Abstract
New terpendoles N-P (1–3) were isolated along with 8 structurally related known compounds including terpendoles and voluhemins from a culture broth of the fungus Volutella citrinella BF-0440. The structures of 1–3 were elucidated using various spectroscopic experiments including 1D- and 2D-NMR. All compounds 1–3 contained a common indole–diterpene backbone. Compounds 2 and 3 had 7 and 6 consecutive ring systems with an indole ring, respectively, whereas 1 had a unique indolinone plus 4 consecutive ring system. Compounds 2 and 3 inhibited both sterol O-acyltransferase 1 and 2 isozymes, but 1 lost the inhibitory activity. Structure–activity relationships of fungal indole–diterpene compounds are discussed.
Highlights
Natural compounds derived from animals, plants, and microbes have historically been used as a rich source for new drug discovery
Sterol O-acyltransferase (SOAT), an enzyme that catalyzes the formation of cholesteryl ester (CE), has been a potential target for development as a post-statin drug
Researchers understand that SOAT has two isozymes, SOAT1 and SOAT2, with distinct functions in the human body [2,3,4,5], and that selective inhibition of SOAT2 is responsible for the prevention of atherosclerosis and fatty liver disease [6,7,8,9,10]
Summary
Natural compounds derived from animals, plants, and microbes have historically been used as a rich source for new drug discovery. These sources provide more structurally diversity than synthetic compounds [1]. A set of structurally related compounds tend to be produced by a single organism, allowing us to identify and associate the chemical groups responsible for evoking a target biological effect. This structure–activity relationship (SAR) information becomes a key approach for lead optimization in drug discovery. Terpendole L (9), tolypocladin A (10), terpendole J (11), and sespendole (12)
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