Description
Cycloheximide is a glutarimide antibiotic produced by
S. griseus that inhibits protein synthesis in eukaryotes (IC
50 = 5-
50 μM) by interfering with translational elongation. Its effects on protein synthesis can either induce or inhibit apoptosis depending on cell type. Cycloheximide is widely used as a tool in molecular biology research for ribosome profiling and translational profiling as well as to determine the half-
life of a protein.
Description
Cycloheximide is a glutarimide-type antibiotic produced by Streptomyces
griseus. Colorless crystals, C15H23NO4 (281.4), melting
point: 115.5–117 C, weak acidic substance (pKa 11.2),
Soluble in chloroform, isopropanol and methanol; water >
21 g/L (2 C). Stable in pH 3–5, but rapidly destroyed in
alkaline solutions.
Chemical Properties
Off-white to light tan powder
Chemical Properties
Cycloheximide is a colorless crystalline sub-
stance.
Uses
potent and selective 5-HT uptake inhibitor
Uses
Cycloheximide is the most recognised member of the glutarimide microbial metabolites. Cycloheximide was isolated from Streptomyces griseus in the late 1940s as a potent and broad spectrum antifungal. Cycloheximide inhibits protein synthesis by interfering with translocation. Cycloheximide is an established bioprobe and widely-used antifungal reagent in research with over 25,000 literature citations.
Uses
Cycloheximide is an antibiotic substance isolated from the beers of streptomycin-producing strains of Streptomyces griseus. Cycloheximide is used as fungicide.
Definition
ChEBI: Cycloheximide is a dicarboximide that is 4-(2-hydroxyethyl)piperidine-2,6-dione in which one of the hydrogens attached to the carbon bearing the hydroxy group is replaced by a 3,5-dimethyl-2-oxocyclohexyl group. It is an antibiotic produced by the bacterium Streptomyces griseus. It has a role as a bacterial metabolite, a protein synthesis inhibitor, a neuroprotective agent, an anticoronaviral agent and a ferroptosis inhibitor. It is a member of piperidones, a piperidine antibiotic, an antibiotic fungicide, a dicarboximide, a secondary alcohol and a cyclic ketone. It is functionally related to a piperidine-2,6-dione.
General Description
Colorless crystals. Used as a fungicide and as a anticancer drug.
Air & Water Reactions
Water soluble.
Reactivity Profile
Actidione is an imide. Actidione is incompatible with strong oxidizing agents, acid chlorides and acid anhydrides. Actidione decomposes rapidly in alkali at room temperature.
Health Hazard
Actidione is extremely toxic; the probable oral lethal dose in humans is 5-50 mg/kg, or 7 drops to 1 teaspoonful for a 150-lb. person.
Fire Hazard
When exposed to heat, Actidione emits toxic fumes, including nitrogen oxides.
Agricultural Uses
Fungicide; plant growth regulator: A U.S. EPA restricted Use Pesticide (RUP). Used
as an antibiotic, plant growth regulator, and protein synthesis inhibitor. Inhibits growth of many plant pathogenic
fungi. Effective for control of powdery mildew on roses
and many other ornamentals, rusts and leaf spots on lawn
grasses, and azalea petal blight. Also used as a repellent for
rodents and other animal pests and in cancer therapy. Not
listed for use in EU countries
Trade name
ACTI-AID®[C]; ACTIDIONE®[C];
ACTIDIONE® TGF[C]; ACTIDONE®; ACTIDONE®
PM; ACTIDONE® TGF; ACTISPRAY; HIZAROCIN®;
KAKEN®; NARAMYCIN®; NARAMYCIN A®;
NEOCYCLOHEXIMIDE®; U-4527
Biological Activity
Selective inhibitor of eukaryotic (over prokaryotic) protein synthesis, blocking tRNA binding and release from ribosomes. Induces apoptosis in a variety of transformed and normal cell lines, including T-cells. Competitively inhibits the PPIase hFKBP12 (K i = 3.4 μ M). Antifungal antibiotic.
Pharmacology
Strongly inhibits the growth of pathogenic fungi but no
effects on bacterial growth, even at 100 mg/ml. Inhibits
protein synthesis by interfering with the translocation
step in eukaryotes, but not in prokaryotes. When
ingested by animals, the agent causes excitement, tremors,
salivation, diarrhea, and melena.
Potential Exposure
A potential danger to those involved
in the manufacture, formulation, or application of this fun-
gicide and pesticide. Used as an antibiotic, plant growth
regulator, and protein synthesis inhibitor. Used on oranges
for processing and to inhibit growth of many pathogenic
plant fungi. Also used as a repellent for rodents and other
animal pests; and in cancer therapy.
in vitro
cycloheximide blocks the movement of peptidyl-trna from acceptor site to the donor site on reticulocyte ribosomes. this translocation reaction is dependent on the transfer enzyme, tf-ii, and gtp hydrolysis. cycloheximide has no effect on the ribosome dependent gtpase activity of tf-ii or peptidyl transferase reaction by which peptides on trna in the donor ribosomal site are transferred to an amino acid on trna in the acceptor site [1].
in vivo
cycloheximide treatment was effective in attenuating rat brain injury within a 6 hr therapeutic window after hypoxia-ischemia in a newborn rat pup model. these data support the possibility that protein synthesis inhibitors, as well as other anti-apoptotic strategies, may have therapeutic utility in hypoxic-ischemic (hi) events of the developing newborn brain even when treatment is delayed for up to 6 hr after the primary asphyxial insult [2].
First aid
If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit.Medical observation is recommended for 24-48 h following skin contact.
Carcinogenicity
Cycloheximide is genotoxic in Escherichia
coli with metabolic activation and in the mouse
sperm morphology assay. Carcinogenicity
bioassays in the mouse and rat are inconclusive.
Environmental Fate
CHX is a potent inhibitor of protein synthesis in animals. It
binds to E-site of 70S ribosome-mRNA complex, blocking the
translational step of protein biosynthesis. It causes an increase
in adrenal RNA and increased production of glucocorticoids.
Metabolism
Rapidly inactivated at room temperature by diluted alkali
with the formation of a volatile, fragrant ketone, 2,4-
dimethylcyclohexanone. Hazardous to fish and wildlife.
Purification Methods
It crystallises from H2O /MeOH (4:1), amyl acetate, isopropyl acetate/isopropyl ether or H2O. [Beilstein 21/13 V 434.]
Toxicity evaluation
Skin irritant. LD
50 2 mg/kg (rat, orl);
133 mg/kg (mice, Ipr); 65 mg/kg (guinea pig); 60 mg/kg
(monkey). Teratogenic effects.
To remove toxicant
from gut, activated charcoal and a catharitic dose of sodium sulfate are effective. Mechanisms of toxicity
are not well defined, but hydrocortisone is antidotal,
particularly in combination with the adrenergic agent
methoxyphenamine.
Incompatibilities
Incompatible with oxidizers, acid anhy-
drides; strong bases.
Waste Disposal
High-temperature incinerator
with flue gas scrubbing equipment.
Background
Cycloheximide is a protein synthesis inhibitor in eukaryotes. Although its precise mechanism of action has yet to be fully elucidated, it has been shown to inhibit translation elongation through binding to the E-site of the 60S ribosomal unit and interfering with deacetylated tRNA. Although not all cell types are equally sensitive to the apoptosis-inducing effects of cycloheximide, it has been shown to induce cell death in T cells through a FADD-dependent mechanism. In addition, cycloheximide and Tumor Necrosis Factor possess a synergistic cytotoxicity, and consequently they are routinely used together to induce cell death. Investigators have demonstrated that cycloheximide blocks bortezomib-stimulated protein ubiquitination.
References
[1] Merck’s Index, Nachtrag 1930. Verlag von E. Merck, Darmstadt. 14 Seiten[J]. Archiv der Pharmazie, 1930, 268 6: 444-445. DOI:
10.1002/ardp.19302680608
