Epothilones

Title: Epothilones
Literature References: Microtubule stablilizing 16-membered macrolides which mimic the biological effects of paclitaxel, q.v., while retaining multidrug-resistant activity. Structurally lacking the taxane ring. Isoln of A and B from the myxobacterium Sorangium cellulosum: G. Höfle et al., DE 4138042, (1993 to Ges. Biotech. Forsch.), C.A. 120, 52841 (1994). Purification of A and B, and mechanism of action: D. M. Bollag et al., Cancer Res. 55, 2325 (1995). Total synthesis of A: A. Balog et al., Angew. Chem. Int. Ed. 35, 2801 (1996); of B and D: D.-S. Su et al., ibid. 36, 757 (1997). Crystal structure of A and B, and conformation in soln: G. Höfle et al., ibid. 35, 1567 (1996). Isoln and structural studies of 39 natural epothilone variants: I. H. Hardt et al., J. Nat. Prod. 64, 847 (2001). Isoln and crystallization of D: R. L. Arslanian et al., ibid. 65, 570 (2002). Effects of A and B on microtubule proteins in comparison with paclitaxel: R. J. Kowalski et al., J. Biol. Chem. 272, 2534 (1997). Review of properties and clinical potential: D. M. Bollag, Expert. Opin. Invest. Drugs 6, 867-873 (1997); of biology, chemistry and therapeutic potential: K. C. Nicolaou et al., Angew. Chem. Int. Ed. 37, 2014-2045 (1998); idem et al., Chem. Commun. 2001, 1523-1535.
Derivative Type: Epothilone A
CAS Registry Number: 152044-53-6
CAS Name: (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
Molecular Formula: C26H39NO6S
Molecular Weight: 493.66
Percent Composition: C 63.26%, H 7.96%, N 2.84%, O 19.45%, S 6.50%
Properties: Colorless crystals from ethyl acetate/toluene, mp 95°. Soly at 20° (g/l): water 0.7. uv max (methanol): 211, 249 nm (e 17800, 12500). [a]D21 -47.1° (c = 1.0 in methanol).
Melting point: mp 95°
Optical Rotation: [a]D21 -47.1° (c = 1.0 in methanol)
Absorption maximum: uv max (methanol): 211, 249 nm (e 17800, 12500)
Derivative Type: Epothilone B
CAS Registry Number: 152044-54-7
Additional Names: Patupilone
Manufacturers' Codes: EPO-906
Molecular Formula: C27H41NO6S
Molecular Weight: 507.68
Percent Composition: C 63.88%, H 8.14%, N 2.76%, O 18.91%, S 6.32%
Properties: Colorless crystals from ethyl acetate, mp 93-94°. uv max (methanol): 211, 249 nm (e 18600, 14100). [a]D21 -35° (c = 0.7 in methanol).
Melting point: mp 93-94°
Optical Rotation: [a]D21 -35° (c = 0.7 in methanol)
Absorption maximum: uv max (methanol): 211, 249 nm (e 18600, 14100)
Derivative Type: Epothilone D
CAS Registry Number: 189453-10-9
CAS Name: (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]oxacyclohexadec-13-ene-2,6-dione
Additional Names: desoxyepothilone B
Manufacturers' Codes: KOS-862
Molecular Formula: C27H41NO5S
Molecular Weight: 491.68
Percent Composition: C 65.96%, H 8.40%, N 2.85%, O 16.27%, S 6.52%
Properties: Colorless crystals from ethanol + water, mp 120-121° (Arslanian). Also reported as colorless amorphous solid. [a]D22 -61.3° (c = 2.5 in methanol). uv max (methanol): 210, 248 nm (e 18400, 13200) (Hardt).
Melting point: mp 120-121° (Arslanian)
Optical Rotation: [a]D22 -61.3° (c = 2.5 in methanol)
Absorption maximum: uv max (methanol): 210, 248 nm (e 18400, 13200) (Hardt)
Epoxiconazole Epratuzumab Eprazinone Eprinomectin Epristeride

Epothilones
Epothilones A (R = H) and B (R = Me)

Epothilones A (R = H) and B (R = CH3)

Chemical formulae

A: C26H39NO6S
B: C27H41NO6S

Molecular masses

A: 493.66 g/mol
B: 507.68 g/mol

CAS numbers

A: 152044-53-6
B: 152044-54-7

PubChem

A: 448799
B: 448013

Epothilones C (R = H) and D (R = Me)

Epothilones C (R = H) and D (R = CH3)

Chemical formulae

C: C26H39NO5S
D: C27H41NO5S

Molecular masses

C: 477.66 g/mol
D: 491.68 g/mol

CAS numbers

D: 189453-10-9

PubChem

C: 9891226
D: 447865

Epothilones E (R = H) and F (R = Me)

Epothilones E (R = H) and F (R = CH3)

Chemical formulae

E: C26H39NO7S
F: C27H41NO7S

Molecular masses

E: 509.66 g/mol
F: 523.68 g/mol

Disclaimer and references

The epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epithilones have better efficacy and milder adverse effects than taxanes.[1]

As of September 2008, epothilones A to F have been identified and characterised.[2] Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for paclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed.[3] Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.[4]

Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum.