Thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of demethylpenclomedine as novel anticancer agents

Abstract

The purpose of this investigation was to synthesize a series of thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) in patients observed subsequently to be an active antitumor agent and non-neurotoxic in a rat model, in order to compare their antitumor activity with that of DM-PEN. Derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted in the mammary fat pad, several of which were also evaluated against human brain tumor xenografts. Thiolocarbonate and thiocarbamate derivatives were found to be superior to DM-PEN against MX-1 tumor and modestly active against glioblastoma. The activity of the thiolocarbonates and thiocarbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.