roridin E

Roridin E consists of a trichothecene core structure consisting of a six-membered ring containing one single oxygen atom, flanked by two carbon rings.{{Cite journal |last1=McCormick |first1=Susan P. |last2=Stanley |first2=April M. |last3=Stover |first3=Nicholas A. |last4=Alexander |first4=Nancy J. |date=2011-07-01 |title=Trichothecenes: From Simple to Complex Mycotoxins |journal=Toxins |volume=3 |issue=7 |pages=802–814 |doi=10.3390/toxins3070802 |doi-access=free |issn=2072-6651 |pmc=3202860 |pmid=22069741}} This core ring structure contains an epoxide bridging carbons 12 and 13, as well as a double bond between carbons 9 and 10.{{Cite book |url=https://www.nap.edu/catalog/19461 |title=Protection Against Trichothecene Mycotoxins |date=1983-01-01 |publisher=National Academies Press |isbn=978-0-309-03430-2 |location=Washington, D.C. |doi=10.17226/19461}} These two functional groups are mainly responsible for the trichothecene's ability to inhibit protein synthesis and exhibits cytotoxic effects.{{Cite journal |last1=Bennett |first1=J. W. |last2=Klich |first2=M. |date=July 2003 |title=Mycotoxins |journal=Clinical Microbiology Reviews |volume=16 |issue=3 |pages=497–516 |doi=10.1128/cmr.16.3.497-516.2003 |pmc=164220 |pmid=12857779}} This core structure is also amphipathic, containing polar and nonpolar components.{{Cite journal |last1=Middlebrook |first1=John L. |last2=Leatherman |first2=Dennis L. |date=September 1989 |title=Specific association of T-2 toxin with mammalian cells |url=https://linkinghub.elsevier.com/retrieve/pii/0006295289900208 |journal=Biochemical Pharmacology |volume=38 |issue=18 |pages=3093–3102 |doi=10.1016/0006-2952(89)90020-8|pmid=2783163 }} Roridin E differentiates from other mycotoxins due to it macrocyclic structure bridging carbons 4 and 15. Due to this macrocyclic structure, Roridin E is assigned to group D of the trichothecenes.

File:General_chemical_struccture_of_trichothecenes.svg

The inhibition of protein synthesis and cytotoxic effects are caused by the reactivity of the double bond between carbons 9 and 10, and the epoxide bridging carbons 12 and 13. To prevent these reactive functional groups from causing cytotoxic effects, methods have been developed to reduce the reactivity of roridin E. One of these methods is to incubate with aqueous Ozone at approximately 25 ppm, which oxidates the double bond between carbons 9 and 10 within 4-5 hours.{{Cite journal |last1=Young |first1=J. Christopher |last2=Zhu |first2=Honghui |last3=Zhou |first3=Ting |date=2006-03-01 |title=Degradation of trichothecene mycotoxins by aqueous ozone |url=https://linkinghub.elsevier.com/retrieve/pii/S0278691505002589 |journal=Food and Chemical Toxicology |volume=44 |issue=3 |pages=417–424 |doi=10.1016/j.fct.2005.08.015 |pmid=16185803 |issn=0278-6915}} Another method is to use molecular genetics. For example, the Eubacteria strain BBSH 797 produces de-epoxidase enzymes which reduce the epoxide bridging carbons 12 and 13 to a double bond and thus significantly reduce the toxicity of roridin E.{{Cite journal |last1=Devreese |first1=M. |last2=De Backer |first2=P. |last3=Croubels |first3=S. |date=2013-08-29 |title=Verschillende methoden om mycotoxineproductie en de impact op de diergezondheid tegen te gaan |url=https://openjournals.ugent.be/vdt/article/id/75566/ |journal=Vlaams Diergeneeskundig Tijdschrift |volume=82 |issue=4 |doi=10.21825/vdt.v82i4.16695 |issn=0303-9021|doi-access=free }}

Roridin E is produced via a coupling between a verrucarol molecule and a macrocyclization of a carbon chain, as shown in the reaction scheme below. This entails a series of steps whereby the secondary alcohol is converted into the desired carboxylic acid via a Jones oxidation yielding compound 2. In an additional step, the alcohol of verrucarol on carbon 15 is esterified selectively by adding compound 2, DCC, and 4-pyrrolidinopyridine (4-pp). And the alcohol on carbon 4 was converted to the desired phosphono ester, yielding compound 3. Then the cyclopentylidene was removed and a diol was produced. This diol was then cleaved, deformylated, and treated with excess (formylmethylene)triphenylphosphorane, resulting in the formation of an aldehyde and yielding compound 4. Macrocyclization was accomplished by using finely ground potassium carbonate and 18-crown-6, yielding compound 5. In the final step, compound 5 was treated with potassium tert-butoxide in isopropyl alcohol. These conditions resulted in a conjugation of the C3'=C4' olefin to yield the final compound roridin E.{{Cite journal |last1=Still |first1=W. C. |last2=Gennari |first2=C. |last3=Noguez |first3=J. A. |last4=Pearson |first4=D. A. |date=1984-01-01 |title=Synthesis of macrocyclic trichothecanoids. Baccharin B5 and roridin E |url=https://pubs.acs.org/doi/abs/10.1021/ja00313a056 |journal=Journal of the American Chemical Society |volume=106 |issue=1 |pages=260–262 |doi=10.1021/ja00313a056 |bibcode=1984JAChS.106..260S |issn=0002-7863}}

File:Chemical_synthesis_of_Roridin_E.svg

Roridin E is a cytotoxic compounds that creates a significant risk towards all Eukaryotic Cell bearing organisms such as plants and animals because of the ability to inhibit different receptors responsible for protein production.{{Cite journal |last=Kiessling |first=K.-H. |date=1986-01-01 |title=Biochemical mechanism of action of mycotoxins |url=https://www.degruyter.com/document/doi/10.1351/pac198658020327/html |journal=Pure and Applied Chemistry |volume=58 |issue=2 |pages=327–338 |doi=10.1351/pac198658020327 |issn=1365-3075}} Exposure of roridin E can occur through direct skin contact with cytotoxic producing fungi or through ingestion of contaminated food, fungal matter or plant matter.{{Cite web |date=2025|publisher=Illinois department of public health |title=Trichothecene mycotoxin |url=https://dph.illinois.gov/topics-services/emergency-preparedness-response/public-health-care-system-preparedness/trichothecene-mycotoxin.html#:~:text=Trichothecene%20mycotoxin%20(T%2D2),nucleic%20acid%20in%20the%20body..}} Trichothecenes such as roridin E are rapidly absorbed due to their low molecular weight an amphipathic nature. This allows them to penetrate the gastrointestinal membrane and distributed throughout the body.{{Cite journal |last1=Janik |first1=Edyta |last2=Niemcewicz |first2=Marcin |last3=Podogrocki |first3=Marcin |last4=Ceremuga |first4=Michal |last5=Stela |first5=Maksymilian |last6=Bijak |first6=Michal |date=2021-11-14 |title=T-2 Toxin—The Most Toxic Trichothecene Mycotoxin: Metabolism, Toxicity, and Decontamination Strategies |journal=Molecules |volume=26 |issue=22 |pages=6868 |doi=10.3390/molecules26226868 |doi-access=free |issn=1420-3049 |pmc=8618548 |pmid=34833960}}

Studies on acute toxicity in mice have determined a median lethal dose (IC₅₀) for injection of 2.0 mg\kg.{{Cite journal |last1=Hughes |first1=B. J. |last2=Hsieh |first2=G. C. |last3=Jarvis |first3=B. B. |last4=Sharma |first4=R. P. |date=1989 |title=Effects of macrocyclic trichothecene mycotoxins on the murine immune system |url=http://link.springer.com/10.1007/BF01062363 |journal=Archives of Environmental Contamination and Toxicology |volume=18 |issue=3 |pages=388–395 |doi=10.1007/BF01062363 |pmid=2786385 |bibcode=1989ArECT..18..388H |issn=0090-4341}} However, no specific lethal or save dose has been documented for humans.

Exposure of high levels of roridin E has been associated with severe itching, soreness and redness in direct physical contact with the skin. Other reported effects include loss of muscle coordination, nausea, vomiting, diarrhea, difficulty breathing, chest pain, hemoptysiss and bleeding disorders.

Roridin E is known to be cytotoxic toward eukaryotic cellss and is also recognized as a phytotoxin.{{Cite journal |last1=Li |first1=Yong |last2=Liu |first2=Dong |last3=Cheng |first3=Zhongbin |last4=Proksch |first4=Peter |last5=Lin |first5=Wenhan |date=2017-01-20 |title=Cytotoxic trichothecene-type sesquiterpenes from the sponge-derived fungus Stachybotrys chartarum with tyrosine kinase inhibition |journal=RSC Advances |volume=7 |issue=12 |pages=7259–7267 |doi=10.1039/C6RA26956G |bibcode=2017RSCAd...7.7259L |issn=2046-2069|doi-access=free }} This compound is a trichothecene, which are known protein synthesis inhibitors. Trichothecenes specifically bind to the ribosome and interfere with the active site of peptidyl transferase, inhibiting the initiation, elongation, or termination steps of protein synthesis.

Roridin E has been shown to inhibit certain receptor tyrosine kinase, including FGFR3, IGF-1R, PDGFRβ, and TrkB, which are involved in cell growth and signaling. The precise mechanism by which roridin E inhibits receptor tyrosine kinases remains unclear. However, trichothecene mycotoxins, including roridin E, are known to interfere with cellular signaling by modifying key proteins involved in phosphorylation.

Research on structurally related trichothecenes suggests that roridin E may inhibit kinase activity through covalent modification of cysteine residues within the enzyme's active site, potentially leading to Irreversible inhibition. Additionally, these compounds are known to disrupt adenosine triphosphate binding, a critical step for kinase activation, which can impair phosphorylation and downstream signal transduction.

By inhibiting receptor tyrosine kinases, roridin E interferes with pathways essential for cell growth, survival, and proliferation. These disruptions can lead to apoptosis or reduced cellular viability, contributing to its potential as an anticancer agent. However, further studies are needed to fully characterize the specific molecular interactions and biological effects of roridin E.

While there is no specific study on the metabolism of roridin E, there have been studies on the metabolism of structurally related trichothecenes. Trichothecenes are easily absorbed through the skin, gastrointestinal tract, and pulmonary mucosa due to their lipophilicity.{{Cite book |title=Selected mycotoxins: ochratoxins, trichothecenes, ergot |date=1990 |publisher=World health organization |isbn=978-92-4-157105-0 |editor-last=Programme international sur la sécurité des substances chimiques |series=Environmental health criteria |location=Geneva}} The biotransformation process involves the introduction of functional groups (e.g., hydroxy group) into the roridin E molecule, converting it into more polar metabolites. This occurs through various reactions, such as hydrolysis, hydroxylation, and de-epoxidation.

Metabolism primarily takes place in the liver and is facilitated mainly by cytochrome P450 enzymes and carboxylesterase. After metabolism, the less harmful polar metabolites are excreted via the kidneys into the urine or through the bile into the feces.

Isolated roridin E from various fungi have been studied for its cytotoxic effects on different cancer cell lines, including Leukemia and Breast cancer cells In vitro. In one study on the effects of roridin E in 5 different types of human breast cancer cells treated with a roridine E showed significant signs of morphological changes. A reduction of in cell count was observed along with signs of cellular breakage and cell death compared to the control group. The IC50 for human breast cancer cells was determined to be 0.002 mg/L showing significant cytotoxic effects.{{Cite journal |last1=Ha |first1=Si Young |last2=Lee |first2=Dong Hwan |last3=Jung |first3=Ji Young |last4=Park |first4=Han Min |last5=Yang |first5=Jae-Kyung |date=2023-06-30 |title=Antioxidant, anticancer, and wound-healing properties of roridin E isolated from mycelial culture medium of Podostroma cornudamae mushroom |url=https://doi.org/10.14480/JM.2023.21.2.33 |journal=Journal of Mushroom |volume=21 |issue=2 |pages=33–40 |doi=10.14480/JM.2023.21.2.33}}

In studies on leukemia cells roridin E showed cytotoxic effects with cell death as a result and a IC50 range from 0.0005 and 0.042 μg/mL depending on the strain.{{Cite journal |last1=González |first1=María Laura |last2=Joray |first2=Mariana Belén |last3=Laiolo |first3=Jerónimo |last4=Crespo |first4=María Inés |last5=Palacios |first5=Sara María |last6=Ruiz |first6=Gustavo Miguel |last7=Carpinella |first7=María Cecilia |date=2018 |title=Cytotoxic Activity of Extracts from Plants of Central Argentina on Sensitive and Multidrug-Resistant Leukemia Cells: Isolation of an Active Principle from Gaillardia megapotamica |journal=Evidence-Based Complementary and Alternative Medicine |volume=2018 |issue=1 |pages=9185935 |doi=10.1155/2018/9185935 |doi-access=free |issn=1741-4288 |pmc=5971282 |pmid=29861776}}

However the uses of roridin E in effective anti cancer treatment has not been studied in much detail because of the high cytotoxic effects, which makes it difficult to use it as an effective treatment.

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Category:Mycotoxins

Category:Heterocyclic compounds with 4 rings

Category:Lactones

Category:Secondary alcohols

Category:Trichothecenes