ANTITUMOR AND ANTIVIRAL NUCLEOSIDE ANALOGS

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Novel nucleoside analogs will be prepared and studied as potential antitumor and antiviral agents. These compounds will include: (i) "Hydroxycarbocyclic" analogs of adenosine and cytidine, (ii) Hydroxycarbocyclic analogs of antitumor and antiviral agents araC [Cytarabine, 1-(Beta-D-arabinofuranosyl)cytosine] and araA [Vidarabine, 9-(Beta-D-arabinofuranosyl)-adenine] related to the neplanocin group of antitumor nucleoside antibiotics, and (iii) neplanocin A (NPC-A) and the corresponding cytidine analog. All compounds will be obtained by chemical synthesis using anti-7-tert-butoxy-5-norbornene-exo-cis-2,3-diol as a key common intermediate. Antitumor activity and mechanism of action of NPC-A and synthetic analogs will be studied in vitro and in vivo in murine leukemia L1210, 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 nucleoside analogs will also be investigated.