Structure–activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies

•A SAR was performed starting from a previously identified cN-II inhibitor (cpd 4).•Only minor modification of the sugar counterpart is accepted.•The beta-hydroxyphosphonate scaffold was confirmed as essential for inhibition.•Data indicate that there are two exploitable regions close to the nucleobase.

The cytosolic 5′-nucleotidase II (cN-II) has been proposed as an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other malignant hemopathies. In the present work, synthesis of β-hydroxyphosphonate nucleoside analogues incorporating modifications either on the sugar residue or the nucleobase, and their in vitro evaluation towards the purified enzyme were carried out in order to determine their potency towards the inhibition of cN-II. In addition to the biochemical investigations, molecular modeling studies revealed important structural features for binding affinities towards the target enzyme.

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