ABSTRACT
Epothilone is a secondary metabolite of the myxobacterium Sorangium cellulosum. It is a macrolactone of a novel structural type characterized by an epoxy and a ketogroup in the lactone ring and a side chain with a thiazole ring (Figure 21.1), functional groups from which the name epo-thi-lone was coined.1 Two main variants, epothilone A (1a) and epothilone B (1b) are normally isolated from the bacterial culture.2,3 The B variant is a homolog with an extra methyl group at the epoxide that makes it more active by a factor of 5-10. Similarly, minor and trace components are always observed as pairs of homologs with the B-series being invariably more active.4 Epothilone, originally spelled epothilon, was discovered by us in 1987 because of its antifungal activity. Its structure was œrst disclosed in 1991 in the Annual Scientiœc Report of our institute, Gesellschaft für Biotechnologische Forschung (GBF).1 The structure was elucidated mainly by spectroscopic methods and corroborated by x-ray crystallography, which also provided the absolute conœguration.3 Besides antifungal activity, strong cytotoxicity against mammalian cells was also reported. A German patent was œled in November 1991 (granted in May 1994), and an international one in November 1992,5 although it was withdrawn in April 1994, because the impressive antitumor activity of the epothilones was not
21.1 Introduction .......................................................................................................................... 513 21.2 Natural Epothilones .............................................................................................................. 515 21.3 Biosynthesis .......................................................................................................................... 518 21.4 Mechanism of Action............................................................................................................ 521 21.5 Total Synthesis and Semisynthesis ....................................................................................... 529
21.5.1 Total Synthesis .......................................................................................................... 529 21.5.2 Semisynthesis ........................................................................................................... 533
21.6 Structure-Activity Relationships .......................................................................................... 541 21.7 Preclinical Studies ................................................................................................................ 547 21.8 Clinical Studies ..................................................................................................................... 549
21.8.1 Epothilone B-Lactam (BMS 247550, Ixabepilone, Ixempra) ................................... 550 21.8.2 Epothilone B (EPO906, Patupilone) ......................................................................... 553 21.8.3 Epothilone D (KOS-862) .......................................................................................... 554 21.8.4 ZK-EPO (Sagopilone) ............................................................................................... 555 21.8.5 21-Aminoepothilone B (BMS-310705) ..................................................................... 555 21.8.6 Dehydelone (KOS-1584) ........................................................................................... 556
Acknowledgments .......................................................................................................................... 556 References ...................................................................................................................................... 556
yet known, and there was limited interest in purely cytotoxic compounds. The patent strain, S. cellulosum So ce90, was deposited at the German Culture Collection (Deutsche Sammlung von Mikroorganismen und Zellkulturen, DSMZ) in Braunschweig in October 1991, under number DSM 6773, and has since been sent to many laboratories all over the world.
