Background: As a target for anticancer treatment, aminopeptidase N (APN) shows its
overexpression on diverse malignant tumor cells and associates with cancer invasion, angiogenesis
Objective: The objective of the study was the design, synthesis and biological activity evaluation
of alanine hydroxamic acid derivatives as APN inhibitors, and investigation of the binding mode
of inhibitors in the APN active site.
Methods: Alanine hydroxamic acid derivatives were synthesized and evaluated for their in vitro
anti-cancer activity using CCK-8 assay. Molecular docking and 4D-QSAR studies were carried out
to suggest the mechanism of biological activity.
Results: Compared with Bestatin, compound 9b showed the best APN inhibition activity. The putative
binding mode of 9b in the APN active site was also discussed. Moreover, the robust and reliable
4D-QSAR model exhibited the following statistics: R2 = 0.9352, q2
LOO = 0.8484, q2
Pred = 0.8739.
Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation
of the current scaffold would be beneficial.