Toyocamycin

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Toyocamycin
Toyocamycin.svg
Names
IUPAC name
4-Amino-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
Other names
  • 7-Deaza-7-cyanoadenosine
  • Naritheracin
  • Siromycin
  • Toyokamycin
  • Unamycin B
  • Uramycin B
  • Vengicide
Identifiers
3D model (JSmol)
4-26-00-01419
ChEBI
ChEMBL
ChemSpider
DrugBank
MeSH Toyocamycin
PubChem CID
UNII
  • InChI=1S/C12H13N5O4/c13-1-5-2-17(11-7(5)10(14)15-4-16-11)12-9(20)8(19)6(3-18)21-12/h2,4,6,8-9,12,18-20H,3H2,(H2,14,15,16)/t6-,8-,9-,12-/m1/s1
    Key: XOKJUSAYZUAMGJ-WOUKDFQISA-N
  • N#CC1CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C2NCNC(N)C12
Properties
C12H13N5O4
Molar mass 291.267 g·mol−1
Melting point 243 [1]  °C (469 °F; 516 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Toyocamycin is a naturally occurring nucleoside antibiotic analog of adenosine. It was first isolated from the bacterium Streptomyces toyocaensis . [2] [3] It has diverse biological activities including anticancer, [4] antifungal, [3] and antiviral properties. Besides S. toyocaensis, it is found in Streptomyces sparsogenes , [5] Streptomyces diastatochromogenes , [6] [7] [8] [9] Streptomyces rimosus , [10] and Tolypothrix tenuis . [11]

Contents

Structure

The chemical name of toyocamycin is 4-amino-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile. It is an N-glycosylpyrrolopyrimidine and a derivative of tubercidin, where the hydrogen at position 5 of the pyrrolopyrimidine ring is substituted with a nitrile group.

Toyocamycin closely resembles adenosine, except that the nitrogen at position 7 of the purine ring is replaced by a carbon atom, and a nitrile group (-C≡N) is attached at that position.

Tubercidin.svg
Toyocamycin.svg
Syn-Adenosine.svg
TubercidinToyocamycinAdenosine
Structural similarity of toyocamycin with tubercidin and adenosine

Biological activity

Toyocamycin exhibits a broad spectrum of biological activities, making it an excellent interest in various research fields

Anticancer activity

Toyocamycin demonstrates cytotoxic effects on various cancer cell lines, including those of multiple myeloma, [12] colon cancer, [4] [13] and pancreatic cancer. [14] It works by triggering apoptosis in these cells. [12] In the case of multiple myeloma, toyocamycin has shown enhanced effectiveness when used in combination with the proteasome inhibitor bortezomib, and it remains active even against cells that have become resistant to bortezomib. Studies in animal models of human multiple myeloma have further demonstrated that toyocamycin can suppress tumor growth in vivo. [12]

Antifungal activity

Toyocamycin has strong antifungal properties. It shows effectiveness against a wide variety of fungal species, [15] including plant pathogens [7] [8] [16] [17] and the human fungal pathogen Candida albicans . [3] Because of this broad-spectrum activity, toyocamycin is considered a promising candidate for use in both agriculture and medicine. [7]

Antiviral activity

Toyocamycin has demonstrated antiviral activity against several viruses, including fowl plague virus, [18] murine oncornavirus (Friend virus), [19] avian tumour virus, [20] and human cytomegalovirus (HCMV). [21] It has been shown to inhibit viral replication and reduce viral titers in infected cells. [19] [21]

Other biological activities

In addition to these activities, toyocamycin has been found to induce the translocation of nucleophosmin/B23 (NPM) from the nucleoli to the nucleoplasm in HeLa cells. [22] It also inhibits phosphatidylinositol kinase, an enzyme involved in cell signaling. [23] Furthermore, toyocamycin specifically disrupts auxin signaling in plants, thereby affecting their growth and development. [24]

Mechanism of action

Toyocamycin exerts its biological effects through multiple mechanisms, mainly due to its structural similarity to adenosine. This resemblance enables it to disrupt various adenosine-dependent cellular processes.

Inhibition of RNA Synthesis and Ribosome Function

Toyocamycin mimics adenosine and can be mistakenly incorporated into RNA during transcription, which disrupts or stops RNA production. [20] [25] There is also evidence that it can interfere with DNA synthesis. One of its key actions is blocking the processing of ribosomal RNA, especially the maturation of 28S and 18S rRNA. [13] [26] At lower doses, Toyocamycin slows down the processing of precursor rRNA, causing intermediate forms like 27S and 20S pre-rRNA to build up. At higher doses, it can completely stop the final processing steps, preventing the formation of mature 25S and 18S rRNA. [27] This interference with ribosome production affects protein synthesis and can seriously reduce cell survival. [13]

Inhibition of IRE1α-XBP1 Pathway

Toyocamycin is a strong blocker of XBP1 mRNA splicing, a key step in the unfolded protein response (UPR) that helps cells deal with stress in the endoplasmic reticulum. It stops XBP1 splicing triggered by common ER stressors like thapsigargin, tunicamycin, and 2-deoxyglucose, without interfering with other parts of the UPR, such as the ATF6 and PERK pathways. While it doesn't stop the phosphorylation of the IRE1α protein, it does prevent IRE1α from cutting XBP1 mRNA in lab experiments. This effect isn't limited to stress situations as toyocamycin also demonstrated blocking the constant activation of XBP1 seen in multiple myeloma cells and samples from patients. [12]

Selective Inhibition of CDK9

Toyocamycin has also been identified as a selective inhibitor of cyclin-dependent kinase 9 (CDK9), particularly in cancer cells. It demonstrates a strong inhibitory effect on CDK9, with an IC50 of 79 nM, while showing considerably weaker activity against other cyclin-dependent kinases such as CDK2, CDK4, CDK6, and CDK7. This selectivity results in reduced phosphorylation of RNA polymerase II, a key process regulated by CDK9 that is essential for gene transcription. Molecular docking studies suggest that toyocamycin fits tightly into CDK9's active site in a unique way compared to its interactions with other CDKs, which likely explains its specificity. [4]

Inhibition of Rio1 kinase

Toyocamycin is known to inhibit Rio1 kinase, a key enzyme required for the proper processing and maturation of the 40S ribosomal subunit. Toyocamycin binds more strongly to Rio1 than its usual substrate, ATP and reduces the enzyme's activity, possibly by stabilizing a form of Rio1 that is less active in catalyzing reactions. [15]

Interference with auxin signaling

In plants, toyocamycin specifically disrupts auxin signaling through the SCFTIR1 pathway. It prevents the activation of genes that typically respond to auxin and blocks the auxin-triggered breakdown of Aux/IAA repressor proteins. As a result, toyocamycin interferes with normal plant development, leading to noticeable effects such as reduced formation of lateral roots and epinastic growth of cotyledons in Arabidopsis thaliana . [24]

Inhibition of phosphatidylinositol kinase

Toyocamycin has also been found to inhibit phosphatidylinositol kinase, an enzyme that plays a role in regulating cell growth and proliferation. Laboratory studies using the enzyme extracted from A431 cell membranes have shown that toyocamycin inhibits its activity with an IC50 value of 3.3 μg/mL. [23]

Transport mechanism in Candida albicans

Toyocamycin shows selective toxicity against Candida albicans , mainly due to its efficient uptake by the fungus through a specific concentrative nucleoside transporter (CNT). In contrast, Saccharomyces cerevisiae is less affected because it lacks this transporter. When the CNT gene from C. albicans is introduced into S. cerevisiae, the yeast becomes sensitive to toyocamycin. Conversely, disrupting the CNT gene in C. albicans makes it resistant, hightlighting the role of this transporter in the drug's antifungal action. [3]

References

  1. ↑ data obtained from Syracuse Research Corporation of Syracuse, New York (US)
  2. ↑ Tolman, Richard L.; Robins, Roland K.; Townsend, Leroy B. (1968-01-01). "Pyrrolo[2,3-d]pyrimidine nucleoside antibiotics. Total synthesis and structure of toyocamycin, unamycin B, vengicide, antibiotic E-212, and sangivamycin (BA-90912)" . Journal of the American Chemical Society. 90 (2): 524–526. Bibcode:1968JAChS..90..524T. doi:10.1021/ja01004a076. ISSN   0002-7863. PMID   5634627.
  3. 1 2 3 4 Ojima, Yoshihiro; Yokota, Naoki; Tanibata, Yuki; Nerome, Shinsuke; Azuma, Masayuki (2022-08-31). "Concentrative Nucleoside Transporter, CNT, Results in Selective Toxicity of Toyocamycin against Candida albicans". Microbiology Spectrum. 10 (4): e0113822. doi:10.1128/spectrum.01138-22. ISSN   2165-0497. PMC   9431476 . PMID   35913167.
  4. 1 2 3 Pandey, Somnath; Djibo, Rahinatou; Darracq, Anaïs; Calendo, Gennaro; Zhang, Hanghang; Henry, Ryan A.; Andrews, Andrew J.; Baylin, Stephen B.; Madzo, Jozef; Najmanovich, Rafael; Issa, Jean-Pierre J.; Raynal, Noël J.-M. (2022-07-08). "Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells". Cancers. 14 (14). MDPI AG: 3340. doi: 10.3390/cancers14143340 . ISSN   2072-6694. PMC   9324262 . PMID   35884401.
  5. ↑ Poehland, B. L.; Chan, J. A. (1988-05-20). "Direct broth assay for sparsomycin and related nucleoside antitumor antibiotics using reversed-phase high-performance liquid chromatography". Journal of Chromatography. 439 (2): 459–465. doi:10.1016/s0021-9673(01)83861-9. PMID   3403654.
  6. ↑ Ma, Zheng; Luo, Shuai; Xu, Xianhao; Bechthold, Andreas; Yu, Xiaoping (2016-04-01). "Characterization of representative rpoB gene mutations leading to a significant change in toyocamycin production of Streptomyces diastatochromogenes 1628". Journal of Industrial Microbiology & Biotechnology. 43 (4): 463–471. doi:10.1007/s10295-015-1732-4. ISSN   1476-5535. PMID   26790416.
  7. 1 2 3 Ma, Zheng; Liu, Jinxiu; Shentu, Xuping; Bian, Yalin; Yu, Xiaoping (2014-04-01). "Optimization of electroporation conditions for toyocamycin producer Streptomyces diastatochromogenes 1628". Journal of Basic Microbiology. 54 (4): 278–284. doi:10.1002/jobm.201200489. ISSN   1521-4028. PMID   23775805.
  8. 1 2 Shentu, Xu-Ping; Cao, Zhen-Yan; Xiao, Yin; Tang, Gu; Ochi, Kozo; Yu, Xiao-Ping (2018). "Substantial improvement of toyocamycin production in Streptomyces diastatochromogenes by cumulative drug-resistance mutations". PLOS ONE. 13 (8): e0203006. Bibcode:2018PLoSO..1303006S. doi: 10.1371/journal.pone.0203006 . ISSN   1932-6203. PMC   6117005 . PMID   30161195.
  9. ↑ Ma, Zheng; Tao, Libin; Bechthold, Andreas; Shentu, Xuping; Bian, Yalin; Yu, Xiaoping (2014-06-01). "Overexpression of ribosome recycling factor is responsible for improvement of nucleotide antibiotic-toyocamycin in Streptomyces diastatochromogenes 1628". Applied Microbiology and Biotechnology. 98 (11): 5051–5058. doi:10.1007/s00253-014-5573-2. ISSN   1432-0614. PMID   24509772.
  10. ↑ Battaglia, Ugo; Long, Jed E.; Searle, Mark S.; Moody, Christopher J. (2011-04-07). "7-Deazapurine biosynthesis: NMR study of toyocamycin biosynthesis in Streptomyces rimosus using 2-13C-7-15N-adenine". Organic & Biomolecular Chemistry. 9 (7): 2227–2232. doi:10.1039/c0ob01054e. ISSN   1477-0539. PMID   21298182.
  11. ↑ Stewart, J. B.; Bornemann, V.; Chen, J. L.; Moore, R. E.; Caplan, F. R.; Karuso, H.; Larsen, L. K.; Patterson, G. M. (1988-08-01). "Cytotoxic, fungicidal nucleosides from blue green algae belonging to the Scytonemataceae". The Journal of Antibiotics. 41 (8): 1048–1056. doi: 10.7164/antibiotics.41.1048 . ISSN   0021-8820. PMID   3139604.
  12. 1 2 3 4 Ri, M.; Tashiro, E.; Oikawa, D.; Shinjo, S.; Tokuda, M.; Yokouchi, Y.; Narita, T.; Masaki, A.; Ito, A.; Ding, J.; Kusumoto, S.; Ishida, T.; Komatsu, H.; Shiotsu, Y.; Ueda, R. (2012-07-01). "Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing". Blood Cancer Journal. 2 (7): e79. doi:10.1038/bcj.2012.26. ISSN   2044-5385. PMC   3408640 . PMID   22852048.
  13. 1 2 3 Cohen, M. B.; Glazer, R. I. (1985-03-01). "Comparison of the cellular and RNA-dependent effects of sangivamycin and toyocamycin in human colon carcinoma cells". Molecular Pharmacology. 27 (3): 349–355. doi:10.1016/S0026-895X(25)12339-0. ISSN   0026-895X. PMID   2579317.
  14. ↑ Chien, Wenwen; Ding, Ling-Wen; Sun, Qiao-Yang; Torres-Fernandez, Lucia A.; Tan, Siew Zhuan; Xiao, Jinfen; Lim, Su Lin; Garg, Manoj; Lee, Kian Leong; Kitajima, Shojiro; Takao, Sumiko; Leong, Wei Zhong; Sun, Haibo; Tokatly, Itay; Poellinger, Lorenz (2014-07-15). "Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells". Oncotarget. 5 (13): 4881–4894. doi:10.18632/oncotarget.2051. ISSN   1949-2553. PMC   4148107 . PMID   24952679.
  15. 1 2 Kiburu, Irene N.; LaRonde-LeBlanc, Nicole (2012). "Interaction of Rio1 kinase with toyocamycin reveals a conformational switch that controls oligomeric state and catalytic activity". PLOS ONE. 7 (5): e37371. Bibcode:2012PLoSO...737371K. doi: 10.1371/journal.pone.0037371 . ISSN   1932-6203. PMC   3358306 . PMID   22629386.
  16. ↑ Ma, Zheng; Hu, Yefeng; Liao, Zhijun; Xu, Jie; Xu, Xianhao; Bechthold, Andreas; Yu, Xiaoping (2020). "Cloning and Overexpression of the Toy Cluster for Titer Improvement of Toyocamycin in Streptomyces diastatochromogenes". Frontiers in Microbiology. 11 2074. doi: 10.3389/fmicb.2020.02074 . ISSN   1664-302X. PMC   7492574 . PMID   32983052.
  17. ↑ Ma, Zheng; Liu, Jinxiu; Lin, Xiaozhen; Shentu, Xuping; Bian, Yalin; Yu, Xiaoping (2014-03-01). "Formation, regeneration, and transformation of protoplasts of Streptomyces diastatochromogenes 1628". Folia Microbiologica. 59 (2): 93–97. doi:10.1007/s12223-013-0271-5. ISSN   1874-9356. PMID   23900861.
  18. ↑ Becker, Yechiel (2012-12-06). Replication of Viral and Cellular Genomes: Molecular events at the origins of replication and biosynthesis of viral and cellular genomes. Springer Science & Business Media. p. 355. ISBN   978-1-4613-3888-8.
  19. 1 2 Mauchauffé, M.; Hamelin, R.; Tavitian, A.; Michel, M. L.; Larsen, C. J. (1979-02-01). "Effects of toyocamycin on the biological activity of a murine oncornavirus produced by a chronically infected cell line". Biomédicine. 31 (1): 17–20. ISSN   0300-0893. PMID   89874.
  20. 1 2 Sverak, L.; Bonar, R. A.; Langlois, A. J.; Beard, J. W. (1970-12-14). "Inhibition by toyocamycin of RNA synthesis in mammalian cells and in normal and avian tumor virus-infected chick embryo cells". Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis. 224 (2): 441–450. doi:10.1016/0005-2787(70)90576-9. ISSN   0006-3002. PMID   4322403.
  21. 1 2 Jacobson, J. G.; Renau, T. E.; Nassiri, M. R.; Sweier, D. G.; Breitenbach, J. M.; Townsend, L. B.; Drach, J. C. (1999-08-01). "Nonnucleoside pyrrolopyrimidines with a unique mechanism of action against human cytomegalovirus". Antimicrobial Agents and Chemotherapy. 43 (8): 1888–1894. doi:10.1128/AAC.43.8.1888. ISSN   0066-4804. PMC   89386 . PMID   10428908.
  22. ↑ Finch, R. A.; Revankar, G. R.; Chan, P. K. (1997-04-01). "Structural and functional relationships of toyocamycin on NPM-translocation". Anti-Cancer Drug Design. 12 (3): 205–215. ISSN   0266-9536. PMID   9154111.
  23. 1 2 Nishioka, H.; Sawa, T.; Hamada, M.; Shimura, N.; Imoto, M.; Umezawa, K. (1990-12-01). "Inhibition of phosphatidylinositol kinase by toyocamycin". The Journal of Antibiotics. 43 (12): 1586–1589. doi: 10.7164/antibiotics.43.1586 . ISSN   0021-8820. PMID   2177464.
  24. 1 2 Hayashi, Ken-ichiro; Kamio, Shuichi; Oono, Yutaka; Townsend, Leroy B.; Nozaki, Hiroshi (2009-01-01). "Toyocamycin specifically inhibits auxin signaling mediated by SCFTIR1 pathway". Phytochemistry. 70 (2): 190–197. Bibcode:2009PChem..70..190H. doi:10.1016/j.phytochem.2008.12.020. ISSN   0031-9422. PMID   19171357.
  25. ↑ Ríman, J.; Sverak, L.; Langlois, A. J.; Bonar, R. A.; Beard, J. W. (1969-09-01). "Influence of toyocamycin on RNA synthesis in chick embryo cells noninfected and infected with strain MC29 avian leukosis virus". Cancer Research. 29 (9): 1707–1716. ISSN   0008-5472. PMID   4309795.
  26. ↑ Iapalucci-Espinoza, Silva; Cereghini, Silvia; Franze-Fernandez, Maria Teresa (2002-05-01). "Regulation of ribosomal RNA synthesis in mammalian cells: effect of toyocamycin" . Biochemistry. 16 (13): 2885–2889. doi:10.1021/bi00632a013. PMID   560201 . Retrieved 2025-04-15.
  27. ↑ Venkov, P. V.; Stateva, L. I.; Hadjiolov, A. A. (1977-01-20). "Toyocamycin inhibition of ribosomal ribonucleic acid processing in an osmotic-sensitive adenosine-utilizing Saccharomyces cerevisiae mutant". Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis. 474 (2): 245–253. doi:10.1016/0005-2787(77)90199-x. ISSN   0006-3002. PMID   318864.
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