Development of a Terpenoid Alkaloid-like Compound Library Based on the Humulene Skeleton.
Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp3-rich terpenoid scaffolds and nitrogen-containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid-like compounds based on Lewis-acid-catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid-like compound library has a high level of three-dimensional-shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid-like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid-like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries.
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba, Aoba-ku, Sendai, 980-8578, Japan. hal@mail.pharm.tohoku.ac.jp.
Haruhisa
H
Kikuchi
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba, Aoba-ku, Sendai, 980-8578, Japan.
Takehiro
T
Nishimura
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, 6-3, Aza-Aoba, Aoba-ku, Sendai, 980-8578, Japan.
Eunsang
E
Kwon
Mushroom Research Laboratory, Hokuto Corporation, Nagano, 381-0008, Japan.
Junya
J
Kawai
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba, Aoba-ku, Sendai, 980-8578, Japan.
Yoshiteru
Y
Oshima
D000470:Alkaloids / Q000737:chemistry*; D055808:Drug Discovery; D015394:Molecular Structure; D000081222:Monocyclic Sesquiterpenes; D010936:Plant Extracts; D012717:Sesquiterpenes; D054852:Small Molecule Libraries; D013729:Terpenes / Q000737:chemistry*
D000470:Alkaloids; D000081222:Monocyclic Sesquiterpenes; D010936:Plant Extracts; D012717:Sesquiterpenes; D054852:Small Molecule Libraries; D013729:Terpenes; C042686:humulene
antihypolipidemics; chemical library; chemoinformatics; diversity-oriented synthesis; drug discovery; terpenoid alkaloids