Cytotoxic Dimeric Epipolythiodiketopiperazines from the Ascomycetous Fungus Preussia typharum

Abstract

Two new dimeric epipolythiodiketopiperazines, preussiadins A (1) and B (2), together with two known diastereomers, leptosins C (6) and A (7), were obtained from the mycelia of a Preussia typharum isolate. The structures of the new compounds were established by spectroscopic methods, and the absolute configurations of 1 and 2 were assigned by chemical transformations and comparisons of quantum chemical ECD and VCD calculations to experimental data. Compound 1 exhibited potent cytotoxic activity in the NCI-60 cell line panel with an average LC50 value of 251 nM. Further studies demonstrated that 1 circumvents P-glycoprotein-mediated drug resistance, yet had no significant antitumor activity in a xenograft UACC-62 melanoma model.

Recent advances in the use of vibrational chiroptical spectroscopic methods for stereochemical characterization of natural products

“…190 The structure of the potassium complex of 189 in solution was also investigated using ROA and theoretical calculations. These compounds had their absolute congurations determined using OR, ECD, and VCD, 195 and compound 191 was assigned as 3S,5aR,10bS,11S,12S,3 0 R,5a 0 S,10b 0 R,11 0 S,12 0 R by comparison of its experimental and calculated [B3LYP/6-31+G(d,p)] chiroptical data. 191 Pexiganan, a 22 amino acid peptide analogous to the magainin peptides present in the skin of the African clawed frog, had its conformational preferences in solution probed by VCD and ECD spectroscopies.…”

Chetracins E and F, cytotoxic epipolythiodioxopiperazines from the marine-derived fungus Acrostalagmus luteoalbus HDN13-530

“…The epidithiodioxopiperazine alkaloids (ETPs) characterized by a bridged polysulde piperazine ring, represent a large family of secondary metabolites with various structure types and interesting biological activities. 1,2 Among them, the representative chaetocin displayed a wide spectrum of antitumor activities in vivo in nanomolar IC 50 level. [1][2][3][4][5][6] Furthermore, recent research showed that chaetocin and the analogue chetracin B (discovered by our group), could function as heat shock protein 90 (Hsp90) inhibitors binding to the C-terminal.…”

“…1,2 Among them, the representative chaetocin displayed a wide spectrum of antitumor activities in vivo in nanomolar IC 50 level. [1][2][3][4][5][6] Furthermore, recent research showed that chaetocin and the analogue chetracin B (discovered by our group), could function as heat shock protein 90 (Hsp90) inhibitors binding to the C-terminal. 7 Hsp90 has proved to be an important target for cancer treatment, and is known as a crucial facilitator of oncogene addiction and cancer cell survival.…”

Plasma pharmacokinetics and bioavailability of verticillin A following different routes of administration in mice using liquid chromatography tandem mass spectrometry

“…The epipolythiodioxopiperazine alkaloids are a class of fungal secondary metabolites that have drawn interest of scientists from a range of disciplines, including natural products chemists [1–3], synthetic organic chemists [4–6], mycologists [7], and pharmacologists [8–11]. The first in this series, verticillin A, was isolated and characterized by Hitato and colleagues in the early 1970’s [12, 13].…”