Synthesis and antitumor activity of several new analogues of penclomedine and its metabolites

Analogues of penclomedine (PEN, 3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl)pyridine) and its metabolites have been synthesized and evaluated as potential antitumor agents. PEN and 4-DMPEN (3,5-dichloro-4-hydroxy-6-methoxy2-(trichloromethyl)pyridine (3a)), the major plasma metabolite in patients, were modified at 4- and 6-positions with different alkyl, aryl, and ester groups. All of the analogues and many of the intermediates were evaluated against the PEN-sensitive MX-1 human breast tumor xenograft in vivo, and several analogues of PEN and 4-DMPEN showed modest to curative activity.