Identification

Name
Cerulenin
Accession Number
DB01034  (APRD00703)
Type
Small Molecule
Groups
Approved
Description

Cerulenin is an antifungal antibiotic that inhibits sterol and fatty acid biosynthesis. In fatty acid synthesis, reported to bind in equimolar ratio to b-keto-acyl-ACP synthase. In sterol synthesis, inhibits HMG-CoA synthetase activity. It is also shown to inhibit feeding and induce dramatic weight loss in mice. It is found naturally in the Cephalosporium caerulensfungus. [Wikipedia]

Structure
Thumb
Synonyms
  • (2R,3S)-3-((4e,7e)-Nona-4,7-dienoyl)-oxirane-2-carboxylic acid amide
  • (2R,3S)-3-((4e,7e)-Nona-4,7-dienoyl)oxirane-2-carboxamide
  • Cerulenin
External IDs
NSC-116069
International/Other Brands
Helicocerin
Categories
UNII
MF286Y830Q
CAS number
17397-89-6
Weight
Average: 223.2683
Monoisotopic: 223.120843415
Chemical Formula
C12H17NO3
InChI Key
GVEZIHKRYBHEFX-NQQPLRFYSA-N
InChI
InChI=1S/C12H17NO3/c1-2-3-4-5-6-7-8-9(14)10-11(16-10)12(13)15/h2-3,5-6,10-11H,4,7-8H2,1H3,(H2,13,15)/b3-2+,6-5+/t10-,11-/m1/s1
IUPAC Name
(2R,3S)-3-(nona-4,7-dienoyl)oxirane-2-carboxamide
SMILES
CC=CCC=CCCC(=O)[C@H]1O[C@H]1C(N)=O

Pharmacology

Indication

For use as a biochemical tool, Cerulenin is shown to cause dramatic weight loss in animals

Pharmacodynamics

Cerulenin is an antifungal antibiotic isolated from Cephalosporium caerulens. It interrupts fungal growth by inhibiting the biosynthesis of sterols and fatty acids (inhibits bacterial fatty acid synthesis). It also inhibits HMG-CoA synthetase activity. Cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors.

Mechanism of action

Irreversibly binds to fatty acid synthase, specifically b-ketoacyl-acyl carrier protein synthase (FabH, FabB and FabF condensation enzymes). A number of tumor cells and cell lines have been observed to have highly upregulated expression and activity of fatty acid synthase (FAS). Inhibition of FAS by cerulenin leads to cytotoxicity and apoptosis in human cancer cell lines, an effect believed to be mediated by the accumulation of malonyl-coenzyme A in cells with an upregulated FAS pathway.

TargetActionsOrganism
A3-oxoacyl-[acyl-carrier-protein] synthase 1
inhibitor
Escherichia coli (strain K12)
A3-oxoacyl-[acyl-carrier-protein] synthase 2
inhibitor
Escherichia coli (strain K12)
A3-oxoacyl-[acyl-carrier-protein] synthase 3
inhibitor
Escherichia coli (strain K12)
AFatty acid synthase
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Oral, mouse LD50: 547 mg/kg. Symptoms of overexposure include moderate to severe erythema (redness) and moderate edema (raised skin), nausea, vomiting, and headache.

Affected organisms
  • Humans and other mammals
  • Fungi
  • Mycobacterium tuberculosis
  • Bacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
Amphotericin BThe therapeutic efficacy of Amphotericin B can be decreased when used in combination with Cerulenin.Approved, Investigational
AmrinoneThe therapeutic efficacy of Cerulenin can be increased when used in combination with Amrinone.Approved
AzimilideThe therapeutic efficacy of Cerulenin can be increased when used in combination with Azimilide.Investigational
BuspironeThe metabolism of Buspirone can be decreased when combined with Cerulenin.Approved, Investigational
BusulfanThe serum concentration of Busulfan can be increased when it is combined with Cerulenin.Approved, Investigational
CisaprideThe serum concentration of Cisapride can be increased when it is combined with Cerulenin.Approved, Investigational, Withdrawn
DidanosineDidanosine can cause a decrease in the absorption of Cerulenin resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
DocetaxelThe metabolism of Docetaxel can be decreased when combined with Cerulenin.Approved, Investigational
EtravirineThe serum concentration of Etravirine can be increased when it is combined with Cerulenin.Approved
FosphenytoinThe serum concentration of Cerulenin can be decreased when it is combined with Fosphenytoin.Approved, Investigational
LipegfilgrastimCerulenin may increase the myelosuppressive activities of Lipegfilgrastim.Approved, Investigational
ProgesteroneThe absorption of Progesterone can be decreased when combined with Cerulenin.Approved, Vet Approved
QuinidineThe serum concentration of Quinidine can be increased when it is combined with Cerulenin.Approved, Investigational
RifabutinThe serum concentration of Rifabutin can be increased when it is combined with Cerulenin.Approved, Investigational
RifapentineThe serum concentration of Rifapentine can be increased when it is combined with Cerulenin.Approved, Investigational
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Cerulenin.Approved, Investigational
SolifenacinThe metabolism of Solifenacin can be decreased when combined with Cerulenin.Approved
SunitinibThe metabolism of Sunitinib can be decreased when combined with Cerulenin.Approved, Investigational
TacrolimusThe metabolism of Tacrolimus can be decreased when combined with Cerulenin.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference

Garfield P. Royer, Craig A. Townsend, "Cerulenin compounds for fatty acid synthesis inhibition." U.S. Patent US5539132, issued July, 1975.

US5539132
General References
  1. Huang P, Zhu S, Lu S, Dai Z, Jin Y: [An experimental study on cerulenin induced apoptosis of human colonic cancer cells]. Zhonghua Bing Li Xue Za Zhi. 2000 Apr;29(2):115-8. [PubMed:11866903]
  2. Straub SG, Yajima H, Komatsu M, Aizawa T, Sharp GW: The effects of cerulenin, an inhibitor of protein acylation, on the two phases of glucose-stimulated insulin secretion. Diabetes. 2002 Feb;51 Suppl 1:S91-5. [PubMed:11815464]
External Links
KEGG Compound
C12058
PubChem Compound
28517
PubChem Substance
46508217
ChemSpider
4445281
BindingDB
50009248
ChEBI
171741
ChEMBL
CHEMBL45627
Therapeutic Targets Database
DAP000659
PharmGKB
PA164764551
HET
1X9
Wikipedia
Cerulenin
PDB Entries
4ls7
MSDS
Download (25.4 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)93.5 °CPhysProp
water solubilitySlightly solubleNot Available
logP1.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.6 mg/mLALOGPS
logP1.38ALOGPS
logP1.5ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)14.16ChemAxon
pKa (Strongest Basic)-4.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area72.69 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity62.54 m3·mol-1ChemAxon
Polarizability23.9 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9957
Blood Brain Barrier+0.9711
Caco-2 permeable-0.8957
P-glycoprotein substrateNon-substrate0.7289
P-glycoprotein inhibitor INon-inhibitor0.5928
P-glycoprotein inhibitor IINon-inhibitor0.8271
Renal organic cation transporterNon-inhibitor0.9197
CYP450 2C9 substrateNon-substrate0.8017
CYP450 2D6 substrateNon-substrate0.8147
CYP450 3A4 substrateNon-substrate0.6391
CYP450 1A2 substrateNon-inhibitor0.6305
CYP450 2C9 inhibitorNon-inhibitor0.7838
CYP450 2D6 inhibitorNon-inhibitor0.9346
CYP450 2C19 inhibitorNon-inhibitor0.64
CYP450 3A4 inhibitorNon-inhibitor0.9438
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8871
Ames testAMES toxic0.6488
CarcinogenicityNon-carcinogens0.8611
BiodegradationNot ready biodegradable0.8853
Rat acute toxicity2.0415 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9659
hERG inhibition (predictor II)Non-inhibitor0.9698
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as oxirane carboxylic acids and derivatives. These are compounds containing an oxirane ring bearing a carboxylic acid group (or a derivative thereof).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Epoxides
Sub Class
Oxirane carboxylic acids and derivatives
Direct Parent
Oxirane carboxylic acids and derivatives
Alternative Parents
Monosaccharides / Primary carboxylic acid amides / Ketones / Oxacyclic compounds / Dialkyl ethers / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Oxirane carboxylic acid or derivatives / Monosaccharide / Carboxamide group / Ketone / Primary carboxylic acid amide / Carboxylic acid derivative / Dialkyl ether / Ether / Oxacycle / Carbonyl group
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
3-oxoacyl-[acyl-carrier-protein] synthase activity
Specific Function
Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Specific for elongation from C-10 to unsaturated C-16 and C-18 fatty...
Gene Name
fabB
Uniprot ID
P0A953
Uniprot Name
3-oxoacyl-[acyl-carrier-protein] synthase 1
Molecular Weight
42612.995 Da
References
  1. Kauppinen S, Siggaard-Andersen M, von Wettstein-Knowles P: beta-Ketoacyl-ACP synthase I of Escherichia coli: nucleotide sequence of the fabB gene and identification of the cerulenin binding residue. Carlsberg Res Commun. 1988;53(6):357-70. [PubMed:3076376]
  2. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO: Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. [PubMed:11050088]
  3. Slabaugh MB, Leonard JM, Knapp SJ: Condensing enzymes from Cuphea wrightii associated with medium chain fatty acid biosynthesis. Plant J. 1998 Mar;13(5):611-20. [PubMed:9681003]
  4. Heath RJ, Rock CO: Fatty acid biosynthesis as a target for novel antibacterials. Curr Opin Investig Drugs. 2004 Feb;5(2):146-53. [PubMed:15043388]
  5. Khandekar SS, Daines RA, Lonsdale JT: Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9. [PubMed:12570782]
  6. Omura S: The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 1976 Sep;40(3):681-97. [PubMed:791237]
  7. Heath RJ, White SW, Rock CO: Lipid biosynthesis as a target for antibacterial agents. Prog Lipid Res. 2001 Nov;40(6):467-97. [PubMed:11591436]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-ketoacyl-acyl-carrier-protein synthase ii activity
Specific Function
Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Has a preference for short chain acid substrates and may function to...
Gene Name
fabF
Uniprot ID
P0AAI5
Uniprot Name
3-oxoacyl-[acyl-carrier-protein] synthase 2
Molecular Weight
43045.39 Da
References
  1. Heath RJ, White SW, Rock CO: Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002 May;58(6):695-703. Epub 2002 Mar 7. [PubMed:12021787]
  2. Schujman GE, Choi KH, Altabe S, Rock CO, de Mendoza D: Response of Bacillus subtilis to cerulenin and acquisition of resistance. J Bacteriol. 2001 May;183(10):3032-40. [PubMed:11325930]
  3. Heath RJ, Rock CO: Fatty acid biosynthesis as a target for novel antibacterials. Curr Opin Investig Drugs. 2004 Feb;5(2):146-53. [PubMed:15043388]
  4. Khandekar SS, Daines RA, Lonsdale JT: Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9. [PubMed:12570782]
  5. Omura S: The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 1976 Sep;40(3):681-97. [PubMed:791237]
  6. Heath RJ, White SW, Rock CO: Lipid biosynthesis as a target for antibacterial agents. Prog Lipid Res. 2001 Nov;40(6):467-97. [PubMed:11591436]
  7. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO: Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. [PubMed:11050088]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-ketoacyl-acyl-carrier-protein synthase iii activity
Specific Function
Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Catalyzes the first condensation reaction which initiates fatty acid...
Gene Name
fabH
Uniprot ID
P0A6R0
Uniprot Name
3-oxoacyl-[acyl-carrier-protein] synthase 3
Molecular Weight
33514.78 Da
References
  1. Young K, Jayasuriya H, Ondeyka JG, Herath K, Zhang C, Kodali S, Galgoci A, Painter R, Brown-Driver V, Yamamoto R, Silver LL, Zheng Y, Ventura JI, Sigmund J, Ha S, Basilio A, Vicente F, Tormo JR, Pelaez F, Youngman P, Cully D, Barrett JF, Schmatz D, Singh SB, Wang J: Discovery of FabH/FabF inhibitors from natural products. Antimicrob Agents Chemother. 2006 Feb;50(2):519-26. [PubMed:16436705]
  2. Heath RJ, White SW, Rock CO: Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002 May;58(6):695-703. Epub 2002 Mar 7. [PubMed:12021787]
  3. Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO: Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem. 2001 Mar 2;276(9):6551-9. Epub 2000 Oct 24. [PubMed:11050088]
  4. Heath RJ, Rock CO: Fatty acid biosynthesis as a target for novel antibacterials. Curr Opin Investig Drugs. 2004 Feb;5(2):146-53. [PubMed:15043388]
  5. Khandekar SS, Daines RA, Lonsdale JT: Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9. [PubMed:12570782]
  6. Omura S: The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 1976 Sep;40(3):681-97. [PubMed:791237]
  7. Heath RJ, White SW, Rock CO: Lipid biosynthesis as a target for antibacterial agents. Prog Lipid Res. 2001 Nov;40(6):467-97. [PubMed:11591436]
Details
4. Fatty acid synthase
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Poly(a) rna binding
Specific Function
Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein.
Gene Name
FASN
Uniprot ID
P49327
Uniprot Name
Fatty acid synthase
Molecular Weight
273424.06 Da
References
  1. Oskouian B, Saba JD: YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae. Mol Gen Genet. 1999 Mar;261(2):346-53. [PubMed:10102370]
  2. Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF, Pizer ES: Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 2001 Feb 15;61(4):1493-9. [PubMed:11245456]
  3. Heiligtag SJ, Bredehorst R, David KA: Key role of mitochondria in cerulenin-mediated apoptosis. Cell Death Differ. 2002 Sep;9(9):1017-25. [PubMed:12181752]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  5. Flavin R, Peluso S, Nguyen PL, Loda M: Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010 Apr;6(4):551-62. doi: 10.2217/fon.10.11. [PubMed:20373869]
  6. Lupu R, Menendez JA: Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharm Biotechnol. 2006 Dec;7(6):483-93. [PubMed:17168665]
  7. Ronnett GV, Kim EK, Landree LE, Tu Y: Fatty acid metabolism as a target for obesity treatment. Physiol Behav. 2005 May 19;85(1):25-35. [PubMed:15878185]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2018 04:30