Asperchalasine A, a Cytochalasan Dimer with an Unprecedented Decacyclic Ring System, from Aspergillus flavipes

Abstract

Asperchalasine A (1), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasines B-D (2-4), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single-crystal X-ray diffraction techniques. Compound 1, which possesses an unprecedented 13-oxatetracyclo[7.2.1.1(2,5).0(1,6)]tridec-8,12-dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1-4 were described starting from the co-isolated compounds 5 and 6. More importantly, 1 induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells.

Epicochalasines A and B: Two Bioactive Merocytochalasans Bearing Caged Epicoccine Dimer Units from Aspergillus flavipes

“…Ther elative configuration of unit A, which is similar to those of asperchalasines Band C, [10] was verified by aNOESY experiment (Figure 1e). TheN OESY cross-peaks of H-5 to H-4 and H-8, H-4 to H-10, and H-8 to Me-25 and the interactions between Me-25, H-16b,and H-19 suggested that these moieties are cofacial and b-oriented.…”

“…[9] In our previous study on Aspergillus flavipes cultured on rice,w ed iscovered ac ytochalasan dimer (asperchalasine A, Scheme 1). [10] Considering that the fermentation of fungi under different conditions may lead to different secondary metabolites,w ef urther investigated the metabolites of A. flavipes cultured in al iquid culture broth. In this study,t wo novel merocytochalasans,e picochalasines A( 1) and B( 2;S cheme 1), with high degrees of functionalization and intricate polycyclics tructures,w ere isolated from the liquid culture broth of A. flavipes.Compounds 1 and 2 appear to belong to the same structural family.However,because of the 1808 8 rotation of the oxidized epicoccine moiety c (Scheme 2) in 2,t heir fusion patterns differ substantially, thus resulting in different carbon skeletons.M ost notably, compounds 1 and 2 are the first examples of cytochalasan adducts characterized by an adamantyl cage in ah endecacyclic 5/6/11/5/6/5/6/5/6/6/5 ring system formed by the polymerization of an epicoccine dimer with acytochalasan moiety.…”

“…Aside from those of unit A, 18 carbon signals remained, which were preliminarily attributed to two epicoccine units (units Ba nd C) on the basis of our reported adducts of cytochalasin and epicoccine (asperchalasines B and C). [10] Theg ross structures of units Ba nd Cw ere elucidated by HMBC correlations and carbon chemical shifts (Figure 1b,c), as follows:H-1' to C7' and C8';H-8' to C1' and C2;Me-9' to C5',C6',and C7';H-6' to C8';H-1'' to C2'',C3'', C7'',and C8'';H-8'' to C1'',C 2 '',and C7'';and Me-9'' to C5'', C6'',a nd C7''.I na ddition, the HMBC correlations (Figure 1d)from H-18 to C3',H-19 to C2',H-1' to C20, and H-8' to C21 revealed the connectivity between units Aa nd B through the newly formed furo[3,2-c]pyran ring system (rings Da nd E). Furthermore,t he HMBC correlations (Figure 1d)from H-6' and H-8' to C6'',Me-9'' to C7',and H-1'' to C4' suggested the connection of units Ba nd Ct hrough C4'/ C2'' and C7'/C6'' bonds,a nd the linkage of C2'/C4'' was proposed to satisfy their quaternary nature and chemical shifts as well as the aforementioned molecular formula.…”

Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities

“…As part of our continued investigation of bioactive metabolites from fungi, 10,11 asperterpenes A ( 1 ) and B ( 2 ), two meroterpenoids with unprecedented carbon skeletons, were isolated from the culture broth of Aspergillus terreus , along with a new biosynthetically related compound, asperterpene C ( 3 ) (Fig. 1).…”

Total Syntheses of Asperchalasines A–E

“…[1] A recent paradigm is the discovery of aseries of unprecedented fungal secondary metabolites,c ollectively termed merocytochalasans,from the fermentation broth of Aspergillus flavipes by Zhang and co-workers. [2] Structurally,a ll of these newly identified molecules consist of two types of subunits of natural origin, the tricyclic cytochalasan [3] and bicyclic epicoccine, [4] as shown in the structures of 1-13 ( Figure 1). Among them, asperchalasines B-H (1-7) [2a,e] possess aT -shaped hexacyclic skeleton consisting of one cytochalasan moiety and one epicoccine moiety,w hereas asperchalasine A ( 8) [2a] bears am ore complicated sandwich-shaped decacyclic framework containing one epicoccine moiety and two cytochalasan moieties.O ther representative merocytochalasans include asperflavipine B ( 9), [2c] epicochalasines A( 10)a nd B ( 11), [2b] and aspergilasine A ( 12), [2d] all of which comprise one cytochalasan unit and two caged epicoccine units.A sperflavipine A ( 13) [2c] is particularly notable,s ince it is the sole cytochalasan-epicoccine heterotetramer within the merocytochalasan family,w hich bears an incredibly complicated dumbbell-shaped tetradecacyclic framework.…”