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Synthesis, Electrochemistry and Biological Evaluation of 6-Substituted and 2,6-Disubstituted Purines Coupled with Ferrocene

Ferrocene conjugates are shown to exhibit diverse biological activity, e.g. antitumor, antibacterial, antiparasitic and antifungal [1]. In order to obtain bioactive ferrocene conjugates, one can incorporate the ferrocene moiety into the structure of well-known drugs or combine it with some biologically and pharmacologically important molecules, e.g. nucleobases and their derivatives. Purine bases modified in the C6-position and their analogues also possess a wide range of biological properties and some of them show cytostatic and chemotherapeutic activity [2]. The mechanism of biological action of ferrocene derivatives is generation of reactive oxygen species (ROS) because of their electrochemical activity and reverse one-electron oxidation. Increased ROS level leads to oxidative stress, apoptosis and cell death [1]. Besides to the parent purine and adenine ferrocenoyls [3], we prepared 6- and 2, 6-substituted purines coupled to ferrocenoyl moiety. Both N7- and N9-isomers (see Figure) were examined for their electrochemical and biological activity. The cellular and acellular ROS generation was examined as well as the cytotoxic effect on L929 and selected cancer cell lines. Cyclic voltammetry showed reverse one-electron oxidation with significant difference between the N7 and N9 regioisomers. Significant ROS generation in acellular assay is observed with derivatives having a Cl, NH2 or CH3 substituents. Most of the compounds showed antiproliferative activity against L929 cells within concentration range of 10-500 μM and are promising cytotoxic agents for cancer cell lines.

ferrocene, purine, ROS, antiproliferative activity, L929

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