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Identification of thienopyrimidine glycinates as selective inhibitors for h-NTPDases.
- Source :
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Bioorganic chemistry [Bioorg Chem] 2022 Dec; Vol. 129, pp. 106196. Date of Electronic Publication: 2022 Oct 12. - Publication Year :
- 2022
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Abstract
- The h-NTPDases is an essential family of ectonucleotidases that consists of eight isozymes with various physiological functions. The undesired activity of the h-NTPDases leads to pathological conditions such as cancer, diabetes, inflammation, and thrombosis. In the present study, a series of thienopyrimidines was synthesized employing a sequential SNAr and Suzuki coupling to synthesize diverse aryl substituted thienopyrimidine glycinate derivatives. The synthesized compounds constituted electron donating, electron-deficient, heteroaryl, and fluorinated substituents. The thienopyrimidines were screened against h-NTPDases to determine the effect on the activity of the h-NTPDases-1, -2, -3, and -8. The compound 3j selectively blocked the isozyme h-NTPDases1, while the compounds 3e, 3m, and 4a were selective inhibitors of h-NTPDases2. The activity of the isozyme h-NTPDases3 was selectively reduced by inhibitor 3k whereas, the compound 3d was found as the most active inhibitor against isozyme h-NTPDase8. The molecular docking study interpreted the interactions of the potent inhibitors of the respective isozymes with important amino acid residues i.e., Asp54, Ser57, His59, Ser58, His59, Asp213, and Phe360 of h-NTPDases1 protein; residues Arg 392, Ala393, Ala347, Tye350 and Arg245 of h-NTPDases2; amino acids Arg67, Ser65, Ala323, Gly222, and Tyr375 of h-NTPDases3 whereas in case of h-NTPDases8, the residues Val436, Gln74, Gly179, and Val71 were involved in interaction with the inhibitors docked into the active sites of these isozymes.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 129
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36279741
- Full Text :
- https://doi.org/10.1016/j.bioorg.2022.106196