2-Alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones as potent and selective inhibitors of ectonucleotidases

Eur J Med Chem. 2016 Jun 10;115:484-94. doi: 10.1016/j.ejmech.2016.02.073. Epub 2016 Mar 3.

Abstract

A facile method for the modulation of 2-alkoxy side chain of 3-formylchromone enamines has been exploited for the synthesis of a series of 2-alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones. This modulation was achieved by simply changing the alcoholic reaction media from methanol to ethanol, iso-propanol and n-butanol while reacting various 3-formylchromones with aminobenzenesulfonamides. Alcohols are sufficiently nucleophilic and add into the C2-C3 olefinic bond of 3-formylchromones without causing any ring cleavage. The resulting 2-alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones were found to be potent and selective inhibitors of ecto-5'-nucleotidase and alkaline phosphatases (TNAP and IAP). Detailed enzyme kinetics studies revealed competitive inhibition against alkaline phosphatases and un-competitive inhibition against rat and human ecto-5'-nucleotidase. The most active TNAP inhibitor 23 (Ki = 0.078 ± 0.001 μM), exhibited 28 times more selectivity for TNAP over IAP (Ki = 2.18 ± 0.12 μM). Compound 9 was most active IAP inhibitor (Ki = 0.24 ± 0.01 μM), and was 300 times more selective towards IAP than TNAP (Ki = 72.9 ± 1.68 μM). Compound 40 was most active human ecto-5'-nucleotidase inhibitor exhibiting inhibition in low nanomolar range (Ki = 14 nM).

Keywords: Chromones; Ecto-5′-nucleotidase; Ectonucleotidase inhibitors; Intestinal alkaline phosphatase; Sulfonamides; Tissue non-specific alkaline phosphatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromans / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Nucleotidases / antagonists & inhibitors*

Substances

  • Chromans
  • Enzyme Inhibitors
  • Nucleotidases