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

The effects of several metal ions and metal ion complexes on the hydrolysis and interconversion of uridylyl(2′,5′)uridine and its 3′,5′‐isomer were studied as a function of pH and metal ion concentration. The hydrolysis was shown to be markedly accelerated by Zn2+, Cd2+ and trivalent lanthanide ions and by tri‐ and tetraaza complexes of Zn2+. In contrast, none of these species appreciably promotes the interconversion of the 2′,5′‐ and 3′,5′‐isomers, in spite of the fact that this reaction proceeds through the same pentacoordinated intermediate as the hydrolysis. Lanthanide ions also promote the hydrolytic dephosphorylation of uridine 2′‐ and 3′‐monophosphates, but have a barely noticeable effect on their interconversion. The mechanisms of the metal ion‐promoted reactions are discussed.

First-order rate constants for the hydrolysis of polyuridylic acid in the absence and presence of various metal ions and their chelates have been determined under neutral and slightly acidic conditions. The hydrolysis has been shown to proceed by cleavage of non-terminal bonds rather than by stepwise release of monomeric nucleotides. Only the hydrolysis of the 3',5'-phosphodiester bonds is accelerated by metal ions, not their isomerization to 2',5'-bonds. The catalytically active species has been shown to be the monohydroxo form of the metal aquo ion. The rate accelerations are parallel, but up to 20 times greater than those obtained with uridylyl(2',5')uridine. The mechanism of the metal-ion action is discussed. '

Several chimeric ribo/2'- O -methylribo oligonucleotides were synthesized and their hydrolytic cleavage studied in the presence of Mg2+, Zn2+, Pb2+and the 1,4,9-triaza-cyclododecane chelate of Zn2+(Zn2+[12]aneN3) to evaluate the importance of RNA secondary structure as a factor determining the reactivity of phosphodiester bonds. In all the cases studied, a phosphodiester bond within a 4-7 nt loop was hydrolytically more stable than a similar bond within a linear single strand, but markedly less stable than that in a double helix. With Zn2+and Zn2+[12]aneN3, the hydrolytic stability of a phosphodiester bond within a hairpin loop gradually decreased on increasing the distance from the stem. A similar but less systematic trend was observed with Pb2+. Zn2+- and Pb2+-promoted cleavage was observed to be considerably more sensitive to the secondary structure of the chain than that induced by Zn2+[12]aneN3. This difference in behaviour may be attributed to bidentate binding of uncomplexed aquo ions to two different phosphodiester bonds. Mg2+was observed to be catalytically virtually inactive compared with the other cleaving agents studied.

The pH-rate profiles for the hydrolysis of the 3',5'-phosphodiester bonds of poly(U) and their isomerization to the 2',5'-bonds have been determined by following the progress of the reactions by enzymatic digestion with RNAase A and subsequent RP HPLC. The kinetics observed are compared with those of the hydrolysis and interconversion of uridylyl(3',5')uridine and uridylyl(2',5')uridine.