Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents

The activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.

Derivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC).

The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors.

Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.