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

Abstract

Purpose: 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.

Methods: 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).

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

Conclusion: 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.

Fig. 1

Where: PEN, R = CH₃ and DM-PEN, R = H

Fig. 2

Carbonate analogs synthesized (MS values)

Fig. 3

Carbamate analogs synthesized (MS values)

Fig. 4

Proposed mechanism of action of 4-demethyl-4-cholesterol-penclomedine (DM-CHOC-PEN)