Hypoxia-Protective Azaphilone Adducts from Peyronellaea glomerata

Abstract

Peyronellones A and B (1 and 2), a pair of rare tetracyclic caged adducts of azaphilone with pyruvic acid, along with four new analogues (3-6), were isolated from solid cultures of the endophytic fungus Peyronellaea glomerata. Their structures were elucidated through spectroscopic analysis, and their absolute configurations were unambiguously determined by a combination of single-crystal X-ray crystallography, Rh(OCOCF)-induced ECD experiments, ECD calculations, and modified Mosher methods. Compound 2 (5 μM) was found to have a significant hypoxia-protective effect that improved the survival rate of hypoxia/reoxygenation-treated human umbilical vein endothelial cells from 35% to 70%, which was equal to the potency of the positive control, verapamil. Flow cytometry analysis suggested 2 could inhibit H/R-induced late-stage apoptosis of this cell line.

Recent advances in the chemistry and biology of azaphilones

“…Among citrinin dimers, peyronellones A-B (21)(22), a pair of rare tetracyclic caged adducts of azaphilone with pyruvic acid, were isolated from Peyronellaea glomerate with antioxidative abilities, stereochemistry of which were deduced by Rh 2 (-OCOCF 3 ) 4 -induced ECD experiments and calculations. 6 Significantly, 22 (5 mM) could inhibit hypoxia/reoxygenation (H/R)induced late-stage apoptosis of human umbilical vein endothelial cells and displayed the same hypoxia-protective activity as the positive control verapamil. 6 Chemical investigation of a mangrove-derived fungus Penicillium chrysogenum HND11-24, led to the characterization of penicitol A (23), a citrinin dimer with a novel tetracyclic skeleton, which was found with cytotoxicity against HeLa, BEL-7402, HEK-293, HCT-116, and A549 cell lines (IC 50 ¼ 4.6-10.5 mM).…”

“…6 Significantly, 22 (5 mM) could inhibit hypoxia/reoxygenation (H/R)induced late-stage apoptosis of human umbilical vein endothelial cells and displayed the same hypoxia-protective activity as the positive control verapamil. 6 Chemical investigation of a mangrove-derived fungus Penicillium chrysogenum HND11-24, led to the characterization of penicitol A (23), a citrinin dimer with a novel tetracyclic skeleton, which was found with cytotoxicity against HeLa, BEL-7402, HEK-293, HCT-116, and A549 cell lines (IC 50 ¼ 4.6-10.5 mM). 24 Citrifurans A-D (24)(25)(26)(27), four uncommon heterodimers of azaphilone and furanone derivatives, were discovered from Aspergillus sp., meanwhile structure of 24 was conrmed by single-crystal X-ray diffraction, among which 24-26 displayed moderate inhibitory on NO production in RAW 264.7 macrophages with IC 50 values of 18.3, 22.6, and 25.3 mM, respectively.…”

“…Annulohypoxylomans A-C (1-3) Annulohypoxylon truncatum JS540 11 Annulohypoxylomanols A-B (4)(5) Annulohypoxylon truncatum JS540 11 Annulohypoxyloside (6) Annulohypoxylon truncatum JS540 11 7 Talaromyces stipitatus ATCC 10500 18 (3S,4R)-6-Hydroxy-8-methoxy-3,5-dimethyl isochromanol (8) Penicillium sp. 19 Cytotoxic (L5178Y: 26.20% at 10 mg mL À1 ) (3S)-6-Hydroxy-8-methoxy-3-methylisochroman (9) Penicillium sp.…”

“…5 Peyronellones A and B (21)(22) were identied as a pair of unusual tetracyclic caged adducts of azaphilones and pyruvic acid with hypoxia-protective activity. 6 them were monomeric citrinin derivatives like annulohypoxylomans A-C (1-3), 11 annulohypoxylomanols A and B (4-5), 11 annulohypoxyloside (6), 11 and the novel pentaketide (7). 18 The fungus Penicillium sp., collected in the sediment of the hyper saline lake Wadi El-Natrun in Egypt, produced two novel cytotoxic citrinin analogues, (3S,4R)-6-hydroxy-8-methoxy-3,5dimethyl isochromanol (8) and (3S)-6-hydroxy-8-methoxy-3methylisochroman (9).…”

Hot off the Press

“…The tetracyclic caged structure of peyronellone A 2, from Peyronellaea glomerata, is thought to be an adduct of an azaphilone and pyruvic acid. 2 Four metabolites, including lithocarpin A 3, of the deep sea derived Phomopsis lithocarpus are proposed to be formed by a [4+2] cycloaddition of an isobenzofuran derived from tenellone B and a macrolide. 3 The acylphloroglucinol derivatives hypermonins A 4 and B 5, from Hypericum monogynum, have a new skeleton.…”