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Harziachalasins A-G,polycyclic-fused cytochalasins from the endophytic fungus Trichoderma harzianum MLJ-4 with HIV latency reversal activity

摘要Seven new polycyclic-fused cytochalasins(CYTs),harziachalasins A-G(1-7),together with three known analogues(8-10)were isolated from the solid culture of the endophytic fungus Trichoderma harzianum MLJ-4,which was originally isolated from the leaves of Asclepias curassavica.The planar and absolute structures of all new compounds were deter-mined on the basis of extensive spectroscopic data(1D,2D NMR and HR-ESI-MS),NMR calculations with DP4+prob-ability analysis,and theoretical simulations of ECD spectra.Compound 1 represents the first example of 5/6/6 tricyclic CYT featuring a 2-methyl-4-oxopentyl side chain at the C-14 position.This novel architecture originates from a 5/6/6/7 tetracyclic CYT precursor through sequential oxidative cleavage of the C-19-C-20 bond followed by decarboxylative elimination ofC-19.Compound 2 features an unprecedented 5/6/6/6/7 pentacyclic scaffold incorporating a 1,3-diox-ane moiety,may be constructed by the acetalization of the 7-OH and 13-OH on a 5/6/6/7 tetracyclic CYT with acetal-dehyde.Compounds 1-10 were screened for HIV latency reversal activity using J-Lat A72 and J-Lat 10.6 cell models.Compound 4 showed strong activity,with half-maximal effective concentrations(EC50)values of 2.68 μM(J-Lat A72 cells)and 2.99 μM(J-Lat 10.6 cells),demonstrating consistent potency.Mechanistic studies revealed 4 activated the NF-κB pathway to reverse HIV latency,offering insights for new therapeutic strategies targeting this pathway.

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