Epothilone O, a new member of this family from Sorangium cellulosum strain So0157-2

Epothilones are a new class of 16-membered macrolides with taxol-like effects produced by myxobacterium Sorangium cellulosum.^{1, 2} In contrast to taxol, they are active against taxol-resistant tumors and are water soluble. Following the isolation and characterization of the major metabolites, epothilones A and B from the strain S. cellulosum So ce90, some natural and synthetic epothilone variants have been reported,^{3, 4, 5, 6, 7} and a few of them have undergone preclinical or clinical evaluations.⁸ As a result, ixabepilone, a lactam analog of epothilone B, has been approved for clinical use for treatment of certain forms of breast cancer.⁹ In our previous investigation, five new epothilone glycosides and two new epothilone congeners have been isolated from the epothilones A and B producing strain S. cellulosum strain So0157-2.^{10, 11} As part of our ongoing research on the metabolites produced by the S. cellulosum strain So0157-2, a new 16-membered macrolide, designed as epothilone O (1), was obtained from the 120 l fermentation broth of S. cellulosum strain So0157-2. Herein, we describe the isolation, structure elucidation and biological activity of the new compound.

The producing organism S. cellulosum strain So0157-2 was provided by Professor Yuezhong Li at the Shandong University, China, and was deposited in the China Center of Typical Culture Collection (CCTCC) with accession No.CCTCC M 208078. The culture and fermentation of S. cellulosum strain So0157-2 were conducted according to the procedure as described in the literature.¹⁰ The adsorber resin XAD-1600 (Rohm and Haas, Philadelphia, PA, USA; 2.4 l) was separated from the 120 l fermentation broth with a process filter. After washing the resin with water, the resin was eluted with four bed volumes of 95% ethanol. The ethanol eluent was diluted to about 30% ethanol and charged to a XAD-1600 resin column eluting with 30, 40, 50, 60 and 70% ethanol (two bed volumes each). The fractions eluting with 60 and 70% ethanol were pooled and evaporated at 50 °C to give a mixture, which was dissolved in CHCl₃ and chromatographed on silica gel (100–200 mesh) eluting with petroleum ether/acetone solvent gradient from 70:30 to 40:60. The polar fraction eluting with petroleum ether/acetone (60:40) was further chromatographed on a Sephadex LH-20 (GE Healthcare, Glies, UK) column and eluted with ethanol and detected by TLC developed with petroleum ether/acetone (3:2) and visualized under UV light at 254 nm (Rf=0.46) to give a subfraction. The subfraction was further isolated by semipreparative HPLC (Agilent 1100 instrument, Agilent, Palo Alto, CA, USA; C18 column: Zorbax SB-C18, Agilent, 9.4 × 250 mm, 5 μm) using CH₃CN/H ₂O (40:60) with a flow rate of 1.5 ml min⁻¹ at a room temperature to give compound 1 (t_R 37.80 min, 3.5 mg).

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