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PubMed1978

Influence of toyocamycin on the assembly and processing of preribosomal ribonucleoproteins in the nucleolus of mammalian cells.

The adenosine analogue toyocamycin inhibits the maturation of ribosomal RNA, but permits the synthesis of other RNA species, including 45 S preribosomal RNA. In this work, the dose vs. response analysis of rRNA processing upon toyocamycin treatment of L5178Y cells is studied. It is shown that the latter steps of rRNA processing are more affected than the earlier. The mechanism responsible for the lack of conversion of toyocamycin-containing 45 S RNA into mature rRNA has not yet been elucidated. In order to investigate whether protein factors are involved in this mechanism, the effects of toyocamycin on the ability of preribosomal RNA to bind proteins and on the assembly of nucleolar preribosomes are investigated. The analogue allows the formation and the accumulation, in the nucleolus, of ribonucleoprotein complexes which contain 45 S RNA and newly synthesized proteins, but cannot be converted to mature ribosomal subunits. These complexes are not clearly distinguishable from 80 S particles synthesized in the absence of toyocamycin, with respect to their sedimentation rate in linear sucrose gradients, to their protein/RNA ratio and to their density measured in metrizamide gradients.

Antibiotics, Antineoplastic↗

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

Comparison of the cellular and RNA-dependent effects of sangivamycin and toyocamycin in human colon carcinoma cells.

The effects of the pyrrolopyrimidine antibiotics sangivamycin and toyocamycin on the synthesis of RNA and protein, ribosomal RNA processing, and cell viability were examined in colon carcinoma cell line HT-29. Exposure for 24 hr to toyocamycin caused an exponential type of cell lethality resulting in a 4-log reduction of cell viability, while sangivamycin produced a gradual and self-limiting type of cell lethality resulting in a 1-log reduction of cell viability. Toyocamycin, at a concentration of 1 microM produced total cessation of precursor rRNA processing, while 10 microM sangivamycin produced little or no effect on processing. On the contrary, sangivamycin caused a significant decrease in protein synthesis after 6 hr, while toyocamycin had less effect. The inhibition of protein synthesis by sangivamycin results from an inhibition of the formation of complexes essential to the initiation of protein synthesis. The results suggest that the mechanisms of action of these closely related agents are quite distinct. The marked loss of cell viability caused by toyocamycin correlates with its effect on rRNA processing, while the slow inhibition of protein synthesis appears to be secondary to the loss of ribosome synthesis. On the other hand, the lesser cytotoxicity produced by sangivamycin results from a more direct effect on protein synthesis. Importantly, cells are much less capable of resuming normal proliferative activity after 24 hr of impaired rRNA processing than after a similar interval of reduced protein synthesis.

Antibiotics, Antineoplastic↗

PubMed1977

Toyocamycin inhibition of ribosomal ribonucleic acid processing in an osmotic-sensitive adenosine-utilizing Saccharomyces cerevisiae mutant.

An adenosine-utilizing mutant of Saccharomyces cerevisiae (SY 15 ado) is isolated after remutagenesis of an osmotic-sensitive strain, auxotrophic for adenine, with ethyl methanesulfonate. It is shown that the SY15ado mutant can be used to achieve experimental conditions under which cell growth and RNA Synthesis are directly dependent on exogenous adenosine. After starvation for adenosine, toyocamycin is incorporated into pre-rRNA chains of SY15ado cells replacing adenosine residues. The extent of this replacement depends on the concentration of added toyocamycin. Lower doses slow down processing of pre-rRNA into mature rRNA with an accumulation of 27 S and 20 S pre-rRNA. At higher concentrations toyocamycin blocks the last steps of pre-rRNA processing i.e. the conversions 27 S pre-rRNA leads to 25 S rRNA and 20 S pre-rRNA leads to 18 S rRNA. It appears that the main site of toyocamycin action is at the last steps of ribosome formation, while transcription and the early stages of pre-RNA processing are less affected.

Adenosine↗

PubMed1981

[Effect of toyocamycin on the biosynthesis of viral glycoproteins in a cell line chronically infected with a murine retrovirus].

Toyocamycin (TMC), an adenosine analog has been previously reported to inhibit both number and infectivity of retrovirus particles released by chronically infected cells (Bonar et al., 1970; Riman, 1971; Mauchauffé et al., 1979). We have previously shown that loss of infectivity could result from the incorporation of TMC in place of adenosine in the genomic 35S RNA (Larsen et al., 1979). This phenomenon is likely to impair the structure of the viral genome in such a way that reverse transcriptase cannot properly copy the template. Another consequence of the Toyocamycin action on the retrovirus particles released by analog-treated cells was their reduced content in envelope glycoprotein or gp70 (Mathieu - Mahul et al., 1979). In order to find the origin of this defect, which could also explain the loss of infectivity, viral polypeptides present in the cytoplasm of Toyocamycin-treated cells were analyzed by immunoprecipitation with specific antisera. The results indicated a diminution of the biosynthesis of the envelope glycoprotein and other GAG gene-related polypeptides. However, the gpr85env precursor was normally synthesized and processed into its final products (gp70 + p15E), which accumulated in the cells. These result make it likely that Toyocamycin has no specific effect on the virus replicative process in chronically infected cells but acts by deteriorating cellular functions, which are necessary to virus assembly. Indeed, it was found that a membrane fraction corresponding to smooth endoplasmic reticulum and Golgi apparatus was severely reduced if not totally suppressed in TMC-treated cells.

Animals↗

PubMed2001

Synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins.

Toyocamycin and some analogues have shown potent antitumor activities; however, none of them could be used clinically primarily owing to their cytotoxicity to normal human cells. In order to overcome the weakness of these nucleoside analogues, substitution of a variety of modified sugars for the ribofuranose was explored in our laboratories with expectation that certain sugar-modified toyocamycin analogues may be selectively cytotoxic to cancer cells. In this article, we report synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins, which were prepared via the condensations of 4-C- and 5-C-substituted ribofuranose derivatives 11, 12, 13, 20, 21, and 26 with the silylated form of 4-amino-6-bromo-5-cyanopyrrolo[2,3-]pyrimidine (27) and subsequent debromination and debenzoylation. When compared to the parent toyocamycin, all these analogues showed much lower cytotoxicity to human prostate cancer cells (HTB-81), mouse melanoma cancer cells (B16) as well as normal human fibroblasts. Compound 1e showed a significant cytotoxicity to the prostate cancer cells and a moderate selectivity. The results suggested that sugar modifications, especially those that may affect phosphorylation of nucleosides, could alter cytotoxicity profile significantly.

Animals↗

PubMed1977

Regulation of ribosomal RNA synthesis in mammalian cells: effect of toyocamycin.

The present study shows that the antitumor agent toyocamycin (4-amino-5-cyano-7beta-D-ribofuranosylpyrrolo(2-3d)pyrimidine) affects rRNA transcription in Ehrlich ascites cells. This action of the antibiotic is dependent on the amino acid composition of the cell culture medium. In cells incubated in a medium rich in amino acids, the high transcription rate of rRNA is lowered by the addition of 2 X 10(-6) M toyocamycin, while in amino acid starved cells the decreased level of rRNA synthesis remains unaffected. Processing of the 45S rRNA precursor is markedly inhibited by toyocamycin in cells incubated in either medium, indicating that the uptake of the drug is unimpaired by amino acid starvation. Toyocamycin does not affect RNA polymerase I (RNA nucleotidyltransferase EC 2.7.7.6) activity when added to in vitro assay systems derived from cells grown in complete or in amino acid deficient media. The drug prevents the activation of rRNA synthesis following the refeeding of amino acid starved cells without affecting the stimulation of protein synthesis.

Amino Acids↗

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↗

PubMed1997

Structural and functional relationships of toyocamycin on NPM-translocation.

Toyocamycin is an antitumor antibiotic which has a pyrrolo[2,3-D]pyrimidine aglycone with a -CN substituent on the 5-carbon. Treatment of HeLa cells with toyocamycin induces redistribution of the nuclear phosphoprotein nucleophosmin/B23 (NPM) from nucleoli to nucleoplasm (NPM-translocation) which can be detected by immunofluorescence. NPM-translocation is useful in showing drug effects and in detecting drug-resistant cancer cells. To study which structural features of toyocamycin are important for NPM-translocation, we used toyocamycin analogs in which the 5-position -CN was either deleted (tubercidin) or replaced with a -CONH2 (sangivamycin) or -C(NOH)NH2. HeLa cells were incubated with these analogs for 4 h and assayed for NPM-translocation by immunofluorescence. We found that the analog with the deletion of the -CN group (tubercidin) did not induce translocation while those with replacement of the -CN group with -CONH2 or -C(NOH)NH2 retained the NPM-translocation activity. When these or similar modifications were applied to 7-deazaguanosine, none of the guanosine analogs were effective. These results indicate that modifications at the 5-position of the pyrrolo[2,3-D]pyrimidine ring and a structure similar to adenine rather than guanine are essential for NPM-translocation. Since inhibition of RNA synthesis did not induce NPM-translocation, our results suggest that interference with NPM's binding in nucleoli by these analogs causes NPM-translocation.

Antibiotics, Antineoplastic↗

PubMed1984

Fast atom bombardment mass spectrometry and tandem mass spectrometry in antibiotics: identification of nucleoside antitumor antibiotic toyocamycin in fermentation broth.

The presence of the nucleoside antitumor antibiotic toyocamycin in the fermentation broth was determined by a combination of negative and positive ion fast atom bombardment (FAB) mass spectrometry, high resolution FAB mass spectrometry and mass-analysed ion kinetic energy spectrometry (MIKES). A reasonable limit of detection for toyocamycin in the whole broth was obtained by combining the specificity of mass spectrometry/mass spectrometry (also called tandem mass spectrometry) to FAB. The role played by the fermentation matrix upon the production and the observation of characteristic ions by FAB using xenon atoms was examined. High-performance liquid chromatography (HPLC) and FAB mass spectrometry were used to monitor toyocamycin at all stages of strain development, fermentation and recovery.

Antibiotics, Antineoplastic↗

PubMed1982

Effect of toyocamycin on oncornaviral production by acutely infected cells.

The adenosine analogue toyocamycin incorporates into the RNA species of mammalia cells and abolishes at low concentrations of the processing of 45S preribosomal nucleolar RNA into the mature 28 and 18S cytoplasmic ribosomal RNAs. We have previously shown that toyocamycin depresses the production of the Friend leukemia viral complex by chronically infected cells. In this article, we report the study of the action of the drug on viral RNA in acutely infected cells. We found that, although abolishing viral production, the incorporation of toyocamycin does not inhibit the formation of mature viral messenger RNAs nor prevent the synthesis of specific viral proteins. These results are obtained at concentrations of analogue sufficient to abolish the appearance of mature cytoplasmic ribosomal RNA.

Animals↗

PubMed2002

Induction of p16/INK4a gene expression and cellular senescence by toyocamycin.

We constructed an assay system of a luciferase reporter with p16/lNK4a gene transcriptional regulatory domain to identify p16-inducing substances, and found toyocamycin to induce gene expression from the screening of culture fluids of Streptomyces. Toyocamycin is a nucleoside analog, and it increased the p16 mRNA level in human normal fibroblasts or synovial cells as assessed by Northern blot hybridization or real time RT-PCR. It also induced cellular senescence in normal human fibroblasts. The transcriptional regulatory regions of human p16 gene that were responsible for the induction were analyzed using deletion mutants of the transcriptional regulatory region of p16 linked to the luciferase gene. The DNA fragment -111 to +1 bp from the cap site was sufficient to drive toyocamycin-activated transcription of p16/luciferase reporter. Nucleotide sequences within this domain contained the Sp1- and Ets-binding sequences. Mutations were introduced into these sequences, and the Sp1 sequence was found to be critical for the induction, and this notion was confirmed from gel-mobility shift assay.

Base Sequence↗

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↗

PubMed2005

Synthesis of 2'-beta-C-methyl toyocamycin and sangivamycin analogues as potential HCV inhibitors.

Coupling reaction of 2-beta-C-methyl-1,2,3,4-tetra-O-benzoyl-d-ribofuranose with 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine, followed by debromination and debenzoylation, gave the 2'-beta-C-methyl toyocamycin in high yield. Based on this result, a series of 2'-beta-C-methyl-4-substituted toyocamycin and sangivamycin analogues were synthesized for biological screening as potential inhibitors of HCV RNA replication.

Adenosine↗

PubMed1976

Synthesis and biological activity of pyrazolo[3,4,-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin.

The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at less than or equal to 1 mug/ml. 4-Amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5'-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRNA to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylsine in a cellfree system. The copolymer consiting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4degreesC.

Antibiotics, Antineoplastic↗

PubMed1987

Nucleic acid related compounds. 51. Synthesis and biological properties of sugar-modified analogues of the nucleoside antibiotics tubercidin, toyocamycin, sangivamycin, and formycin.

Treatment of 7-amino-3-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine (formycin) with alpha-acetoxyisobutyryl bromide followed by deprotection of the resulting trans-vicinal acetoxy bromides and hydrogenolysis of the separated bromohydrins gave 2'-deoxy-(23%) and 3'-deoxyformycin (32%) after complete deprotection and purification of their hydrochloride salts. An analogous sequence gave 3'-deoxytoyocamycin and/or 3'-deoxysangivamycin in approximately 80% yields from toyocamycin. Antiviral, antineoplastic, and antimetabolic effects were evaluated for the formycin compounds and 4-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine (tubercidin), its 5-cyano- (toyocamycin), and 5-carbamoyl-(sangivamycin) antibiotic congeners in comparison with their 2'-deoxy, 3'-deoxy, and arabino analogues. In all cases, the modified-sugar compounds were less cytotoxic than the parent antibiotics. The majority also exhibited lower antiviral potency. However, the xylo-tubercidin analogue retained potent antiherpes 1 and 2 activity with decreased cytotoxicity. Labeled metabolite studies suggested that effects of these compounds on RNA and/or protein synthesis might be more significant than interference with DNA synthesis.

Animals↗

PubMed1996

Synthesis of non-nucleoside analogs of toyocamycin, sangivamycin, and ++thiosangivamycin: influence of various 7-substituents on antiviral activity.

A number of 7-substituted 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1). Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (1) with triethyl orthoformate followed by alkylation via the sodium salt method with a variety of alkylating agents furnished the corresponding 1-substituted pyrroles 2a-k. Ring annulation was achieved with methanolic ammonia affording the 7-substituted 4-amino-6-bromopyrrolo++-[2,3-d]pyrimidine-5-carbonitrile derivatives 3a-k. Debromination of 3a-k, via catalytic hydrogenation, gave the corresponding 7-substituted 4-aminopyrrolo[2,3-d]pyrimidine-5-carbonitrile analogs 4a-j,l. A selective reduction of 4-amino-6-bromo-7-allylpyrrolo[2,3-d]-pyrimidine-5-carbon ril e (3k) in zinc and acetic acid furnished 4-amino-7-allylpyrrolo-[2,3-d]pyrimidine-5-carbonitrile (4k). Conventional functional group transformations involving the 5-cyano group of 4 furnished the 5-carboxamide derivatives 5a-1 and the 5-thio-amide analogs 6a-l. A similar transformation of the aglycone of toyocamycin (4m) furnished the corresponding aglycone of thiosangivamycin (6m). Several of the new compounds (4-6a-ej-l) were evaluated for their ability to inhibit the growth of L1210 murine leukemic cells. Whereas a number of the carboxamide (5) and thioamide (6) derivatives had modest activity, the corresponding nitrile analogs (4) were all inactive. All compounds were tested for activity against HCMV and HSV-1. The non-nucleoside nitrile analogs 4a-m and carboxamide derivatives 5a-l were, with a few exceptions, essentially inactive against HCMV and HSV-1 and relatively nontoxic. In direct contrast, nearly all of the thioamide derivates 6a-1, including the aglycone of thiosangivamycin (6m), were good inhibitors of HCMV and HSV-1. Most were noncytotoxic in their antiviral concentration range. Cytotoxicity which was observed appeared to be a consequence of DNA synthesis inhibition. Several of these compounds, such as 6b,e, were particularly interesting inhibitors of HCMV with IC(50)'s ranging from 0.1 to 1.3 muM. The antiviral activity of both compounds was well separated from cytotoxicity in KB, HFF, and L1210 cells.

Antiviral Agents↗

PubMed1979

Effect of toyocamycin on the synthesis of the 70S RNA of a murine retrovirus.

The murine Eveline cell line chronically infected by Friend virus was treated with Toyocamycin (TMC), an adenosin analog and the virions released in the presence of the drug were examined for their RNA. It was found that 70S RNA which was synthesized incorporated Toyocamycin. However, its subunit structure and its poly (A) content were apparently preserved. This incorporation may explain loss of endogenous reverse transcriptase activity.

Animals↗