Pochonins A−F, New Antiviral and Antiparasitic Resorcylic Acid Lactones from Pochonia chlamydosporia var. catenulata

Abstract

Monorden (1) and the novel resorcylic acid lactones pochonins A (2), B (4), C (6), D (7), and E (8) as well as tetrahydromonorden (5) and pseurotin A (22) were isolated from cultures of the clavicipitaceous hyphomycete Pochonia chlamydosporia var. catenulata strain P 0297. Fermentation of P 0297 in bromide-containing culture media led to a shift in secondary metabolite production and yielded monocillins III (3) and II (9) as major metabolites besides monorden (1) as well as the novel compounds pochonin F (10) and a monocillin II glycoside (11) as minor metabolites. Most of these compounds showed moderate activities in a cellular replication assay against Herpes Simplex Virus 1 (HSV1) and against the parasitic protozoan Eimeria tenella. In contrast to the structurally related zearalenone derivatives none of the metabolites of strain P 0297 were found to be active in a fluorescence polarization assay for determination of modulatory activities on the human estrogenic receptor ERbeta. Beta-zearalenol (17), but not zearalenone (15) and alpha-zearalenol (16), showed antiherpetic effects. We report the production, isolation, and structure elucidation of compounds 1-11 and their biological characterization.

Total Syntheses of Cochliomycin B and Zeaenol

“…In addition, removal of the acetonide functionality from compound 6 was achieved by treatment of 6 with AcCl in methanol (1 %) to afford another natural product zeaenol (22) in a yield of 91 %. The analytical data ( 1 H, 13 C NMR, and optical rotation values) for both compounds 6 and 22 are consistent with those of the natural products.…”

“…The reaction mixture was extracted with EtOAc (3 ϫ 20 mL) and the combined organic solvents were dried with anhydrous Na 2 SO 4 83 (m, 2 H), 1.47 (s, 3 H), 1.35 (s, 3 H), 0.89 (d, J = 1.6 Hz, 9 H), 0.07 (dd, J = 2.0 Hz, 6 H) ppm. 13 3-iodoallyl]-2,2-dimethyl-1,3-di . After cooling to room temp., saturated aqueous NH 4 Cl (5 mL) was added and the mixture extracted with EtOAc (3 ϫ 10 mL).…”

“…51 (s, 3 H), 1.35 (s, 3 H), 0.91 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3 H) ppm. 13 -2,2-dimethyl-1,3-dioxolan-4-yl]prop-1-en-1-yl}-6hydroxy-4-methoxybenzoate (19): To a solution of pent-4-en-2-ol (11; 90 mg, 1.046 mmol) in dry THF was added NaH (62 mg, 60 % in mineral oil, 1.55 mmol) under nitrogen at 0°C. The reaction mixture was stirred at this temperature for 30 min and then a solution of 18 (100 mg, 0.193 mmol) in THF (5 mL) was added to the above suspension.…”

“…Saturated aqueous NH 4 Cl (2 mL) was added to quench the reaction until TLC showed completion of the reaction (about 4 h). The mixture was extracted with EtOAc (3 ϫ 5 mL), concentrated under reduced pressure, and the residue purified by silica gel column chromatography (EtOAc/petroleum ether, 1:25) 13 13 13 Supporting Information (see footnote on the first page of this article): 1 H and 13 C NMR spectra for all new compounds and H-H COSY for cochliomycin B and zeaenol.…”

“…[9] For example, aigialomycin D (2; Figure 1) shows cytotoxicity in human cells through CDK/GSK-3 inhibition, [10] (5Z)-7-oxozeaenol (3) is an inhibitor of TAK-1, [11] and hypothemycin (4) has been reported to inhibit the ras signaling pathway. [12] Surprisingly, structurally similar radicicol and pochonin C [13] do not inhibit specific kinase, but rather the specific ATPase (HSP90) [ In 2011, Wang and co-workers [16] reported the isolation and structural determination of potent antifouling RALs from the culture broth of the fungus Cochliobolus lunatus from the South China Sea. Among the species showing antibacterial and cytotoxic activities, two new 14-membered resorcylic acid lactones with a rare natural acetonide group and one new 5-chloro-substituted lactone were discovered and named as cochliomycins A-C (5-7, respectively, in Figure 2),.…”