(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

• ChemBase ID: 72615
• Molecular Formular: C26H39NO6S
• Molecular Mass: 493.65596
• Monoisotopic Mass: 493.24980897
• SMILES: O1[C@@H]2CCC[C@H]([C@@H]([C@H](C(=O)C([C@H](CC(=O)O[C@@H](C[C@H]12)/C(=C/c1nc(sc1)C)/C)O)(C)C)C)O)C
• Canonical SMILES: O=C1O[C@@H](C[C@@H]2O[C@@H]2CCC[C@H]([C@@H]([C@H](C(=O)C([C@H](C1)O)(C)C)C)O)C)/C(=C/c1csc(n1)C)/C
• InChI: InChI=1S/C26H39NO6S/c1-14-8-7-9-19-21(32-19)11-20(15(2)10-18-13-34-17(4)27-18)33-23(29)12-22(28)26(5,6)25(31)16(3)24(14)30/h10,13-14,16,19-22,24,28,30H,7-9,11-12H2,1-6H3/b15-10+/t14-,16+,19+,20-,21-,22-,24-/m0/s1
• InChIKey: HESCAJZNRMSMJG-KKQRBIROSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione; (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[(1E)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
• IUPAC Traditional name: (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione; epothilone A
• Synonyms: EpoA; (-)-Epothilone A; Epothilone A

Database IDs

• CAS Number: 152044-53-6
• PubChem SID: 24724476; 162037540
• PubChem CID: 448799

CALCULATED PROPERTIES

• Acid pKa: 14.086929
• H Acceptors: 6
• H Donor: 2
• LogD (pH = 5.5): 3.8414474
• LogD (pH = 7.4): 3.842148
• Log P: 3.8421571
• Molar Refractivity: 130.1218 cm^3
• Polarizability: 51.57048 Å^3
• Polar Surface Area: 109.25 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO
• Apperance: solid

Safety Information

• Storage Condition: -20°C; desiccated; protect from light
• German water hazard class: 3
• Storage Temperature: -20°C

Pharmacology Properties

• Target: Microtubule Formation

Product Information

• Purity: >95% (HPLC)
• Salt Data: Free Base
• Biological Source: from Sorangium cellulosum
• Empirical Formula (Hill Notation): C26H39NO6S

DETAILS

Selleck Chemicals - S1297

Research Area

• Description: Cancer

Biological Activity

• Description: Epothilone A is a Taxol-like microtubule-stabilizing agent with EC_0.01 of 2 μM.
• Targets: Tubulin
• IC50: 2 μM (EC_0.01) ^[1]
• In Vitro: Epothilone A, discovered from the myxobacterium Sorangium cellulosum, is a Taxol-like microtubule-stabilizing agent that induces tubulin polymerization, leading to cell cycle arrest at the G2-M transition, cytotoxicity, and apoptosis.Epothilone A potently inhibits cell proliferation in HCT116 cells, with IC50 of 4.4 nM. ^[1]Epothilone A also displays cytotoxicity in KB3-1, KBV-1, Hela, and Hs578T cells, with IC50 values ranging from 13 nM to 160 nM. Epothilone A is more water soluble than Taxol and competes with Taxol in binding with microtubules, with IC50 of 2.3 μM. ^[2]However, both Epothilone A and Taxol don’t share a common pharmacophore and exploits the tubulin-binding pocket uniquely and independently. ^[3]Recently, it is found that microbiological transformation of Epothilone A by Aspergillus niger AS 3.739 yields several metabolites that is also toxic to MCF-7 cells, but with much higher IC50 values. ^[4]
• Clinical Trials: Currently Epothilone A is in advanced clinical development where it is being investigated for breast, ovarian and endometrial cancers

Protocol

• Protocol: Kinase Assay ^[1]
• Tubulin polymerization assay: Calf brain microtubule proteins (MTP) are purified, which includes approximately 15%–20% microtubule associated proteins. The buffer (MES buffer) used for the Epothilone A-microtubule studies contains 0.1 M 2-morpholinoethanesulfonic acid (MES), 1 mM EGTA, 0.5 mM MgCl₂, and 3 M glycerol at pH 6.6. Samples for electron microscopy are placed on carbon-over-Parlodion-coated grids (300 mesh) and negatively stained with 2% uranyl acetate. Microtubule assembly in the presence or absence of Epothilone A is monitored spectrophotometrically by using a spectrophotometer equipped with a thermostatically regulated liquid circulator. The temperature is held at 35 °C and changes in turbidity (representative of polymer mass) are monitored at 350 nm. Effective concentration (EC_0.01), defined as the interpolated concentration capable of inducing an initial slope of 0.01 OD/min rate, is calculated using the formula EC_0.01 = concentration/slope and expressed as the mean with standard deviation obtained from three different concentrations.
• Protocol: Cell Assay ^[2]
• Cell Lines: KB3-1, KBV-1, Hela, and Hs578T cells
• Concentrations: 0–2 μM
• Incubation Time: 24 hours for mitotic arrest or 72 hours for cytotoxicity
• Methods: For mitotic block and aberrant mitosis, cells are plated either in 48-well plates (for trypan blue and cell counting) or onto coverslips. After 24 hours, cells are treated with Epothilone A and are scored at regular intervals. For the cytotoxicity analysis, cells are counted and scored as trypan blue positive or negative. Concurrently, coverslips and aliquots of cells in the culture supernatant are fixed and stained with Hoechst 33342 in PBS. These cells are scored for cells blocked at the G2-M transition and aberrant mitosis.

References

• References: [1] Regueiro-Ren A , et al. Org Lett, 2001, 3(17), 2693-2696.
• References: [2] Bollag DM, et al. Cancer Res, 1995, 55(11), 2325-2333.
• References: [3] Nettles JH, et al. Science, 2004, 305(5685), 866-869.
• References: [4] Wang YL, et al. J Asian Nat Prod Res, 2009, 11(4), 357-364.
• References: [5] Swindell CS, et al. J Med Chem, 1991, 34(3), 1176-1184.

Sigma Aldrich - E3656

Biochem/physiol Actions
(-)-Epothilone A is a microtubule (MT) stabilizing drug and natural macrolide antitumor from myxobacteria Sorangium cellulosum. EpoA exhibits kinetics similar to paclitaxel by inducing tubulin polymerization in vitro and producing enhanced microtubule stability and bundling in cultured cells. In contrast to paclitaxel, Epothilone A exhibits a greater cytotoxicity against P-glycoprotein-expressing multidrug resistant (MDR) cells (IC50 = 20 nM for MDR CCRF-CEM/VBL100 cells). Epothilone A is a competitve inhibitor of 3H-paclitaxel binding with comparable IC50 to paclitaxel in displacement competition assays. EpoA causes cell cycle arrest at the G2/M transition leading to cytotoxicity.

REFERENCES

• Regueiro-Ren A , et al. Org Lett, 2001, 3(17), 2693-2696.
• Bollag DM, et al. Cancer Res, 1995, 55(11), 2325-2333.
• Nettles JH, et al. Science, 2004, 305(5685), 866-869.
• Wang YL, et al. J Asian Nat Prod Res, 2009, 11(4), 357-364.
• Swindell CS, et al. J Med Chem, 1991, 34(3), 1176-1184.