Natural Products in Parallel Chemistry––Novel 5-Lipoxygenase Inhibitors from BIOS-Based Libraries Starting from α-Santonin

Abstract

Recently, we developed a concept known as biology-oriented synthesis (BIOS), which targets the design and synthesis of small- to medium-sized compound libraries on the basis of genuine natural product templates to provide screening compounds with high biological relevance. We herein describe the parallel solution phase synthesis of two BIOS-based libraries starting from alpha-santonin (1). Modification of the sesquiterpene lactone 1 by introduction of a thiazole moiety followed by a Lewis-acid-mediated lactone opening yielded a first library of natural product analogues. An acid-mediated dienone-phenol rearrangement of 1 and a subsequent etherification/amidation sequence led to a second natural product-based library. After application of a fingerprint-based virtual screening on these compounds, the biological screening of 23 selected library members against 5-lipoxygenase resulted in the discovery of four potent novel inhibitors of this enzyme.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[189] One of the first implementationso ft his methodology was demonstrated by Analyticon, who commercialized two libraries based on andrographolide and a-santonin. [193] To synthesize thesel ibraries, the corresponding natural terpenoids were transformed into polyfunctional key scaffolds 11 and 12,w hich were suitable for further heterocyclization (Scheme 9). These scaffoldsw ere used to generate compound libraries with two diversity pointst hrough subsequentH antzsch thiazoles ynthesis and amide formation.…”

(−)-Cytisine: Access to a stereochemically defined and functionally flexible piperidine scaffold

“…Taking this further, an ability to harness further the reactivity of a readily available natural product to widen the reach of the structural diversity available is well exemplified by Schwarz's work on -santonin. 5 Here, both the natural product 1 and a readily available variant 2 (available from 1 by acid-catalysed rearrangement) provided analogues of both of these related scaffolds that were explored as inhibitors of 5-lipoxygenase.…”

Scenarios and Case Studies: Examples for Ligand‐Based Virtual Screening

“…Examples from the Literature Among recent works, Franke et al [13] and Schwarz et al [14] at AnalytiCon Discovery identified novel inhibitors of the 5-lipoxygenase (5-LO) pathway using 2DLBVS on their in-house compound collection. The queries constituted a list of 43 chemically diverse known inhibitors compiled from published data.…”