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

摘要

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.