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.

尽管此前在埃坡霉素（epothilone）领域已有诸多研究，但该化合物家族中仅有伊沙匹隆（ixabepilone）一款药物获批进入临床应用。近年来有机合成与药物化学领域的技术进展，为埃坡霉素先导化合物类似物的进一步优化提供了可能，以期提升其药效活性并改善其他药理学特性，这也是新型抗癌药物研发探索的一部分，其中包括作为潜在靶向癌症治疗手段的抗体药物偶联物（antibody–drug conjugates）。本文报道了一系列新型埃坡霉素B类似物的设计、合成与生物学评价，这类类似物搭载了多种全新结构基序，包括含氟残基、12,13-二氟环丙基基团、单甲基化与二甲基化大环内酯，以及1-酮基大环体系；同时还包含两款N-取代伊沙匹隆类似物，其12,13-环氧基团与大环内酰胺NH基团分别被替换：前者替换为取代氮丙啶环基团，后者替换为NCO-烷基残基（酰亚胺或氨基甲酸酯）。对这些类似物的生物学评价结果显示，多款埃坡霉素B类似物展现出极强的药效活性，证实了埃坡霉素分子结构中含氟残基与氮丙啶环基团对药效的增强作用，同时为本类化合物构建了全新且极具价值的构效关系框架。