2.2.2. Inhibition of PARP-1 and PARP-2 by Natural and Modified Nucleosides

Morpholino nucleosides and ribonucleosides were used to study the contribution of the morpholine cycle to enzyme inhibition. The inhibitory properties of these compounds are shown in Table 2. Natural ribonucleosides were weakly active as inhibitors except **rThd** (IC<sup>50</sup> values 277 µfor PARP-1 and 374 µfor PARP-2), while iodine- and bromine-containing derivatives inhibited both enzymes. The 5-I-uridine was five times more effective than 5-Br-uridine for both enzymes. The ratios of IC<sup>50</sup> values for PARP-1:PARP-2 are also approximately 1:1. The 5-Cl-uridine had a little effect on the activity of PARP-1, while PARP-2 was inhibited with an IC<sup>50</sup> value of 196 µM. Basically, the replacement of ribose by the morpholine cycle leads to an increase in the inhibitory ability of the compounds.

**Table 2.** Residual PARP-1 and PARP-2 activity (%) or IC50, µ, in the presence of 1 mM morpholino nucleosides and ribonucleosides.


Among the morpholino nucleosides, Ade- and Ura-containing derivatives (**11A** and **11U**, respectively, Table 2) were the least active against both enzymes. For PARP-1, the inhibition activity of nucleosides increases depending on the heterocyclic base of the morpholino nucleoside in the order Ade, Ura < (Cyt, 5-Cl-Ura) < (Gua, Thy) < (Ura, 5-Br-Ura); for PARP-2 the order is (Ade, Ura) < Cyt < Gua < 5-Cl-Ura < 5-Br-Ura < Thy < 5-I-Ura.

Thus, morpholino nucleosides proved to be more effective inhibitors of both enzymes than dinucleotides. Regardless of the other part of the molecule, i.e., nucleobase, linker type, the presence of the adenosine part of the molecule, the most effective inhibitors contained 5-iodouracil. The 5-iodouracil derivatives are characterized by the ratio of IC<sup>50</sup> values for PARP-1 and PARP-2 as 1:1. Adenine dinucleotide **10A** with the P–N bond stands apart inhibiting the activity of PARP-2 but not PARP-1, with the efficacy comparable to 5-iodoururacil containing derivatives. Adenine containing dinucleotide **4A** with the P–O bond is a little active against both enzymes, whereas adenine mononucleosides are completely inactive.
