Synthesis and Anticancer Activity of Novel Actinonin Derivatives as HsPDF Inhibitors

Human mitochondrial peptide deformylase
(HsPDF) is responsible
for removing the formyl group from N-terminal formylmethionines of
newly synthesized mitochondrial proteins and plays important roles
in maintaining mitochondria function. It is overexpressed in various
cancers and has been proposed as a novel therapeutic target. Actinonin,
a naturally occurring peptidomimetic HsPDF inhibitor, was reported
to inhibit the proliferation of a broad spectrum of human cancer cells
in vitro. However, its efficacy and pharmacokinetic profile requires
significant improvement for therapeutic purposes. To obtain HsPDF
inhibitors as anticancer therapeutics, we screened an in-house collection
of actinonin derivatives and found two initial hits with antiproliferation
activity. Further optimization along the peptidomimetic backbone lead
to two series of compounds containing substituted phenyl moieties.
They are potent HsPDF inhibitors and exhibited greatly improved antiproliferation
activity in selected cancer cell lines. Finally, compound 15m significantly inhibited the growth of human colon cancer in xenograft
animal models.