Open AccessSynthesis, Characterization, and In Silico Studies of Novel Spirooxindole Derivatives as Ecto-5′-Nucleotidase Inhibitors
Author(s) -
Asfa Ashraf,
Zahid Shafiq,
Muhammad Siraj Khan Jadoon,
Muhammad Nawaz Tahir,
Julie Pelletier,
Jean Sévigny,
Muhammad Yaqub,
Jamshed Iqbal
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00343
Subject(s) - in silico , 5' nucleotidase , small molecule , nucleotidase , chemistry , enzyme , isozyme , biochemistry , ic50 , adenosine , combinatorial chemistry , stereochemistry , in vitro , gene
Ecto-5'-nucleotidase (ecto-5'-NT, CD73) inhibitors are promising drug candidates for cancer therapy. Traditional efforts used to inhibit the ecto-5'-nucleotidase have involved antibody therapy or development of small molecule inhibitors that can mimic the acidic and ionizable structure of adenosine 5'-monophosphate (AMP). Herein, we report an efficient, environment friendly route for the synthesis of non-nucleotide based small molecules, i.e., substituted spirooxindole derivatives 9a - 9l and investigated their inhibitory potential on human and rat recombinant ecto-5'-nucleotidase isozymes. These attempts have resulted in the identification of compound 9f (IC 50 = 0.15 ± 0.02 μM) inhibitor on h -ecto-5'-NT which showed 280-fold higher inhibition and compound 9h (IC 50 ± 0.19 ± 0.03 μM) on r -ecto-5'-NT with 406-fold enhanced inhibition than reference standard sulfamic acid. Moreover, in silico studies were carried out to assess binding interactions of potent compounds within enzyme active sites and demonstrated excellent correlation with the experimental findings.