Toyocamycin

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.

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

Toyocamycin demonstrates cytotoxic effects on various cancer cell lines, including those of multiple myeloma,{{Cite journal |last1=Ri |first1=M. |last2=Tashiro |first2=E. |last3=Oikawa |first3=D. |last4=Shinjo |first4=S. |last5=Tokuda |first5=M. |last6=Yokouchi |first6=Y. |last7=Narita |first7=T. |last8=Masaki |first8=A. |last9=Ito |first9=A. |last10=Ding |first10=J. |last11=Kusumoto |first11=S. |last12=Ishida |first12=T. |last13=Komatsu |first13=H. |last14=Shiotsu |first14=Y. |last15=Ueda |first15=R. |date=2012-07-01 |title=Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing |journal=Blood Cancer Journal |volume=2 |issue=7 |pages=e79 |doi=10.1038/bcj.2012.26 |issn=2044-5385 |pmc=3408640 |pmid=22852048}} colon cancer,{{Cite journal |last1=Cohen |first1=M. B. |last2=Glazer |first2=R. I. |date=1985-03-01 |title=Comparison of the cellular and RNA-dependent effects of sangivamycin and toyocamycin in human colon carcinoma cells |url=https://pubmed.ncbi.nlm.nih.gov/2579317 |journal=Molecular Pharmacology |volume=27 |issue=3 |pages=349–355 |doi=10.1016/S0026-895X(25)12339-0 |issn=0026-895X |pmid=2579317}} and pancreatic cancer.{{Cite journal |last1=Chien |first1=Wenwen |last2=Ding |first2=Ling-Wen |last3=Sun |first3=Qiao-Yang |last4=Torres-Fernandez |first4=Lucia A. |last5=Tan |first5=Siew Zhuan |last6=Xiao |first6=Jinfen |last7=Lim |first7=Su Lin |last8=Garg |first8=Manoj |last9=Lee |first9=Kian Leong |last10=Kitajima |first10=Shojiro |last11=Takao |first11=Sumiko |last12=Leong |first12=Wei Zhong |last13=Sun |first13=Haibo |last14=Tokatly |first14=Itay |last15=Poellinger |first15=Lorenz |date=2014-07-15 |title=Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells |journal=Oncotarget |volume=5 |issue=13 |pages=4881–4894 |doi=10.18632/oncotarget.2051 |issn=1949-2553 |pmc=4148107 |pmid=24952679}} It works by triggering apoptosis in these cells. 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.

Toyocamycin has strong antifungal properties. It shows effectiveness against a wide variety of fungal species,{{Cite journal |last1=Kiburu |first1=Irene N. |last2=LaRonde-LeBlanc |first2=Nicole |date=2012 |title=Interaction of Rio1 kinase with toyocamycin reveals a conformational switch that controls oligomeric state and catalytic activity |journal=PLOS ONE |volume=7 |issue=5 |pages=e37371 |doi=10.1371/journal.pone.0037371 |doi-access=free |issn=1932-6203 |pmc=3358306 |pmid=22629386|bibcode=2012PLoSO...737371K }} including plant pathogens{{Cite journal |last1=Ma |first1=Zheng |last2=Hu |first2=Yefeng |last3=Liao |first3=Zhijun |last4=Xu |first4=Jie |last5=Xu |first5=Xianhao |last6=Bechthold |first6=Andreas |last7=Yu |first7=Xiaoping |date=2020 |title=Cloning and Overexpression of the Toy Cluster for Titer Improvement of Toyocamycin in Streptomyces diastatochromogenes |journal=Frontiers in Microbiology |volume=11 |pages=2074 |doi=10.3389/fmicb.2020.02074 |doi-access=free |issn=1664-302X |pmc=7492574 |pmid=32983052}}{{Cite journal |last1=Ma |first1=Zheng |last2=Liu |first2=Jinxiu |last3=Lin |first3=Xiaozhen |last4=Shentu |first4=Xuping |last5=Bian |first5=Yalin |last6=Yu |first6=Xiaoping |date=2014-03-01 |title=Formation, regeneration, and transformation of protoplasts of Streptomyces diastatochromogenes 1628 |url=https://pubmed.ncbi.nlm.nih.gov/23900861 |journal=Folia Microbiologica |volume=59 |issue=2 |pages=93–97 |doi=10.1007/s12223-013-0271-5 |issn=1874-9356 |pmid=23900861}} and the human fungal pathogen Candida albicans. Because of this broad-spectrum activity, toyocamycin is considered a promising candidate for use in both agriculture and medicine.

Toyocamycin has demonstrated antiviral activity against several viruses, including fowl plague virus,{{Cite book |last=Becker |first=Yechiel |url= |title=Replication of Viral and Cellular Genomes: Molecular events at the origins of replication and biosynthesis of viral and cellular genomes |date=2012-12-06 |publisher=Springer Science & Business Media |isbn=978-1-4613-3888-8 |pages=355 |language=en}} murine oncornavirus (Friend virus),{{Cite journal |last1=Mauchauffé |first1=M. |last2=Hamelin |first2=R. |last3=Tavitian |first3=A. |last4=Michel |first4=M. L. |last5=Larsen |first5=C. J. |date=1979-02-01 |title=Effects of toyocamycin on the biological activity of a murine oncornavirus produced by a chronically infected cell line |url=https://pubmed.ncbi.nlm.nih.gov/89874 |journal=Biomédicine |volume=31 |issue=1 |pages=17–20 |issn=0300-0893 |pmid=89874}} avian tumour virus,{{Cite journal |last1=Sverak |first1=L. |last2=Bonar |first2=R. A. |last3=Langlois |first3=A. J. |last4=Beard |first4=J. W. |date=1970-12-14 |title=Inhibition by toyocamycin of RNA synthesis in mammalian cells and in normal and avian tumor virus-infected chick embryo cells |url=https://pubmed.ncbi.nlm.nih.gov/4322403 |journal=Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis |volume=224 |issue=2 |pages=441–450 |doi=10.1016/0005-2787(70)90576-9 |issn=0006-3002 |pmid=4322403}} and human cytomegalovirus (HCMV).{{Cite journal |last1=Jacobson |first1=J. G. |last2=Renau |first2=T. E. |last3=Nassiri |first3=M. R. |last4=Sweier |first4=D. G. |last5=Breitenbach |first5=J. M. |last6=Townsend |first6=L. B. |last7=Drach |first7=J. C. |date=1999-08-01 |title=Nonnucleoside pyrrolopyrimidines with a unique mechanism of action against human cytomegalovirus |journal=Antimicrobial Agents and Chemotherapy |volume=43 |issue=8 |pages=1888–1894 |doi=10.1128/AAC.43.8.1888 |issn=0066-4804 |pmc=89386 |pmid=10428908}} It has been shown to inhibit viral replication and reduce viral titers in infected cells.

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.{{Cite journal |last1=Finch |first1=R. A. |last2=Revankar |first2=G. R. |last3=Chan |first3=P. K. |date=1997-04-01 |title=Structural and functional relationships of toyocamycin on NPM-translocation |url=https://pubmed.ncbi.nlm.nih.gov/9154111 |journal=Anti-Cancer Drug Design |volume=12 |issue=3 |pages=205–215 |issn=0266-9536 |pmid=9154111}} It also inhibits phosphatidylinositol kinase, an enzyme involved in cell signaling.{{Cite journal |last1=Nishioka |first1=H. |last2=Sawa |first2=T. |last3=Hamada |first3=M. |last4=Shimura |first4=N. |last5=Imoto |first5=M. |last6=Umezawa |first6=K. |date=1990-12-01 |title=Inhibition of phosphatidylinositol kinase by toyocamycin |url=https://pubmed.ncbi.nlm.nih.gov/2177464 |journal=The Journal of Antibiotics |volume=43 |issue=12 |pages=1586–1589 |doi=10.7164/antibiotics.43.1586 |issn=0021-8820 |pmid=2177464}} Furthermore, toyocamycin specifically disrupts auxin signaling in plants, thereby affecting their growth and development.{{Cite journal |last1=Hayashi |first1=Ken-ichiro |last2=Kamio |first2=Shuichi |last3=Oono |first3=Yutaka |last4=Townsend |first4=Leroy B. |last5=Nozaki |first5=Hiroshi |date=2009-01-01 |title=Toyocamycin specifically inhibits auxin signaling mediated by SCFTIR1 pathway |url=https://pubmed.ncbi.nlm.nih.gov/19171357 |journal=Phytochemistry |volume=70 |issue=2 |pages=190–197 |doi=10.1016/j.phytochem.2008.12.020 |issn=0031-9422 |pmid=19171357|bibcode=2009PChem..70..190H }}

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.

Toyocamycin mimics adenosine and can be mistakenly incorporated into RNA during transcription, which disrupts or stops RNA production.{{Cite journal |last1=Ríman |first1=J. |last2=Sverak |first2=L. |last3=Langlois |first3=A. J. |last4=Bonar |first4=R. A. |last5=Beard |first5=J. W. |date=1969-09-01 |title=Influence of toyocamycin on RNA synthesis in chick embryo cells noninfected and infected with strain MC29 avian leukosis virus |url=https://pubmed.ncbi.nlm.nih.gov/4309795 |journal=Cancer Research |volume=29 |issue=9 |pages=1707–1716 |issn=0008-5472 |pmid=4309795}} 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.{{Cite journal |last1=Iapalucci-Espinoza |first1=Silva |last2=Cereghini |first2=Silvia |last3=Franze-Fernandez |first3=Maria Teresa |date=2002-05-01 |title=Regulation of ribosomal RNA synthesis in mammalian cells: effect of toyocamycin |url=https://pubs.acs.org/doi/pdf/10.1021/bi00632a013 |access-date=2025-04-15 |journal=Biochemistry |volume=16 |issue=13 |pages=2885–2889 |language=EN |doi=10.1021/bi00632a013|pmid=560201 |url-access=subscription }} 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.{{Cite journal |last1=Venkov |first1=P. V. |last2=Stateva |first2=L. I. |last3=Hadjiolov |first3=A. A. |date=1977-01-20 |title=Toyocamycin inhibition of ribosomal ribonucleic acid processing in an osmotic-sensitive adenosine-utilizing Saccharomyces cerevisiae mutant |url=https://pubmed.ncbi.nlm.nih.gov/318864 |journal=Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis |volume=474 |issue=2 |pages=245–253 |doi=10.1016/0005-2787(77)90199-x |issn=0006-3002 |pmid=318864}} This interference with ribosome production affects protein synthesis and can seriously reduce cell survival.

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.

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.

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.

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.

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.

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.

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Category:Ribosides

Category:Antibiotics

Category:Pyrrolopyrimidines

Category:Nitriles