Environment-selective synergism using self-assembling cytotoxic and antimicrobial agents

Rideout, Darryl; Jaworski, James; Dagnino, Raymond

doi:10.1016/0006-2952(88)90666-1

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…This can be explained by PKC-inhibitory activity caused by A and B (see Fig. 2A (1)(2)(3). As reported by some of us in a previous publication (3), the combination of aldehyde A and hydrazine derivative B (Fig.…”

Section: Resultssupporting

confidence: 53%

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A self-assembling protein kinase C inhibitor.

Rotenberg

Calogeropoulou

Jaworski

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Resultssupporting

confidence: 53%

“…One approach to combination chemotherapy of tumors involves "self-assembling antineoplastic agents"-i.e., direct covalent combination of less toxic prodrugs to form a more active drug in situ (1)(2)(3). When the prodrugs assemble into the active drug in or near cells, the prodrugs exhibit synergistic cytotoxic effects.…”

mentioning

confidence: 99%

A self-assembling protein kinase C inhibitor.

Rotenberg

Calogeropoulou

Jaworski

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…It could also allow less cell-permeable drugs to be generated inside cells, avoiding the difficulties of getting the drugs into cells. The first implementation of this idea was performed by Rideout in 1986, using octanal and N-amino-decylguanidine to form a hydrazone which caused breakdown of biological membranes resulting in cell death, and related chemistry was also used to assemble a protein kinase C inhibitor . (While aldehydes and ketones are not technically bioorthogonal, they are not found on the outside of cell membranes and so can be considered biooorthogonal in that environment.)…”

Section: Applications Of Bioorthogonal Chemistrymentioning

confidence: 99%

“…The first implementation of this idea was performed by Rideout in 1986, 142 using octanal and N-aminodecylguanidine to form a hydrazone which caused breakdown of biological membranes resulting in cell death, and related chemistry was also used to assemble a protein kinase C inhibitor. 143 (While aldehydes and ketones are not technically bioorthogonal, they are not found on the outside of cell membranes and so can be considered biooorthogonal in that environment.) In 2014, the group of Paul Dyson prepared a dimeric ruthenium complex for potential use as an antitumor agent by the strain-promoted azide−alkyne cycloaddition of a bicyclononyne-substituted ruthenium complex with a dimeric tetrazine, yielding a complex with enhanced toxicity toward tumor cells.…”

Section: Applications Of Bioorthogonal Chemistrymentioning

confidence: 99%