Background: The aminopeptidase N (APN) over-expressed in tumor cells plays a critical
role in angiogenesis which makes the development of APN inhibitors an attractive strategy for
Aims and Objectives: It is clinically significant to develop potential APN inhibitors for cancer
treatment. The design, synthesis, biological evaluation and molecular simulation of mandelic acid
peptidomimetic derivatives as APN inhibitors are reported.
Materials and Methods: Analysis of the binding mode of bestatin to APN led to the design and
synthesis of mandelic acid peptidomimetic derivatives. APN inhibitory activities in vitro were
evaluated by the spectrophotometric method. The binding mode of the target compounds with the
APN binding site was studied relying on docking studies, molecular dynamics simulation experiments
and binding energies calculation.
Results: The structures of target compounds were confirmed by IR, 1H-NMR and MS. All compounds
exhibited a different range of inhibitory ability with IC50 values lying in the micromolar
level. The compound 9m was found to be most potent as compared to other target derivatives. The
molecular simulation revealed that ligand coordinating with the catalytic zinc ion is very important
for inhibitory activities.
Conclusion: The compound 9m might represent a promising scaffold for the further development
of novel anti-cancer drugs.