ANTITUMOR AND ANTIVIRAL NUCLEOSIDE ANALOGUES

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Novel nucleoside analogous will be prepared and studied as potential antitumor and antiviral agents. These compounds will include: (i) "Hydroxycarbocyclic" analogous of cytidine, 3- deazaadenosine, vidarabine and cytarabine, (ii) unsaturated carbocyclic nucleoside analogues related to neplanocin A including L-homocysteinylneplanocin A, (iii) phosphonate derivatives of open- chain unsaturated nucleoside analogues and (iv) analogues of adenosine deaminase inhibitor EHNA. All compounds will be obtained by chemical synthesis. Analogues (i) and (ii) will be obtained either in racemic form or optically pure by a new chemico-enzymatic approach. Antitumor activity and mechanism of action of the active analogues will be studied in vitro and in vivo in murine leukemia L 1210, P388, and sixteen solid tumor systems. Particular attention will be paid to: (i) inhibition of macromolecular synthesis, (ii) reversal studies with specific metabolites, (iii) alterations in nucleotide pool sizes, and (iv) effects on RNA maturation. Antiviral activity of the obtained analogues will also be investigated. Suitable analogues will be studied as substrates (inhibitors) of adenosine deaminase and adenosine homocysteine hydrolase.