Recent developments in the chemistry, biology and medicine of the epothilones.

The epothilones have occupied center stage on the scenes of total synthesis, chemical biology and medicine for the last five years, no doubt because of their intriguing mode of action and unusually high potency against tumor cells, including multidrug-resistant cell lines. This article highlights the most recent advances within this exciting field. Thus, an overview of recent synthetic endeavors culminating in a new generation of total syntheses and analogues, some with higher potencies than the naturally occurring substances, will be given, and the chemical biology, in particular the current understanding of structure-activity relationships of the epothilones, will also be discussed in light of the latest biological results. In addition, the recently elucidated biosynthetic machinery of the natural epothilone-producing myxobacterium Sorangium cellulosum, as it is now understood, will be described. Finally, some preclinical and clinical studies will be summarized.

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction to construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC(50) = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.