OXIDATION CHEMISTRY OF SOME BIOLOGICALLY IMPORTANT PURINE NUCLEOSIDES AND NUCLEOTIDES

Abstract

The understanding of mechanism of redox behavior of biologically significant organic molecules presents a major challenge to the electrochemists. Electrochemistry has presently been the main driving force to explore in vivo redox chemistry of physiologically important biomolecules. The oxidative processes play an important role in a variety of biological processes including respiration, energy production, biosynthesis, substrate metabolism and detoxification. Such redox reactions are chiefly enzyme catalyzed and very difficult to study due to their very fast rate of reaction. It is wellestablished that systematic electrochemical studies coupled with techniques, such as GC/MS, HPLC, 1H NMR etc. provide deep insights into the mechanistic aspects of enzyme catalyzed redox reactions. Owing to the widespread use of the electrochemical techniques in chemical and biochemical research, our laboratory has been investigating the redox behavior of biologically important compounds from the last two decades. Purines and their nucleosides and nucleotides, being the constituents of DNA and RNA have potentialities in biological, clinical and pharmaceutical fields. Moreover, these compounds undergo oxidation on interaction with reactive oxygen species (ROS) and generate several complex oxidation products which have been reported to be the major contributor to mutagenesis and carcinogenesis. Hence, electrochemical investigations of the electron transfer reactions of purine nucleosides and nucleotides have been carried out in the present dissertation. 11 The first chapter of the dissertation is "General Introduction", which highlights the importance of electrochemical studies in biological systems along with its application in diverse areas. The salient features of the various techniques used in the investigations have also been presented in this chapter. Also a compendious review of the pertinent work during last decade and significant results of the studies have also been highlighted. The second chapter of the thesis presents the electron transfer reactions of 2'-deoxyadenosine at pyrolytic graphite electrode (PGE) to monitor the effect of the deoxyribose moiety on the oxidation behavior of adenosine. 2'-deoxyadenosine (I), a purine 2'-deoxyribonucleoside is claimed as a useful precursor in the synthesis of a wide variety of antiviral, antitumor and antileukemic drugs and hence selected for these studies. In cyclic sweep voltammetry oxidation of (I) occurred in a single welldefined peak la over the entire pH range studied. When the direction of the sweep was reversed a cathodic peak llc was observed only in the pH range 7.20-10.07. In the second sweep towards positive potentials, two oxidation peaks lla, Ilia were observed in the pH range 7.20-10.07, at a potential less positive than that of the peak la. Peak lla formed a quasi-reversible couple with peak llc. The peak potentials of the oxidation peaks la, lla, Nla and the reduction peak llc were dependent on pH. The electrooxidation occurred by the loss of the 6.0 ± 0.5 electron per mole both in acidic and neutral medium. The decay of the UV-absorbing intermediate generated during oxidation occurred in a pseudo-first-order reaction. The major products of oxidation were alloxan, C8-C8, C8-0-C2, C2-0-0-C2 dimers in acidic medium whereas allantoin, C8-0-0-C8 dimer and C8-N6-C8 trimer were observed at neutral pH. iii The results of the electrochemical oxidation of 2'-deoxyadenosine have also been compared with adenosine oxidation. It can thus be inferred that deoxyribosyl moiety significantly affects the product distribution and also causes the reaction to proceed via free radical mechanism leading to the formation of (dimers and trimer) along with normal products (alloxan and allantoin).