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

Abstract

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, 12,13difluorocyclopropyl 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.

Epothilones as Natural Compounds for Novel Anticancer Drugs Development

“…These two compounds are only a few examples of the rational or combinatorial synthesis of new epothilone derivatives. Nicolaou, et al [ 123 ] used the structure of EpoB as a starting point for the synthesis of new compounds with better cytotoxic potencies, including different motifs such as fluorine, aziridine moiety, heterocyclic side chain, replacement of the epoxide for a difluorocyclopropyl moiety, or ixabepilone analogs, producing 54 compounds, which were evaluated against cancer cell lines. The most potent compounds are presented in Figure 5 .…”

The preparation and properties of 1,1-difluorocyclopropane derivatives

“…The reaction of various functionalized alkenes with the CF 3 SiMe 3 -NaI system has been studied (Table 2). Difluorocarbene addition to α-fluorostyrenes enabled the efficient synthe- [47] sis of trifluorocyclopropanes 34 [41]. The difluorocyclopropanation of protected cyclohexenone yielded cyclopropane 35 [42].…”

“…The difluorocyclopropana-tion of an alkenyl trifluoroborate using the TMSCF 3 -NaI system afforded the boronate derivative 37 [44]. The reagent was also used for the synthesis of organic spiro compounds, containing selectively fluorinated cyclopropanes 38a,b [45], for the preparation of 6,6-difluoro-3-azabicyclo[3.1.0]hexane (39) (on a 10 g scale) [46], and of the epothilone B analog 40 [47] (Table 2).…”

Applications of the Horner–Wadsworth–Emmons Olefination in Modern Natural Product Synthesis

“…Late-stage HWE olefinations were also used in the modification of epothilone B analogues designed by Nicolaou and co-workers to improve their potencies and pharmacological properties as anticancer drugs (Scheme 19). 35 Introduction of different heterocycle side chains to the macrocyclic core was achieved via HWE reactions in the presence of NaHMDS, n-BuLi, or NaHMDS/t-BuOK, followed by desilylation.…”