Identification of sulfonic acids as efficient ecto-5'-nucleotidase inhibitors.
Ecto-5'-nucleotidase (CD73) is well known for its implication in cancer. Inhibition of ecto-5'-nucleotidases is thought to provide an attractive approach to cancer therapy. This study identifies sulfonic acid compounds as efficient inhibitors of ecto-5'-nucleotidases. The compounds were tested against recombinant human and rat ecto-5'-nucleotidases. The most potent new sulfonic acid inhibitor 6-amino-4-hydroxynaphthalene-2-sulfonic acid (1) of ecto-5'-nucleotidase had an IC₅₀ of 1.32 ± 0.09 μM for the human and 10.4 ± 3.3 μM for the rat enzyme. Generally, all compounds were more active against the human enzyme. Plausible binding mode models were developed for this new class of inhibitors. Furthermore, several sulfonic acid inhibitors were efficient cytotoxic agents when tested on H157 cancer cell lines. Hence, new ecto-5'-nucleotidases inhibitors displayed significant potential for further development as compounds for anti-cancer therapy.
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.
Jamshed
J
Iqbal
Aamer
A
Saeed
Rabia
R
Raza
Abdul
A
Matin
Abdul
A
Hameed
Norbert
N
Furtmann
Joanna
J
Lecka
Jean
J
Sévigny
Jürgen
J
Bajorath
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013451:Sulfonic Acids; D014750:Vincristine; D015720:5'-Nucleotidase
Adenosine; Binding mode; Cytotoxicity; Ecto-5′-nucleotidase; Enzyme inhibition; Sulfonic acids