Synthesis and anti-trypanosomal evaluation of novel N-branched acyclic nucleoside phosphonates bearing 7-aryl-7-deazapurine nucleobase
- Eur J Med Chem. 2022 Sep 5:239:114559. doi: 10.1016/j.ejmech.2022.114559.
- 1. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
- 2. Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Branišovská 31, České Budějovice, 37005, Czech Republic.
- 3. Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Branišovská 31, České Budějovice, 37005, Czech Republic; Faculty of Science, University of South Bohemia, Branišovská 31, České Budějovice, 37005, Czech Republic. Electronic address: [email protected].
- 4. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic. Electronic address: [email protected].
A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC50 values in the range of 0.58-6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC50 = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or Cancer cell lines tested.