Synthesis of new sulphonate derivatives containing adamantane and 4-chlorophenyl moieties as nucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors

Abstract

Elevated levels of nucleotide pyrophosphatases/phosphodiesterases (NPPs) are associated with chondrocalcinosis, osteoarthritis, type 2 diabetes, neurodegenerative diseases, allergies, and cancer metastasis. A new series of sulphonate derivatives was synthesized and tested against the isozymes NPP1 and NPP3. The compound 4q was found as the more active and comparatively selective inhibitor of the isozyme NPP1 with IC50 ± SEM = 1.97 ± 0.03 µM vs. NPP3 whereas, the compound 4n was a potent and moderately selective inhibitor of NPP3 (IC50 ± SEM = 0.85 ± 0.04 µM). The compounds 4c, 4e, 4f, 4j, and 7b efficiently blocked the activity of both NPP1 and NPP3 with IC50 values of submicromolar level. The compounds demonstrated negligible effect on MCF-7 or HeLa cancer cell viability tested through MTT assay. The molecular docking studies of the selected inhibitors showed strong binding linkages with Thr256, Asn277, Leu290, His380, and Lys255 residues of NPP1 crystallographic protein, whereas with residues Asn226, Asn227, Thr205, His329, Leu239, Asp167, and Phe206 of the NPP3 isozyme crystallographic structure.