Design, Synthesis, and Biological Investigation of Epothilone B Analogues Featuring Lactone, Lactam, and Carbocyclic Macrocycles, Epoxide, Aziridine, and 1,1-Difluorocyclopropane and Other Fluorine Residues

Despite previous
studies within the epothilone field, only one
member of this compound family, ixabepilone, made it to approval for
clinical use. Recent advances in organic synthesis and medicinal chemistry
allow further optimization of lead epothilone analogues aiming to
improve their potencies and other pharmacological properties as part
of the quest for discovery and development of new anticancer drugs,
including antibody–drug conjugates as potential targeted cancer
therapies. Herein, we report the design, synthesis, and biological
evaluation of a series of new epothilone B analogues equipped with
novel structural motifs, including fluorine-containing residues, 12,13-difluorocyclopropyl
moieties, mono- and dimethylated macrolactones, and 1-keto macrocyclic
systems, as well as two N-substituted ixabepilone analogues in which
the 12,13-epoxide and macrolactam NH moieties were replaced, the former
with a substituted aziridine moiety and the latter with an NCO-alkyl
residue (imide or carbamate). Biological evaluation of these analogues
revealed a number of exceptionally potent epothilone B analogues,
demonstrating the potency enhancing effects of the fluorine residues
and the aziridinyl moiety within the structure of the epothilone molecule
and providing new and useful structure–activity relationships
within this class of compounds.