Natural products in parallel chemistry--novel 5-lipoxygenase inhibitors from BIOS-based libraries starting from alpha-santonin.
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.
Schwarz
Oliver
O
Analyticon Discovery GmbH, Hermannswerder Haus 17, 14473 Potsdam, Germany. o.schwarz@ac-discovery.com
Jakupovic
Sven
S
Ambrosi
Horst-Dieter
HD
Haustedt
Lars Ole
LO
Mang
Christian
C
Müller-Kuhrt
Lutz
L
D000143:Acids / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D000969:Antinematodal Agents / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis*; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004987:Ethers / Q000737:chemistry; D016859:Lipoxygenase Inhibitors; D008956:Models, Chemical; D010636:Phenols / Q000737:chemistry; D012500:Santonin / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry
D000143:Acids; D000577:Amides; D000969:Antinematodal Agents; D001688:Biological Products; D004791:Enzyme Inhibitors; D004987:Ethers; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D013844:Thiazoles; D012500:Santonin