Alterlactone

Selective C‒H functionalization in a pool of proximal C‒H bonds, predictably altering their innate reactivity is a daunting challenge. We disclose here, an expedient synthesis of privileged seven-membered lactones, dibenzo[c,e]oxepin-5(7H)-one through a highly chemoselective benzylic C(sp3)‒H activation. Remarkably, the formation of widely explored six-membered lactone via C(sp2)‒H activation is suppressed under the present conditions. The reaction proceeds smoothly on use of inexpensive metallic copper catalyst and di-tert-butyl peroxide (DTBP). Owing to the hazards of stoichiometric DTBP, further, we have developed a sustainable metallic copper/rose bengal dual catalytic system coupled with molecular oxygen replacing DTBP. A 1,5-aryl migration through Smiles rearrangement was realized from the corresponding diaryl ether substrates instead of expected eight-membered lactones. The present methodology is scalable, applied to the total synthesis of cytotoxic and neuroprotective natural product alterlactone. The catalyst is recyclable and the reaction can be performed in a copper bottle without any added catalyst.

Seven dibenzopyrone phenolic derivatives, i.e., alternariol (1), alternariol 5-O-methyl ether (2), altenusin B (3), dehydroaltenusin (4), altenuene (5), altenusin (6), and alterlactone (7), were isolated from endophytic fungi Alternaria alternata extract, and these compounds' structures were elucidated based on various spectroscopic data. Compound 3, a diphenic acid derivative, was determined as a new compound. In this study, compounds 3, 4, 6, and 7 displayed remarkable neuroprotective effects against oxidative injuries by acting as potent activators of nuclear factor-erythroid derived 2-like 2 (Nrf2) in PC12 cells. A mechanistic study indicated that these compounds induced the nuclear accumulation of Nrf2, promoted the expression of Nrf2-governed cytoprotective genes, and increased the cellular antioxidant capacity. More importantly, genetic silence of Nrf2 expression deprived the observed cytoprotection, highlighting the important role of Nrf2 in the protection of these compounds.

β-Ketoacyl-acyl carrier protein synthase III (KAS III, FabH) is essential for bacterial fatty acid biosynthesis. Recent studies indicate that FabH can be a potential target for bactericide development. In the present study, an immobilized FabH column was developed and used to screen FabH inhibitors from complex natural product extracts. Combined with HPLC, four secondary metabolites, alternariol (1), altenuisol (2), alterlactone (3), and dehydroaltenusin (4), were site-directed, isolated, and identified from the crude extract of Alternaria alternata ZHJG5. These compounds showed inhibitory activities on FabH of Xanthomonas oryzae pv. oryzae (Xoo) with IC50 values from 29.5 to 74.1 μM and also displayed a varying degree of antibacterial activities against Xoo with minimal inhibitory concentration values from 4 to 64 μg/mL. Molecular modeling was then used to picture how the compounds interact with XooFabH. Two inhibitors, compounds 1 and 3, exhibited significant bactericidal activity against rice bacterial leaf blight with a protective efficiency of 66.2 and 82.5% at the concentration of 200 μg/mL, respectively, suggesting that they could be lead candidates to develop novel bactericides.