Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

Abstract

Abstract:A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated. Starting from fifteen structurally diverse natural products, a focused library featured by Michael acceptors is constructed with IBX mediated oxidation. Biological assay on five tumor cell lines indicates that four Michael acceptors, 8a, 11a, 12a, 14a, are with improved cytotoxicity (3-10 folds more potent than the parent compounds), which merit further investigations. Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor. The results suggest that the strategy is not only effective and relatively high discovery rate (28%), but also resource saving.

Natural‐Like Spirocyclic Δα,β‐Butenolides Obtained from Diazo Homophthalimides

“…On the one hand, Michael acceptors are often viewed as ‘stay‐away‐from’ structural features in bioactive compound design as they can, through non‐specific reactivity towards nucleophilic centers in proteins, generate false positive response in biological assays [18] . At the same time it is apparent that in the natural product domain, unrivaled by its success as a source of drug leads, Michael acceptor motifs (e. g., butenolides and Δ α,β ‐spirobutenolides, vide supra ) are omnipresent [19] and could even be responsible for the important biological activity (such as anticancer) displayed by such naturally occurring compounds [20] . The selective cytotoxic activity often displayed by Michael acceptors towards cancer cells could be linked to their perturbation of critical cancer cell survival mechanisms (such as ubiquitin proteasome system [21] or thioredoxin system [22] ).…”

Spirocyclizations Involving Oxonium Ylides Derived from Cyclic α-Diazocarbonyl Compounds: An Entry into 6-Oxa-2-azaspiro[4.5]decane Scaffold

“…Compounds 2 and 6 obtained in this work contain an arylidene pyrrolidine-2,5-dione system, a potential Michael acceptor. Michael acceptors are omnipresent in natural products and could be specifically responsible for the anticancer activity displayed by some of the naturally occurring compounds . Synthetic Michael acceptors have also found utility in medicinal chemistry as covalent targeted enzyme inhibitors and inhibitors of critical cancer cell survival mechanisms .…”

Spiralyde A, an Antikinetoplastid Dolabellane from the Brown Alga Dictyota spiralis

“…Additionally, the presence of an α,β-unsaturated aldehyde functionality in spiralyde A ( 1 ), which may act as a Michael acceptor, seems to result in an enhanced antikinetoplastid activity with respect to 2 . The existence of Michael acceptor moieties both in natural products and synthetic compounds is considered a key feature due to the biological effects that these compounds usually display [21,22].…”