Abstract
Ecto-5′-nucleotidase (e5′NT), a membrane-bound enzyme and an essential member of ecto-nucleotidases which regulates extracellular purinergic signalling. Their upregulation results in various disease conditions, for example, inflammation, hypoxia and cancer. Therefore, efforts have been made to synthesize potent and selective inhibitors of e5′NT. Here we have synthesized, characterized and evaluated six thiazole derivatives (3a–3f) as potent e5′NT inhibitors. Among all derivatives, the compound (E)-1-(4-methyl-2-(2-(pyridin-3-ylmethylene)hydrazinyl) thiazol-5-yl)ethanone (3a) exhibited maximum inhibition towards both human and rat enzymes. However, their potency against h-e5′NT was 24-fold higher than r-e5′NT. Only two compounds exhibited inhibitory behaviour towards r-e5′NT. The molecular structures of these derivatives were confirmed with the help of solid-state characterization through NMR (1H and 13C), FTIR and elemental analysis. Additionally, molecular docking was also implemented to explain putative bonding interaction between the active site of an enzyme and potent inhibitors.
Highlights
As a regulator of adenosine signalling pathway, the membrane-bound ecto-50-nucleotidase (e50NT, CD73) speeds up the final reaction step that involves the hydrolysis of extracellular nucleotides and their conversion from adenosine monophosphate (AMP) to adenosine [1]
It is evident from previous reports that numerous cancer cells display high levels of e50NT, which increases the intensity of adenosine production to promote angiogenesis and T-cells death [4]
An uncontrolled enzymatic activity results in stimulation of adenosine receptors that reflects its role in breast cancer cells migration as well as invasion and adhesion to the extracellular membrane (ECM)
Summary
As a regulator of adenosine signalling pathway, the membrane-bound ecto-50-nucleotidase (e50NT, CD73) speeds up the final reaction step that involves the hydrolysis of extracellular nucleotides and their conversion from adenosine monophosphate (AMP) to adenosine [1]. These enzymes belong to metallophosphoesterase superfamily which contains divalent cation in its active site [2]. Several other molecules like anthraquinone, sulfonamide and flavonoid-based compounds were found to be active against e50NT [9,10] All these known molecules lack specificity and selectivity towards their target. The therapeutic importance of e50NT plus need of potent and selective moieties encourages us to synthesize a series of compounds as a potential therapeutic agent in various disease conditions
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
