Darin D. DuMez

Induction of aerobic peroxidation of liposomal membranes by bis(cyclopentadienyl)-vanadium(IV) (acetylacetonate) complexes.

The ability of bis(cyclopentadienyl)-vanadium(IV) (acetylacetonate) (1) to initiate oxygen-dependent lipid peroxidation in zwitterionic liposomal membranes was examined in detail. A comparison of the rates of the lipid peroxidation reaction demonstrated that the electron-donating capacity of the substituted acetylacetonate ligand significantly influences the rate of reaction. An increase in the rate of lipid peroxidation correlated to a decrease in the V(IV)/V(V) redox potential. Notably, lipid peroxidation initiated with 1 proceeded without the formation of radicals as shown by EPR spin trap techniques. In contrast, lipid peroxidation initiated with non-chelated bis(cyclopentadienyl)-vanadium(IV) dichloride (6) was associated with the production of radicals under similar experimental conditions. There also was a significant pH effect on the extent of peroxidation initiated with 6 versus the reaction initiated with 1. The mode of action of 1 likely involves the activation of molecular oxygen by the vanadium(IV) center followed by allylic hydrogen atom abstraction from the lipid.

ELECTROCHEMICAL AND REACTIVITY COMPARISONS AMONG ISOELECTRONIC OXO, IMIDO,AND NITRIDO COMPLEXES OF RHENIUM AND OSMIUM

Abstract Cyclic voltammetry has been used to study the electrochemical properties of 29 isoelectronic and isostructural osmium(VI)nitrido, rhenium(V)oxo, and rhenium(V)imido complexes of the form Tp (*) M(E)(X)(Y) [Tp (*) =Tp, HB(pz) 3 ; or Tp * , HB(3,5-Me 2 pz) 3 ]. Oxidations from d 2 to d 1 species are typically reversible or quasi-reversible, while reductions to d 3 species are usually irreversible. The E 1/2 values for oxidation vary from >+2 V for TpOs(N)(Cl) 2 to −0.11 V for TpRe(Ntolyl)(Ph)(Me) (vs. Cp 2 Fe +/0 in MeCN/ n Bu 4 NPF 6 ). The potentials follow simple trends, Os(N)>Re(O)>Re(Ntolyl) and Tp>Tp * . Potentials for TpM(E)(X)(Y) are also affected by the X and Y ligands, with OTf>Cl≅I>Ph>alkyl, correlating with the Hammett σ values for X and Y. In contrast, peak potentials for reduction of the compounds (ca. −1.0 to −1.5 V) do not follow simple patterns. The reactivity of these complexes as inner-sphere oxidants does not correlate with their peak reduction potentials. Rather, the ease of oxidation of the compounds better parallels their reactivity as oxidants.

Targeting JAK3 and BTK tyrosine kinases with rationally-designed inhibitors.

Multifunctional rational drug design of protein tyrosine kinases inhibitors allows a potent drug to be utilized to treat more than one disease for greater patient benefits. Many protein tyrosine kinases (PTK), including Janus kinase 3 (JAK3) and Brutons tyrosine kinase (BTK), have been identified as potential drug targets to treat diverse diseases including cancer and disorders of the immune system. Here we review advances in JAK3 and BTK inhibitors and describe the therapeutic potential of these potent agents in the clinical setting.