Electrophilic Triterpenoid Enones: A Comparative Thiol-Trapping and Bioactivity Study

Danilo Del Prete, Orazio Taglialatela-Scafati, Alberto Minassi, Carmina Sirignano, Cristina Cruz, Maria L. Bellido, Eduardo Muñoz, and Giovanni Appendino

J. Nat. Prod., Article ASAP
DOI: 10.1021/acs.jnatprod.7b00271
Publication Date (Web): July 28, 2017

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 Δ1-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.