title: Synthesis, characterization and biological evaluation of novel chalcone sulfonamide hybrids as potent intestinal alkaline phosphatase inhibitors.
abstract: Alkaline phosphatase (AP) and ecto-5'-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±0.004μM, 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±0.02μM. In conclusion, these chalcone-sulfonamide hybrids exhibited dual inhibition of both family of isozymes but was more selective towards c-IAP enzyme.
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Syeda Abida
authors.initials: SA
authors.lastname: Ejaz
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, 45320 Islamabad, Pakistan. Electronic address: aamersaeed@yahoo.com.
authors.forename: Aamer
authors.initials: A
authors.lastname: Saeed
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, 45320 Islamabad, Pakistan.
authors.forename: Muhammad Nasir
authors.initials: MN
authors.lastname: Siddique
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Zaib Un
authors.initials: ZU
authors.lastname: Nisa
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Samiullah
authors.initials: S
authors.lastname: Khan
authors.affiliation: Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada; Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.affiliation: Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada; Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000201:enzymology; D062105:Molecular Docking Simulation; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D013449:Sulfonamides; D002599:Chalcone; C063088:ALPI protein, human; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; C548241:NT5E protein, human
keywords: Alkaline phosphatase; Cancer; Chalcones; Ecto-5′-nucleotidase; Ectonucleotidases; Sulfonamides