Determination of the phamacophore of penclomedine, a clinically-evaluated antitumor pyridine derivative.

The main objective of this investigation was to identify the reactive pharmacophore in penclomedine (PEN, 3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl) pyridine) for in vivo antitumor activity and also to discover related ring structures and sulfur analogues that might exhibit superior antitumor activity in vivo. Several new analogues of PEN and related structural variants have been synthesized and evaluated in vivo against MX-1 human breast tumor xenograft implanted subcutaneously (sc), although none of them demonstrated significant activity.