Bisaspochalasins A–C: Three Cytochalasan Homodimers with Highly Fused Ring System from an Endophytic Aspergillus flavipes

Abstract

Three unprecedented cytochalasan homodimers, bisaspochalasins A–C (1–3), and two known monomers, aspochalasins B and D (4 and 5), were isolated from an endophytic Aspergillus flavipes. Bisaspochalasin A (1) contains a 13-hydroxy-3,24-dioxatricyclo­[11.10.11,13.02,15]­tetracos-4-one cross-linkage, representing an unprecedented carbon skeleton. Bisaspochalasins B (2) and C (3) share a thioether bridge, while 3 has a peroxy modification at C-7, which may be generated by Schenck-ene photooxygenation. Their structures, including their absolute configurations, were elucidated by HRESIMS, NMR, chemical transformation, and X-ray crystallography. Bisaspochalasin A showed inhibitory activity against human T cell proliferation with an IC50 value of 15.8 μM while maintaining low cytotoxicity to T cells.

Bisaspochalasins D and E: Two Heterocycle-Fused Cytochalasan Homodimers from an Endophytic Aspergillus flavipes

“…These newly reported cytochalasan homodimers highlighted the multitudinous polymerization phenomena in cytochalasan family and inspired researchers to explore the working mechanisms of these mysterious (non)­enzymatic steps in nature. As part of our efforts to mine novel natural cytochalasan homodimers, bisaspochalasins D ( 1 ) and E ( 2 ) (Figure ), two unprecedented cytochalasan homodimers both fused with heterocycles, were obtained from a strain named Aspergillus flavipes KIB-392, an endophytic fungus also isolated from the stems of Hevea brasiliensis . Bisaspochalasin D ( 1 ) contains the first reported naturally occurring triple heterobridged 3,8-dioxa-6-azabicyclo[3.2.1]­octane framework, while bisaspochalasin E ( 2 ) is characterized by a pyrrole ring as the dimeric motif.…”

“…During the past decade, the chemical diversity of the cytochalasans has been remarkably enlarged by reports of novel modifications in three different categories: (1) the incorporation of multiple different amino acids into the polyketide backbone including alanine, leucine, phenylalanine, p -methoxyphenylalanine, tryptophan, 1-methyltryptophan, 2-norindole tryptophan, tyrosine, and valine; ,,, (2) multifarious structural modifications on the core cytochalasan skeleton, such as condensation, , rearrangement, − cleavage, − and halogenation of the polyketide macrocycles, as well as the involvement of seco -isoindolone rings; , and (3) examples of dimerization or polymerization, especially for heteropolymers with one or more epicoccine subunits. − Intriguingly, most of the modifications or polymerizations take place on the carbons between C-17 and C-21. The elegant installation of carbonyls or carbon–carbon double bonds between C-17 and C-21 activates these sites so they can interact with additional participating structural motifs, such as epicoccine, − ,, sulfur-bearing ,, or nitrogenous , moieties, or even themselves, just like dimericchalasine A and bisaspochalasins A–C reported recently or bisaspochalasins D ( 1 ) and E ( 2 ) described here. This type of inherent diversification resulting from the reactive α,β-unsaturated diketone in the polyketide chain may play an unprecedented and fascinating role in nature for engineering more polymerized and fused cytochalasans by chemical synthesis and biosynthesis.…”

“…The fermentation of strain KIB-392 was conducted in a way previously reported, and the total fermention scale of strain KIB-392 was 2.4 kg cargo rice. The fermentation solid of strain KIB-392 was then extracted in the same process as reported .…”

“…Distinguished from these cytochalasan heteropolymers mentioned above, four structurally diverse cytochalasan homodimers (dimericchalasine A and bisaspochalasins A–C) have been reported recently. These newly reported cytochalasan homodimers highlighted the multitudinous polymerization phenomena in cytochalasan family and inspired researchers to explore the working mechanisms of these mysterious (non)­enzymatic steps in nature.…”

The endophytic Aspergillus strains: A bountiful source of natural products

“…This inhibition is attributed to immunosuppressive activity rather than cytotoxicity. This was evidenced by measuring the CC 50 value of compound ( 15 ) against resting naïve T cells which give a value greater than 40 μmol l −1 (Wang et al 2020b).…”