Semisynthesis and degradation of the tubulin inhibitors epothilone and tubulysin

• Published in: Pure and applied chemistry 2003-01, Vol.75 (2), p.167-178
• Main Authors: Höfle, G., Glaser, N., Leibold, T., Karama, U., Sasse, F., Steinmetz, H.
• Format: Article
• Language: English
• Subjects: Alkynes; Degradation; Epothilones; Epoxidation; Hydrolysis; Hydroxylation; Medical research; Metathesis; Valine
• ISSN: 0033-4545; 1365-3075
• DOI: 10.1351/pac200375020167

The structure-activity relationships of epothilones indicate that major modifications are only tolerated in the western ring segment. In particular, C2 methyl of the thiazole ring appears to be most flexible. Its broad modification started from epothilone F, which was obtained from natural epothilone B by hydroxylation via the -oxide. Some of the prepared derivatives exhibit improved esterase stability in addition to high cytotoxic activity. For these and other favorable properties, amine (BMS-310705) was recently introduced in clinical trials. In an alternative approach, modified side chains were introduced by replacement of the C12,C15 ring segment via ring-opening olefin metathesis (ROM) of epothilone C in the presence of ethylene to 12,13- -epothilone C, introduction of a synthetic building block followed by ring-closing olefin metathesis (RCM), and epoxidation to the 16-alkyne analog of epothilone A. The structure of the tetrapeptide tubulysin D was confirmed by total hydrolysis to -methyl d-pipecolic acid, l-isoleucine, tubuvaline (Tuv), tubuphenylalanine (Tup), formaldehyde, and 3-methylbutyric acid. Mild acidic hydrolysis to cyclo-tubulysin andoxidative degradation to l-valine allowed the assignment of the stereocenters of Tuv, hydrazinolysis, and comparison with synthetic reference samples to that of Tup. The absolute configuration of tubulysin D is: ( )-Mep, (2,3 )-Ile, (1' ,3' )-Tuv, and (2 ,4 )-Tup.