BIOLOGICAL ACTIVITY OF SOME NATURAL AND SYNTHETIC N6-SUBSTITUTED ADENOSINE DERIVATIVES (CYTOKININ RIBOSIDES)

In this Ph.D project, some natural N6 – substituted adenosine derivatives, cytokinin ribosides (CKRs) have been investigated with the aim to draw a profile of their biological activity. CKRs belong to a class of plant hormones playing various roles in many aspects of plant development. We chose the most representative among natural cytokinin ribosides, namely N6 – isopentenyl adenosine (iPAdo), kinetin riboside (KR), N6-benzyl adenosine (BA) and its hydroxylated derivative, ρ- topolin riboside (p-TR). In the first part of the thesis, the platelet anti aggregation activity CKRs has been evaluated in vitro as inhibitors of platelet aggregation. The activity has been interpreted by in silico docking experiments as due to interaction of CKRs with P2Y12 receptor. ρ -Topolin riboside showed the best platelet anti aggregation activity and in silico interaction with P2Y12 receptor, followed by N6 – benzyladenosine. Some synthetic N6 – substituted adenosine derivatives have been synthesized and investigated as antagonists toward the human adenosine receptors A1, A2A, A2B, A3. p-TR again was the best antagonist of A2A and A2B adenosine receptors, both involved in the platelet aggregation mechanism. Synthetic N6 – substituted adenosine derivatives were antagonists of A3 adenosine receptor much stronger than natural CKRs. In a structure-activity study, the cytotoxic activity of natural CKRs and the synthetic analogues of p-TR were evaluated on 661W and Neuro2A cell lines trough Trypan blue and Tunel assays. Synthetic N6 – substituted adenosine derivatives showed a cytotoxic activity stronger than p-TR itself, that, in turn, exhibited the best apoptotic property. Many biological activities shown by the CKRs examined in this thesis could be related to an effect of these compounds on the cellular oxidative stress. Thus, as a part of the PhD project, the antioxidant profile of natural and synthetic CKRs has been investigated using the most common antioxidant tests in vitro. The heterogeneity of the results suggests in some instance a possible structure – activity relationship. However, since not all the compounds are active in every antioxidant assay, further characterization of the antioxidant profile of CKRs seems desirable, including suitable cellular assays.