Synthesis and anti-trypanosomal evaluation of novel N-branched acyclic nucleoside phosphonates bearing 7-aryl-7-deazapurine nucleobase

0559133 - ÚOCHB 2023 RIV FR eng J - Journal Article
Vaňková, Karolína - Doleželová, Eva - Tloušťová, Eva - Hocková, Dana - Zíková, Alena - Janeba, Zlatko
Synthesis and anti-trypanosomal evaluation of novel N-branched acyclic nucleoside phosphonates bearing 7-aryl-7-deazapurine nucleobase.
European Journal of Medicinal Chemistry. Roč. 239, September (2022), č. článku 114559. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR(CZ) GA19-07707S; GA MŠMT(CZ) EF16_019/0000759
Institutional support: RVO:61388963 ; RVO:60077344
Keywords : acyclic nucleoside phosphonates * nucleotides * Suzuki reaction * Trypanosoma * tubercidin
OECD category: Organic chemistry
Impact factor: 6.7, year: 2022
Method of publishing: Limited access
https://doi.org/10.1016/j.ejmech.2022.114559

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.
Permanent Link: https://hdl.handle.net/11104/0332552