Del Prete Danilo, Taglialatela-Scafati Orazio, Minassi Alberto, Sirignano Carmina, Cruz Cristina, Bellido Maria L, Muñoz Eduardo, Appendino Giovanni
Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale , Largo Donegani 2, 28100 Novara, Italy.
Dipartimento di Farmacia, Università di Napoli Federico II , Via Montesano 49, 80131 Napoli, Italy.
J Nat Prod. 2017 Aug 25;80(8):2276-2283. doi: 10.1021/acs.jnatprod.7b00271. Epub 2017 Jul 28.
Bardoxolone methyl (1) is the quintessential member of triterpenoid cyanoacrylates, an emerging class of bioactive compounds capable of transient covalent binding to thiols. The mechanistic basis for this unusual "pulsed reactivity" profile and the mode of its biological translation are unknown. To provide clues on these issues, a series of Δ-dehydrooleanolates bearing an electron-withdrawing group at C-2 (7a-m) were prepared from oleanolic acid (3a) and comparatively investigated in terms of reactivity with thiols and bioactivity against a series of electrophile-sensitive transcription factors (Nrf2, NF-κB, STAT3). The emerging picture suggests that the triterpenoid scaffold sharply decreases the reactivity of the enone system by steric encumbrance and that only strongly electrophilic and sterically undemanding substituents such as a cyanide or a carboxylate group can re-establish Michael reactivity, albeit in a transient way for the cyanide group. In general, a substantial dissection between the thiol-trapping ability and the modulation of biological end-points sensitive to thiol alkylation was observed, highlighting the role of shape complementarity for the activity of triterpenoid thia-Michael acceptors.
巴多昔芬甲酯（1）是三萜类氰基丙烯酸酯的典型成员，三萜类氰基丙烯酸酯是一类新兴的生物活性化合物，能够与硫醇发生瞬时共价结合。这种不同寻常的“脉冲反应性”特征的机制基础及其生物学转化模式尚不清楚。为了提供有关这些问题的线索，从齐墩果酸（3a）制备了一系列在C-2位带有吸电子基团的Δ-脱氢齐墩果酸盐（7a-m），并就其与硫醇的反应性以及对一系列亲电敏感转录因子（Nrf2、NF-κB、STAT3）的生物活性进行了比较研究。新出现的情况表明，三萜类骨架通过空间位阻大幅降低了烯酮系统的反应性，只有强亲电且空间需求小的取代基（如氰基或羧基）才能重新建立迈克尔反应性，尽管氰基是以瞬时方式进行。总体而言，观察到硫醇捕获能力与对硫醇烷基化敏感的生物学终点调节之间存在显著差异，突出了形状互补性对三萜类硫杂迈克尔受体活性的作用。
