| Abstract: |
the thesis is prefaced by a brief description of cytarabine (Ara-c),possible sites of action, metabolism pharmacokinetic problems restricting its therapeutic efficacy and literature survey on biochemical modulation and approaches aimed at improving Ara-C effectiveness .the design and synthesis of the following N4-ara-C derivatives are described in this dissertation.Chemical structures of the novel derivatives as well as the reported ones (denoted by*) are verified on the basis elemental and spectroscopic (UV,1H-NMR and MS ) methods of analysis.The lipophilicity of the synthesized derivatives, expressed by partition coefficient, was determined in comparison with Ara-C at room temperature using chloroform/water system .all of the target compounds revealed better lipophilic, characters compared to the parent drug, Ara-C.Chemical reactivity of the derivatives7 (a- i) and 8(a-f) as well as Ara-C was measured at 37o C in aqueous buffer solutions of pH values 2,4,7 and 10.relatively rapid reversion of Ara-C from these derivatives was observed in pH 2 and 10 while in the other 2 pHs they showed high stability .Ara-C was found to be stable in pHs ,its slow degradation process appeared to go through the formation of biologically inactive Ara-U as reported.Enzymatic susceptibility of the previous 2 series of compounds and Ara-C was also investigated at 37o c in presence of 4 different enzyme systems, rat plasma, rat liver homogenate, porcine liver esterase and mouse kidney cytidine deaminase .Ara-C was not affected by the first three enzyme system under the investigations however, the other compounds were hydrolyzed to different extent according to the enzyme catalytic system .as a general pattern the succinate series (8a-f) is more liable to enzymatic hydrolysis than carbamate one (7a-i) release of Ara-C as a product of enzymatic degradation was detected either by HPLC or UV scanning of the solutions remaining after complete hydrolysis as shown by HPLC. Furthermore, these derivatives are quite resistant to cytidine deaminase enzyme compared to Ara-C.Similarly, recovery of Ara-C from Ara-C-N4- acetate derivatives (6 and 9a-o) as a result of biotransformation reactions was estimated using rat plasma and liver homogenate as multienzyme supply systems .nonetheless Ara-C was detected in minute amounts by HPLS, the results indicated that the N-decarboxylation and dealkylation of these series were not so efficient compared with the hydrolysis process.
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