Development of potent and selective inhibitors of ecto-5'-nucleotidase based on an anthraquinone scaffold.
ecto-5'-Nucleotidase (eN, CD73) plays a major role in controlling extracellular adenosine levels. eN inhibitors have potential as novel drugs, for example, for the treatment of cancer. In the present study, we synthesized and investigated a series of 55 anthraquinone derivatives as potential inhibitors of eN, 11 of which are novel compounds and another 11 of which had previously been described but have now been synthesized by an improved method. We identified several potent inhibitors of rat eN. The most potent compounds were 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (45, PSB-0952, K(i) = 260 nM) and 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (52, PSB-0963, 150 nM), with 52 being the most potent eN inhibitor described to date. Selected compounds were further characterized and found to exhibit a competitive mechanism of inhibition. Investigations of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and the P2Y receptor subtypes P2Y(2), P2Y(4), P2Y(6), and P2Y(12) showed that compound 45 exhibited the highest degree of selectivity (>150-fold).
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Younis
Y
Baqi
Sang-Yong
SY
Lee
Jamshed
J
Iqbal
Peter
P
Ripphausen
Anne
A
Lehr
Anja B
AB
Scheiff
Herbert
H
Zimmermann
Jürgen
J
Bajorath
Christa E
CE
Müller
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019075:Electrophoresis, Capillary; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D058914:Purinergic Antagonists; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D000880:Anthraquinones; D004791:Enzyme Inhibitors; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D015720:5'-Nucleotidase