Contents 1. Introduction 961 2. Specific Acid/Base Catalyzed Cleavage and Isomerization of the 3′,5′-Phosphodiester Bonds 963 3. General Acid/Base Catalyzed Cleavage and Isomerization of the 3′,5′-Phosphodiester Bonds 969 4. Structural Effects 974 5. Reactions of 2′,3′-Cyclic Phosphates 977 6. The Cleavage and Isomerization of the Phosphodiester Bonds of Polyribonucleotides 980 7. Cleaving Agents. Toward Artificial Nucleases by Proton-Transfer Catalysis 980 8. The Effect of Thia and Aza Substitutions on the Transesterification of Ribonucleoside 3′-Phosphodiesters 985 9. References 988

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Hydrolytic reactions of the R? and Sp diastereomers of the phosphoromonothioate analog of uridylyl-(3',5')uridine (3',5'-UpU), having a nonbridging oxygen replaced with sulfur, have been followed by HPLC over a wide pH range at 363.2 K. Under neutral and acidic conditions three reactions compete: (i) desulfurization to an equilibrium mixture of 3',5'-and 2',5'-UpU, (ii) hydrolysis to uridine 2'-and 3'-monophosphates with release of uridine (either via a 2',3'-cyclic phosphoromonothioate, or a desulfurized cyclic triester), and (iii) isomerization to the 2',5'-dinucleoside phosphoromonothioate. With both diastereomers, desulfurization predominates over hydrolysis and migration at pH 1-8. Migration proceeds by retention of configuration at phosphorus and is most pronounced in very acidic solutions (Hq < 0.2, i.e., [HC1] > 0.5 mol Lr1), representing 20-30% of the total disappearance of the starting material. At pH 3-6, the proportion of this reaction is less than 10%. In the latter pH range, all the reactions are pH-independent. At lower pH, first-order dependence on acidity is observed, but at Ho < 0.2 desulfurization becomes slower than the competing reactions. The R? diastereomer is at pH < 7 up to three times as reactive as the Sp isomer. Under alkaline conditions (pH > 9), only base-catalyzed hydrolysis to uridine 2'-and 3'thiophosphates with release of uridine takes place. At pH < 1, the thioate analogs are more than 1 order of magnitude more stable than UpU, while at higher pH the reactivities are comparable.

Olignucleotide-based drugs show promise as a novel form of chemotherapy. Among the hurdles that have to be overcome on the way of applicable nucleic acid therapeutics, inefficient cellular uptake and subsequent release from endosomes to cytoplasm appear to be the most severe ones. Covalent conjugation of oligonucleotides to molecules that expectedly facilitate the internalization, targets the conjugate to a specific cell-type or improves the parmacokinetics offers a possible way to combat against these shortcomings. Since workable chemistry is a prerequisite for biological studies, development of efficient and reproducible methods for preparation of various types of oligonucleotide conjugates has become a subject of considerable importance. The present review summarizes the advances made in the solid-supported synthesis of oligonucleotide conjugates aimed at facilitating the delivery and targeting of nucleic acid drugs.

Mimicking the action of enzymes by simpler and more robust man-made catalysts has long inspired bioorganic chemists. During the past decade, mimics for RNA-cleaving enzymes, ribonucleases, or, more precisely, mimics of ribozymes that cleave RNA in sequence-selective rather than base-selective manner, have received special attention. These artificial ribonucleases are typically oligonucleotides (or their structural analogs) that bear a catalytically active conjugate group and catalyze sequence-selective hydrolysis of RNA phosphodiester bonds.