Undobolins A–L, Ophiobolin-Type Sesterterpenoids from Aspergillus undulatus

Abstract

Twelve previously undescribed ophiobolin-type sesterterpenoids, undobolins A−L (1−12), were isolated from Aspergillus undulatus, and their structures were elucidated by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction experiments. Compound 1 was the second example of 20-nor-ophiobolin reported, while compounds 2−6 were notable for oxygenation of C-2, and compound 6 showed significant inhibitory activity against ConAinduced T lymphocyte proliferation with an IC 50 value of 2.3 μM, which suggests a promising new direction in the quest for immunosuppressive agents.O phiobolins are sesterterpenoids with a 5/8/5 tricyclic ring system, which have been mainly isolated from Bipolaris and Aspergillus sp. 1−8 Since the identification of the first ophiobolin-type sesterterpenoid, ophiobolin A, from Ophiobolus miyabeanus in 1958, 9 more than 120 ophiobolins have been reported. 5,10−14 21-epi-Ophiobolin O demonstrated cytotoxicity against A549 and HL-60 human cancer cell lines with an IC 50 value of 0.6 and 0.8 μM, respectively. 8 Bipolarolide A, uniquely d e fi n e d b y a m u l t i c y c l i c c a g e d o x a p e n t a c y c l o -[9.3.0.0. 1,6 0. 5,9 1 8,12 ]pentadecane-bridged system, showed great HMGR inhibitory potency with an IC 50 value of 2.5 ± 0.1 μM, and bipolarolide F was active against C. albicans with a MIC value of 4.0 μg/mL. 15 Ophiobolin-type sesterterpenoids have received much attention from the synthetic and biosynthetic communities. Five total syntheses of ophiobolins have been developed in the past three decades. 16−20 (+)-Ophiobolin C was the first example, syntheszed by Kishi and co-workers in 38 steps in 1989, 16 and Jia's team accomplished the first total syntheses of bipolarolides A and B in 28 steps and 25 steps from (−)-citronellal. 21 Metabolites from Aspergillus have attracted considerable attention due to the diverse structural types that exhibit a wide range of biological activities. 6,22−27 Our group has a longstanding interest in the sesterterpenoids from the Aspergillus genus. The first examples of hexacarbocyclic sesterterpenoids with a 5/5/5/5/3/5 carbon skeleton were identified from Aspergillus nidulans, 28 and a series of sesterterpenoids with 5/ 12/5 or 5/8/6/5 ring systems were identified from Aspergillus spectabilis. 29 In the ongoing project focusing on structurally complex and bioactive secondary metabolites from Aspergillus sp., the solid fermentation of Aspergillus undulatus was conducted, and 12 novel ophiobolin-type sesterterpenoids, named undobolins A−L (1−12), were isolated. Herein, the isolation, structure elucidation, and bioactivity evaluation for these compounds are described.