(3aS,11aR)-6,10-dimethyl-3-methylidene-2H,3H,3aH,4H,5H,8H,9H,11aH-cyclodeca[b]furan-2-one

• ChemBase ID: 72623
• Molecular Formular: C15H20O2
• Molecular Mass: 232.3181
• Monoisotopic Mass: 232.14632988
• SMILES: C1CC(=C[C@@H]2[C@@H](CCC(=C1)C)C(=C)C(=O)O2)C
• Canonical SMILES: CC1=C[C@H]2OC(=O)C(=C)[C@@H]2CCC(=CCC1)C
• InChI: InChI=1S/C15H20O2/c1-10-5-4-6-11(2)9-14-13(8-7-10)12(3)15(16)17-14/h5,9,13-14H,3-4,6-8H2,1-2H3/b10-5+,11-9+/t13-,14+/m0/s1
• InChIKey: HRYLQFBHBWLLLL-AHNJNIBGSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (3aS,11aR)-6,10-dimethyl-3-methylidene-2H,3H,3aH,4H,5H,8H,9H,11aH-cyclodeca[b]furan-2-one
• IUPAC Traditional name: costunolide
• Synonyms: Costunolide

Database IDs

• CAS Number: 553-21-9
• PubChem SID: 162037548
• PubChem CID: 6436243

CALCULATED PROPERTIES

• H Acceptors: 1
• H Donor: 0
• LogD (pH = 5.5): 3.8161666
• LogD (pH = 7.4): 3.8161666
• Log P: 3.8161666
• Molar Refractivity: 69.9464 cm^3
• Polarizability: 26.945713 Å^3
• Polar Surface Area: 26.3 Å^2
• Rotatable Bonds: 0
• Lipinski's Rule of Five: true

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: Telomerase

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1319

Research Area

• Description: Cancer

Biological Activity

• Description: Costunolide inhibits FPTase with IC50 of 20 μM and also inhibits telomerase with IC50 of 90 μM and 65 μM in MCF-7 and MDA-MB-231 cells.
• Targets: Telomerase (MCF-7); Telomerase (MDA-MB-231); FPTase
• IC50: 90 μM; 65μM ^[1]; 20 μM ^[2]
• In Vitro: Costunolide inhibits the growth and telomerase activity of MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner. ^[1] Costunolide also inhibits the farnesylation process of human lamin-B by farnesyl–proteinttransferase (FPTase), in a dose dependent manner. Continuously treatment of Costunolide for 48 hours will significantly decrease proliferation of human tumor cells (A549, SK-OV-3, SK-MEL-2, XF498 and HCT-1) in a dose-dependent manner. ^[2] Costunolide induces apoptosis by ROS-mediated mitochondrial permeability transition and cytochrome C release to the cytosol in HL-60 human leukemia cells. ^[3] A recent study indicates that Costunolide shows significant antifungal activity, including Trichophyton mentagrophytes, T.simlii, T.rubrum, and so on. ^[4]
• In Vivo: Costunolide inhibits angiogenic response by blocking the angiogenic factor signaling pathway. In a mouse corneal micropocket assay, Costunolide reduces VEGF-stimulated neovascularization in mice. ^[5]

Protocol

• Protocol: Kinase Assay ^[1]
• Telomerase activity assay: The telomerase activity is measured by the TRAP assay using the TRAPez Telomerase Detection Kit, which includes primers of a 36-bp internal control (IC) for quantifying the amplification of telomerase activity within a linear range close to 2.5 logs. For RNase treatment, 10μL of extract are incubated with 1μg of RNase at 37 °C for 20 minutes. The products of the TRAP assay are resolved by electrophoresis in a nondenaturing12% PAGE in a buffer containing 0.5 × Tris–borate EDTA and detected by autoradiograph. For quantification of TRAP products, the dried gels are exposed to Fuji Imaging Plate at room temperature. Results are corrected for background, and a standard value of 100 is given to the untreated control cell signal. Signal intensities of Costunolide-treated cells are compared to the standard and are expressed as a fraction of the maximum value of 100. ^[1]
• FPTase assay: FPTase is partially purified from rat brain by ammonium sulfate fractionation and Mono Q column chromatography. A human lamin-B carboxy-terminus sequence peptide (biotin-TRASNRSCAIM) as a substrate of FPTase is supplied. The FPTase assay is performed. Briefly, the standard reaction mixture (25μL) containing [^3H]farnesyl pyrophosphate, biotinylated TRANSRSCAIM, partially purified FPTase, reaction buffer and the indicated concentrations of test material is incubated at 37 °C for 20 minutes. The FPTase activity is determined by measuring the incorporation of the [^3H]farnesyl group from [^3H]farnesyl pyrophoshate into the substrate peptide using a liquid scintillation counter. The 1-HFP (1-hydroxyfarnesyl phosphonate) is used as a reference drug for the enzyme inhibition (IC50 1.0 μM). The FPTase activity is calculated as mean of three distinct experiments. ^[2]
• Protocol: Cell Assay ^[1]
• Cell Lines: MCF-7 and MDA-MB-231 cells
• Concentrations: 0-100 μM
• Incubation Time: 48 hours
• Methods: 1) Plate 500-10,000 cells in 200 μL media per well in a 96 well plate. Leave 8 wells empty for blank controls.2) Incubate (37 °C, 5% CO₂) overnight to allow the cells to attach to the wells.3) Add 2 μL of Costunolide dissolved in DMSO to each well. Place on a shaking table, 150 rpm for 5 minutes, to thoroughly mix the samples into the media. 5) Incubate (37 °C, 5% CO₂) for 48 hours to allow Costunolide to take effect.6) Make 2 mL or more of MTT solution per 96 well plate at 5 mg/mL in PBS. Do not make a stock as MTT in solution is not stable long-term.7) Add 20 μL MTT solution to each well. Place on a shaking table, 150 rpm for 5 minutes, to thoroughly mix the MTT into the media. 8) Incubate (37 °C, 5% CO₂) for 1-5 hours to allow the MTT to be metabolized.9) Dump off the media. (Dry plate on paper towels to remove residue if necessary.10) Resuspend formazan (MTT metabolic product) in 200 μL DMSO. Place on a shaking table, 150 rpm for 5 minutes, to thoroughly mix the formazan into the solvent.11) Read optical density at 560 nm and subtract background at 670 nm. Optical density should be directly correlated with cell quantity.
• Protocol: Animal Study ^[5]
• Animal Models: Hydron N containing VEGF are implanted into mouse cornea.
• Formulation: Costunolide is dissolved in dimethylsulfoxide (DMSO).
• Doses: 100 mg/kg
• Administration: Intraperitoneal injection once daily.

References

• References: [1] Choi SH, et al, Cancer Lett, 2005, 227(2), 153-162.
• References: [2] Park SH, et al, Planta Med, 2001, 67(4), 358-359.
• References: [3] Lee MG, et al, Biol Pharm Bull, 2001, 24(3), 303-306.
• References: [4] Duripandiyan V, et al, BMC Complement Altern Med, 2012, 12, 13.
• References: [5] Jeong SJ, et al, Cancer Lett, 2002, 187(1-2), 129-133.

REFERENCES

• Choi SH, et al, Cancer Lett, 2005, 227(2), 153-162.
• Park SH, et al, Planta Med, 2001, 67(4), 358-359.
• Lee MG, et al, Biol Pharm Bull, 2001, 24(3), 303-306.
• Duripandiyan V, et al, BMC Complement Altern Med, 2012, 12, 13.
• Jeong SJ, et al, Cancer Lett, 2002, 187(1-2), 129-133.