Design and synthesis of selective inhibitors of placental alkaline phosphatase

Abstract

Placental Alkaline Phosphatase (PLAP) is a tissue-restricted isozyme of the Alkaline Phosphatase (AP) superfamily. PLAP is an oncodevelopmental enzyme expressed during pregnancy and in a variety of human cancers, but its biological function remains unknown. We report here a series of catechol compounds with great affinity for the PLAP isozyme and significant selectivity over other members of the AP superfamily. These selective PLAP inhibitors will provide small molecule probes for the study of the pathophysiological role of PLAP.

Figure 1

Examples of AP inhibitors

Figure 2

Depiction of the three regions of screening “hit” 1 explored by chemical synthesis: Left Hand Side (LHS), Right Hand Side (RHS) and Linker region (encircled).

Figure 3

Examples of commercially available analogs 27-33 purchased and their IC₅₀ values in the PLAP assay.

Figure 4

Effect of increasing concentrations of compound 1, 8, 11 and 17 on the inhibition of PLAP (●) and GCAP (○).

Figure 5

Summary of the IC₅₀ values for selective PLAP inhibitors 10, 13 and 20.

Scheme 1

Synthetic approach to explore the SAR of the LHS and RHS of screening “hit” 1; preparation of analogs 3-20, X is nitrogen or sulfur. (a) 1 equiv. HXR2R3, dioxane.

Scheme 2

Synthetic approach to explore the linker region of screening “hit” 1: preparation of analogs 22, 25 and 26. (a) 2-amino 4,6-dimethyl pyrimidine, NaBH(OAc)₃, DCE; (b) 4,5-dimethyl 2-furoic acid, HBTU, DIEA, DMF