IC50 values of 3.4, 10.6 and 1.4 microM, respectively. Since MdAdo is a substrate for adenosine deaminase, the presence of EHNA was required to give maximal growth inhibition. 8-Aminoguanosine was not required to maximize the cytotoxic effects of MdGuo. The 2'-deoxy-2'-methylene derivatives of tubercidin and uridine did not inhibit L1210 cell growth at concentrations as high as 50 microM (MdTu) or 100 microM (MdUrd). L1210 cell lines resistant to hydroxyurea (directed at the non-heme iron subunit of ribonucleotide reductase) or deoxyadenosine (directed at the effector binding subunit of ribonucleotide reductase) were not resistant to MdCyd. An L1210 cell line that was highly resistant to dGuo due to the loss of a relatively specific deoxyribonucleoside kinase (Cory et al., J Biol Chem 268: 405-409, 1993) had a 6.6-fold increase in the IC50 value toward MdCyd, but showed only a 2-fold increase in resistance to MdGuo. Another L1210 cell line that was markedly deficient in adenosine kinase activity was highly resistant to MdAdo. Analysis by flow cytometry showed that MdCyd showed the transit of the cells through the G2/M phase of the cell cycle resulting in the buildup of the G2/M population. MdAdo, MdGuo and MdCyd inhibited the incorporation of [14C]cytidine into DNA without an effect on RNA synthesis or total cellular uptake of [14C]cytidine. The conversion of [14C]cytidine to deoxycytidine nucleotides was partially inhibited by MdGuo, but not by MdAdo or MdCyd. These data show that the 2'-deoxy-2'-methylene derivatives of adenosine, guanosine and cytidine are activated via specific nucleoside kinases and that the modes of action of these compounds are not identical.

Animals↗

PubMed1995

Inhibition of adenosine kinase and adenosine uptake in guinea-pig CNS tissue by halogenated tubercidin analogues.

Two halogenated analogues of tubercidin (7-deazaadenosine) viz. 5-iodotubercidin and 5'-deoxy-5-iodotubercidin, previously were shown to be potent inhibitors of guinea-pig brain adenosine kinase activity and adenosine uptake in guinea-pig cerebral cortex slices. A further series of halogenated tubercidin analogues have been investigated; of the 9 compounds tested, 5'-deoxy-5-iodotubercidin was the most potent adenosine kinase inhibitor while 5-iodotubercidin was the most potent in inhibiting the facilitated uptake of adenosine. These compounds may be useful for elucidating the involvement of adenosine kinase in adenosine uptake, the maintenance of intracellular adenosine levels and in the neuromodulatory actions of adenosine in the CNS.

Adenosine↗

PubMed1991

Activity of acyclic halogenated tubercidin analogs against human cytomegalovirus and in uninfected cells.

Novel acyclic halogenated tubercidins (4-amino-5-halo-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidines) were examined for their ability to inhibit human cytomegalovirus (HCMV) in yield reduction assays. 5-Bromo acyclic tubercidin (compound 102) was a more potent inhibitor of virus replication than the chloro- and iodo-substituted analogs (compounds 100 and 104). At a 100 microM concentration, the bromo and chloro compounds were more potent than acyclovir but not ganciclovir. Virus titers were reduced more than 99% by compounds 102 and 104 whereas compound 100 and the equally potent acyclovir reduced titers by only 90%. Quantitation of viral DNA by DNA hybridization demonstrated strong inhibition of HCMV DNA synthesis by these compounds. The most potent inhibitor, compound 102, had a 50% inhibitory (I50) concentration (1.6 microM) comparable to that of ganciclovir (1.8 microM). Cytotoxicity in uninfected human cells was evaluated and revealed the following: cell growth rates slowed markedly in the presence of 10 microM compound 102 whereas the same concentration of compounds 100 and 104 led to only a slight prolongation of population doubling time; these compounds inhibited cellular DNA synthesis but not RNA or protein synthesis, as measured by incorporation of radiolabeled precursors into acid-precipitable macromolecules; flow cytometry indicated that compound 102 was a mid-S phase blocker, and adenosine antagonized the inhibition of [3H]dThd incorporation by compound 102. Together, these results demonstrate that compound 102 is a potent and selective inhibitor of viral and cellular DNA synthesis and that acyclic halogenated pyrrolo-pyrimidine nucleosides may have therapeutic potential.

Adenosine↗

PubMed1998

Structural polymorphism in a tubercidin analogue of the DNA double helix.

A high-angle X-ray fibre diffraction study of a tubercidin analogue of the poly[d(A-T)].poly[d(A-T)] DNA double helix has been carried out using station 7.2 at the Daresbury Laboratory synchrotron radiation source. The polymer has been studied for a wide range of salt strengths and hydration conditions and exhibits conformational polymorphism that is quite distinct from that observed for the unmodified polymer. The replacement of deoxyadenosine by deoxytubercidin in the polynucleotide causes only slight alterations to the structure of A-DNA, but significantly alters the structure of the B conformation. Additionally, the modified polymer does not, in any conditions yet identified, adopt the D conformation. In conditions which would normally favour the D conformation of poly[d(A-T)].poly[d(A-T)], the modified polymer adopts an unusual conformation which is designated here as the K conformation. These observations are important for an understanding of major groove interactions involved in the stabilisation of particular DNA conformations and also more generally for an insight into the pharmacological activity of tubercidin which following its incorporation into nucleic acids may cause stereochemical distortions of the DNA double helix.

DNA↗