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|Title:||STUDIES ON SOME PURINE, PYRIMIDINE BASES AND THEIR METAL COMPLEXES|
|Authors:||Abdullah, Adil Ali|
|Abstract:||Electrochemistry is a branch of physical chemistry in which the relation between electricity and chemical effects is used to monitor and control the extent of aredox reaction. Investigations ofthe redox chemistry ofthe biologically important compounds play a dominant role in providing information in energy conversion and substrate metabolism. Redox pathway of such compounds in biological systems is generally very complex in nature. Hence to understand the transfer and storage of energy occurring via different metabolic processes at a molecular level is very difficult. Electrochemistry provides useful and unique information about redox chemistry of these compounds especially when the electrochemical studies are coupled with other techniques such as GC, GC-Mass, HPLC, 'HNMR ... etc. Purine and pyrimidine base pairs as well as mispair formation and their possible incorporation in the DNA helix has been observed to be assisted by the presence of metal ions. The biological functioning of nucleic acids involve the participation of metal ions either directly or indirectly, hence it is desirable to study the biochemical aspects concerned with metal - nucleic acid interaction. The structural studies of nucleic acids, vis, DNA and RNA and the primary roles of nucleic acids and their derivatives in biological reproduction and growth have been well established but in order to propose the structures and reactions of nucleic acids and their constituents, it is necessary to know the sites for the interaction of these substance. Our laboratory is actively involved in studying the redox behaviour of various biologically important compounds such as purines and pyrimidine derivatives, which are the constituents of nucleic acids. In this thesis an attempt has been made to get insights concerning the electrooxidation of some biologically important compounds and the metal ion interactions with such compounds. The detailed physico - chemical investigations of interaction of some transition metal ions with purines and pyrimidines have been studied. The metal complexes synthesized have also been screened for their antitumor activity against Dalton's Lymphoma (DL) tumor systems both in vivo and in vitro. The results of the investigations are arranged in the thesis as follows: The first chapter of the thesis is "General introduction" which highlights the importance of electrochemical studies in probing the redox chemistry of biomolecules. The general aspects of the basic techniques used in the presents work are also presented. The second chapter of the thesis has been devoted to electrochemical investigations carried out on uracil and 5-halouracil (I) at pyrolytic graphite electrode and the effect of halogens on the ease of oxidation has also been evaluated. in o HN Y^ H X = H, F, CI, Br, I (I) Cyclic voltammetric studies of uracil and 5-halouracil at pyrolytic graphite electrode (PGE) at a sweep rate of 100 mVs'1 exhibited a single well-defined oxidation peak Ia in thepHrange 1.2 - 11.0 and no peak was noticed in the reverse sweep. The Ep of oxidation peak Ia was dependent on pH and shifted to less positive potential with increase in pH and the Ep versus pH plots of various uracils were linear. The UV spectral changes and kinetics of the decay of the UVabsorbing intermediate generated during the reaction were also studied. The products of electrooxidation were lyophilized and characterized by m.p. TLC, IR and 'HNMR. On the basis of the experimental results, tentative mechanism for the oxidation of these compounds has been suggested. The effect of halogen atom on the ease of oxidation of uracil has also been studied qualitatively and quantitatively using Hammett relation. Purine drugs, especially thiopurines are potent antineoplastic agents and are used extensively for the treatment of various leukemia and are in clinical use as IV anticancer drugs for more than forty years. 6-Thioxanthine (II), is well-known as inhibitor of 3',5'-cyclicadenosinemonophosphate phosphodiestrase. The action of 6-thioxanthine on Toxo plasma gondi has been found as long parasitostatic. 6- Thioxanthine and 6-thioguanine exhibited significant antiproliferative effects against tumors formed by C6GPT-7 cells. The third chapter of this thesis deals with the oxidation chemistry of 6-thioxanthine, a well-known purine drug. SH •N\ HO^N^^-N'> (II) Voltammetry of 6-thioxanthine at sweep rate 100 mVs"1 exhibited two welldefined oxidation peaks in the pH range 1.2 - 6.0 (Ia and IIa) at the pyrolytic graphite electrode. At pH > 6.0 peak Ia (at less positive potential) disappeared and only peak IIa was noticed and the peak potential of both the peaks was linearly dependent on pH. In the reverse sweep peak IIIC was observed where Ep was also dependent on pH. The nature of the electrode reaction was established as EC in which charge transfer is followed by irreversible chemical reactions. Coulometric studies indicated that the number of electrons involved in oxidation corresponding to peak Ia and IIa are 1.0 ± 0.1 and 8.1± 0.2 respectively. Spectral changes during electrolysis were monitored to detect the formation of UV-absorbing intermediate. The decay of the UV-absorbing intermediate occurred in a pseudo-first-order v reaction. The products of electrooxidation were characterized by using TLC, IR, GC-Mass and 'HNMR. A plausible mechanism has been suggested for the formation of the products. 2-Thiouracil (III) has been identified in t-RNA and its chemotherapeutic activity has been explained on the basis of its ready incorporation into the nucleic acid. 2-Thiouracil and its derivatives have also been found to induce modifications in the thyroid gland and have been used as antithyroid drugs. O OH N H N SH (HI) The fourth chapter of the thesis is devoted to the electrochemical oxidation of 2-thiouracil in the pH range 1.95 - 11.08. One well-defined oxidation peak Ia (4e, 4H+) in the pH range 1.95 - 11.08 was noticed. When reverse sweep was applied, a reduction peak IIC (2e, 2H+) was observed. The Ep versus pH plots for anodic and cathodic peaks were linear. The kinetics of the decay of the UVabsorbing intermediate generated during the electrooxidation was studied and the decay has been found to occur in a pseudo-first-order reaction. The products of the VI electrooxidation have been characterized and a tentative EC mechanism has been suggested for the oxidation. The interaction of transition metal ions with nucleic acid constituents has become an interesting area of studies due to their biological significance and potential chemotherapeutic properties. Chapter five provides the detail about synthesis, structural and antitumor activity of some mixed ligand complexes of Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) with adenine -5-fluorouracil, adenine-5- chlorouracil and adenine-5-iodouracil base pairs (IV). HN H 0 X= F, CI, I. M= Co(II), Ni(II), Cu(II), Zn(II), Cd(II). (IV) These complexes have been characterized by elemental analysis, IR, UVvisible, magnetic measurements and powder X-ray diffraction and subjected to a vii screening system against Daltons' Lymphoma (DL) tumor cells. The antitumor activities results indicate that some complexes have good antitumor activity both in vivo and in vitro against Daltons' Lymphoma tumor cells.|
|Research Supervisor/ Guide:||Singh, Udai P.|
Goyal, R. N.
|Appears in Collections:||DOCTORAL THESES (chemistry)|
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