Issue 10, 2017

Uncaging carbon disulfide. Delivery platforms for potential pharmacological applications: a mechanistic approach

Abstract

We describe the kinetics of the formation and decay of a series of dithiocarbamates under physiological conditions. The goal is to provide a toolbox of compounds that release CS2 by well-defined kinetics in such media. Carbon disulfide is a known environmental toxin, but there is fragmentary evidence suggesting that CS2 may have bioregulatory and/or therapeutic roles in mammalian biology. Further investigation of such roles will require methodologies for controlled delivery of this bioactive small molecule to specific targets. Reported here are mechanistic and computational studies of CS2 release from a series of dithiocarbamate anions (DTCs), where R2N represents several different secondary amido groups. The various DTCs under physiologically relevant conditions show a tremendous range of reactivities toward CS2 dissociation with decay lifetimes ranging from ∼2 s for imidazolidyldithiocarbamate (ImDTC) to ∼300 s for diisopropyldithiocarbamate (DIDTC) to >24 h for pyrrolidinyldithiocarbamate (PDTC) in pH 7.4 phosphate buffer solution at 37 °C. Thus, by making the correct choice of these tools, one can adjust the flux of CS2 in a biological experiment, while the least reactive DTCs could serve as controls for evaluating the potential effects of the dithiocarbamate functionality itself. Kinetics studies and density functional calculations are used to probe the mechanism of DTC decay. In each case, the rate of CS2 dissociation is acid dependent; however, the DFT studies point to a mechanistic pathway for ImDTC that is different than those for DIDTC. The role of general acid catalysis is also briefly probed.

Graphical abstract: Uncaging carbon disulfide. Delivery platforms for potential pharmacological applications: a mechanistic approach

Supplementary files

Article information

Article type
Edge Article
Submitted
19 Jun 2017
Accepted
03 Sep 2017
First published
04 Sep 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2017,8, 7186-7196

Uncaging carbon disulfide. Delivery platforms for potential pharmacological applications: a mechanistic approach

A. W. DeMartino, M. L. Souza and P. C. Ford, Chem. Sci., 2017, 8, 7186 DOI: 10.1039/C7SC02727C

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