Sphaeropsidin A C15–C16 Cross‐Metathesis Analogues with Potent Anticancer Activity

Abstract

AbstractWe 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.