Sphaeropsidin A C15-C16 Cross-Metathesis Analogues with Potent Anticancer Activity.

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.

Synthetic Models for Nickel-Iron Hydrogenase Featuring Redox-Active Ligands.

The nickel-iron hydrogenase enzymes efficiently and reversibly interconvert protons, electrons, and dihydrogen. These redox proteins feature iron-sulfur clusters that relay electrons to and from their active sites. Reported here are synthetic models for nickel-iron hydrogenase featuring redox-active auxiliaries that mimic the iron-sulfur cofactors. The complexes prepared are NiII(µ-H)FeIIFeII species of formula [(diphosphine)Ni(dithiolate)(µ-H)Fe(CO)2(ferrocenylphosphine)]+ or NiIIFeIFeII complexes [(diphosphine)Ni(dithiolate)Fe(CO)2(ferrocenylphosphine)]+ (diphosphine = Ph2P(CH2)2PPh2 or Cy2P(CH2)2PCy2; dithiolate = -S(CH2)3S-; ferrocenylphosphine = diphenylphosphinoferrocene, diphenylphosphinomethyl(nonamethylferrocene) or 1,1'-bis(diphenylphosphino)ferrocene). The hydride species is a catalyst for hydrogen evolution, while the latter hydride-free complexes can exist in four redox states - a feature made possible by the incorporation of the ferrocenyl groups. Mixed-valent complexes of 1,1'-bis(diphenylphosphino)ferrocene have one of the phosphine groups unbound, with these species representing advanced structural models with both a redox-active moiety (the ferrocene group) and a potential proton relay (the free phosphine) proximal to a nickel-iron dithiolate.