Search

Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety. Several of these compounds triggered severe ER swelling associated with strong proteasomal inhibition and consequently cell death, a feature that was not observed with respect to mode of action of the natural product. Significantly, an analysis from the National Cancer Institute sixty cell line testing did not reveal any correlations between the most potent derivative and any other compound in the database, except at high concentrations (LC 50 ). This study led to the discovery of a new set of sphaeropsidin derivatives that may be exploited as potential anti-cancer agents, notably due to their maintained activity towards multidrug resistant models., (© 2024. The Author(s).)

We recently discovered that sphaeropsidin A (SphA), a fungal metabolite from Diplodia cupressi, overcomes apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase. Previously, we prepared a pyrene-conjugated derivative of SphA by a cross-metathesis reaction involving the phytotoxin's C15,C16-alkene. This derivative's evaluation in a cancer cell panel revealed a significant increase in potency, with the IC50 values 5-10× lower than those displayed by the original natural product. Herein, we describe the preparation and anticancer evaluation of fifteen novel C15,C16-alkene cross-metathesis analogues in which the pyrene moiety was replaced with other aromatic or non-aromatic hydrophobic groups. The idea for this replacement was to prepare a family of compounds that would not be predicted to be mutagenic compared with the original pyrene analogue. We predict several of our new compounds to be non-mutagenic, while retaining the high potency of the original pyrene-containing analogues. Examples of these potential lead compounds included those containing pentamethylphenyl and triphenylethylene pendant groups. As an additional feature of the current investigation, we prepared several deuterated pyrene-containing compounds to overcome intellectual property issues associated with non-patentability of the original pyrene derivative., (© 2024 Wiley‐VCH GmbH.)

(R)-(-)-Mellein, (3R,4R)-4-hydroxymellein and (3R,4S)-4-hydroxymellein obtained from fungi, i. e. from Diplodia globulosa, were investigated as a class of natural products presenting ESIPT (excited state intramolecular proton transfer) phenomenon, through fluorescence and CPL (circularly polarized luminescence). The study was preceded by the assessment of the absolute configuration through ECD and VCD (electronic and vibrational circular dichroism) spectroscopies in addition to NMR spectra. It is found that ESIPT takes place in these systems very rapidly, and no dual fluorescence has been observed. The experimental study is backed up by TD-DFT calculations of ECD and CPL spectra, plus MD calculations to follow proton transfer in the excited state and careful analysis of the puckering dynamics of the lactone ring. Deprotonated forms of the three compounds were also investigated by the same chiroptical experimental and theoretical methods, showing how one can find in natural compounds not only biological activity but also biologically compatible sensing probes., (© 2024 Wiley-VCH GmbH.)