Taichunamides: Prenylated Indole Alkaloids from Aspergillus taichungensis (IBT 19404)

Abstract

Seven new prenylated indole alkaloids,taichunamides A-G,w ere isolated from the fungus Aspergillus taichungensis (IBT 19404). Taichunamides Aa nd Bc ontained an azetidine and 4-pyridone units,r espectively,a nd are likely biosynthesized from notoamide Svia (+ +)-6-epi-stephacidin A. Taichunamides Ca nd Dc ontain endoperoxidea nd methylsulfonyl units,r espectively.T his fungus produced indole alkaloids containing an anti-bicyclo[2.2.2]diazaoctane core, whereas A. protuberus and A. amoenus produced congeners with as yn-bicyclo[2.2.2]diazaoctane core.P lausible biosynthetic pathways to access these cores within the three species likely arise from an intramolecular hetero Diels-Alder reaction.Weh ave been studying the structures,s ynthesis,a nd biosynthesis of the notoamides and stephacidins from the fungi of the genus Aspergillus,a nd found that the marinederived A. protuberus (MF297-2) produced (+ +)-stephacidin A[ ( + +)-16]a nd (À)-notoamide B[ ( À)-15]a sm ajor metabolites (Scheme 1). [1] Curiously, A. amoenus (NRRL 35 600) was found to produce their respective enantiomers [2] (Scheme 1). We have recently documented that both fungi produced (+ +)-versicolamide B[(+ +)-14]asaminor metabolite (Scheme 1). Theputative biosynthetic precursor to (+ +)-14,6epi-stephacidin A( 13), was isolated from A. amoenus as an enantiomeric mixture enriched with (À)-13. [3] These stereo-chemical observations suggested that this fungus produced both enantiomers of 13 and contain ahighly enantiodiscriminating oxidase,w hich converts only (+ +)-13 into (+ +)-14.T he characteristic and unique bicyclo[2.2.2]diazaoctane core common to this family of prenylated indole alkaloids is most likely biosynthesized by an intramolecular hetero-Diels-Alder (IMDA) reaction. Them etabolite profiles of these fungi currently indicate that the biosynthesis of these stereochemically distinct metabolites plausibly proceeds by the pathways a( main) and b( minor) in A. protuberus and pathways c( main) and b/d (minor) in A. amoenus (see Scheme 1). Ther ecent isolation of ap lausible precursor, notoamide S( 22), for these metabolites from A. amoenus provided strong support for this proposal. [3] Most of the alkaloids thus far identified to contain the bicyclo-[2.2.2]diazaoctane ring system, possess ar elative configuration of syn at C6 (see stephacidin numbering). Distinct enantiomers of notoamide B(15)and stephacidin A(16)are among the main metabolites from A. protuberus and A. amoenus,a nd versicolamide B( 14)w as the first alkaloid within this family to be identified with the corresponding relative configuration of anti at C6. Cai et al. recently isolated natural alkaloids with the relative configuration of anti, namely,(+ +)-14 and (+ +)-13,from A. taichungensis ZHN-7-07 [4] (syn and anti relationship is based on the H21 and bridging amide C18/N19). With these stereochemical differences identified, we were interested in elucidating the biosynthetic machinery of the producing organisms which give rise to the specific relative and absolute configurations obs...

Polyhalonitrobutadienes as Versatile Building Blocks for the Biotargeted Synthesis of Substituted N-Heterocyclic Compounds

“…4-Ethoxy-2-(2,3,3-trichloro-1-nitro-2-propenylidene)-benzazetine (a regioisomer of compound 26b ) can modulate RNA binding proteins [ 31 ]. A new prenylated indole alkaloid taichunamide A contains a benzazetidine unit, too [ 32 ]. It was isolated from the fungus Aspergillus taichungensis .…”

Enantioselective inhibitory abilities of enantiomers of notoamides against RANKL-induced formation of multinuclear osteoclasts

“…Notoamide derivatives, used in this study, were isolated from A. protuberus , 1 A. amoenus , 7 and A. taichungensis IBT 19404 15 or synthesized 9 (Figure 1). In order to test the inhibition by notoamides of RANKL-induced formation of multinuclear osteoclasts, the murine RAW264 cells were incubated with RANKL in the presence of samples at a concentration of 10 μg/mL.…”

“…To date, we have been studying the structures, 1–8,15 syntheses, 9,19–24 and biosyntheses 6,9,23,25,26 of prenylated indole alkaloids from three fungi, A. protuberus , A. amoenus , and A. taichungensis . We have, for a long time, been interested in the subject if the enantiomers of notoamide derivatives showed the enantiomerically distinct biological activities.…”

Enzyme evolution in fungal indole alkaloid biosynthesis

“…Taichunamide H ( 36 ), isolated from mangrove‐derived fungus Aspergillus versicolor HDN11‐84, and taichunamides B‐G ( 37 ‐ 42 ), isolated from the fungus Aspergillus taichungensis (IBT 19404), contain an anti ‐bicyclo[2.2.2]diazaoctane core (Fig. 10b) [68,69]. They are proposed to share the common precursors notoamide S ( 5 ), (+)‐6‐ epi ‐notoamide T ( 33 ), and (+)‐6‐ epi ‐stephacidin A ( 9 ).…”