Synthesis, characterization and biological evaluation of novel chalcone sulfonamide hybrids as potent intestinal alkaline phosphatase inhibitors

Alkaline phosphatase (AP) and ecto-50-nucleotidase (e5'NT) belong to same family that hydrolyze the extracellular nucleotides and ensure the bioavailability of nucleotides and nucleosides at purinergic receptors. During pathophysiological conditions, the over expression of AP and e5'NT lead to an increased production of adenosine that enhance tumor proliferation, invasiveness, neoangiogenesis and disrupts the body antitumor response. As both enzymes are abundantly expressed in above mentioned conditions, therefore it is of great interest to synthesize and develop potent inhibitors of these enzymes that augment the antitumor therapy. Herein we reported the synthesis and biological activity of a new series of chalcone-sulfonamide hybrids (4a-j). These derivatives were then evaluated for their inhibitory potential against two members of ecto-nucleotidase family, e5'NT (human and rat) and APs isozyme (intestinal and tissue nonspecific). Only six derivatives were found to inhibit both human and rat e5'NT enzymes. Compounds 4e and 4d showed maximum inhibition of human and rat e5'NT with an IC50 +/- SEM = 0.26 +/- 0.01 and 0.33 +/- 0.004 mu M, respectively. Moreover, on APs, these derivatives were identified as the selective inhibitors of calf intestinal AP (c-IAP). The derivative 4a exhibited maximum inhibition of c-IAP with an IC50 +/- SEM = 0.12 +/- 0.02 mu M. In conclusion, these chalcone-sulfonamide hybrids exhibited dual inhibition of both family of isozymes but was more selective towards c-IAP enzyme. (C) 2017 Elsevier Inc. All rights reserved.