A self-assembling protein kinase C inhibitor.

Abstract

Previous studies have described a dicationic anticarcinoma agent that can chemically assemble in situ from monocationic phosphonium salts. The chemical combination of these monocationic precursors in the micromolar concentration range, occurring after their uptake by cells, was probably responsible for their synergistic inhibition of cell growth and for their selective cytotoxicity to Ehrlich ascites murine carcinoma cells relative to untransformed epithelial cells. Here, we report that the dicationic product that forms in this assembly reaction is an in vitro inhibitor of protein kinase C (PKC) a and When PKC is exposed to combinations of the two precursors, the enzymatic activity decreases steadily as a function of time. Using dose-response data and HPLC kinetic studies, we show that when the two precursor compounds are added as a combination to PKC under these conditions, the rate of formation of the inhibitory product follows the observed time course of decline in PKC activity under identical conditions. We discuss the possibility that antiproliferative effects against carcinoma cells of the preformed dication and of the combined monocationic precursors involve inhibition of PKC.

Phosphonium compounds as new and specific inhibitors of bovine serum amine oxidase

“…Here we report on new types of potent competitive inhibitors, namely phenylphosphonium salts, which are neither carbonyl reagents nor substrate analogues. They are a class of lipophilic molecules, important as chemotherapic agents [20,21], cationic biocides [22,23] and inhibitors of some enzymes such as protein kinase C [24] and HIV integrase [25]. They are also used as sensors of transmembrane potential [26].…”

Metabolic Delivery of Ketone Groups to Sialic Acid Residues

“…The unique functional group is then chemically elaborated with synthetic car-bohydrate epitopes of defined structure. The highly selective condensation reactions of aminooxy or hydrazide groups with ketones, affording the corresponding oximes or hydrazones, are well suited for this strategy as these functional groups are chemically orthogonal to native cell surface moieties (23)(24)(25)(26). Accordingly, we exploited the intrinsic substrate promiscuity of the enzymes in the sialoside biosynthetic pathway (32)(33)(34) for the delivery of ketones into endogenous cell surface glycoconjugates.…”

In Situ Assembly and Screening of Enzyme Inhibitors with Surface‐Tension Microarrays

“…We chose to examine the condensation of aldehydes with hydrazides as an efficient and traceless reaction [8,9] compatible with an enzymatic assay. [9,10] 3',5'-Diformylphenylboronic acid (DFPB) was used as a scaffold for library assembly ( Figure 2). Phenylboronic acids are known inhibitors of serine proteases.…”