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Metal-Ion-Promoted Cleavage, Isomerization, and Desulfurization of the Diastereomeric Phosphoromonothioate Analogues of Uridylyl(3′,5′)uridine
Ora, Mikko,Peltomaeki, Markku,Oivanen, Mikko,Loennberg, Harri
, p. 2939 - 2947 (2007/10/03)
Metal-ion-promoted hydrolytic reactions of the SP and RP diastereomers of the phosphoromonothioate analogues of uridylyl(3′,5′)uridine [3′,5′-Up(s)U] and their cleavage products, diastereomeric uridine 2′,3′-cyclic phosphates [2′,3′-cUMPS], were followed by HPLC as a function of pH (4.7-5.6) and metal ion concentration (1-10 mmol L-1). With 3′,5′-Up(s)U, three reactions compete: (i) cleavage to 2′,3′-cUMPS, (ii) isomerization to 2′,5′-Up(s)U, and (iii) desulfurization to an equilibrium mixture of 2′,5′- and 3′,5′-UpU. Of these, the cleavage to 2′,3′-cUMPS is markedly accelerated by Zn2+, Cd2+, and Gd3+, the rate enhancements observed with the Sp isomer at [Mz+] = 5 mmol L-1 and pH 5.6 (T = 363.2 K) being 410-, 3600-, and 2000-fold, respectively. The effect of Mn2+ and Mg2+ on the cleavage rate is, in turn, modest (6- and 1.7-fold acceleration, respectively). The rate-accelerations are almost equal with the SP and RP diastereomers. The metal-ion-promoted reaction is first-order in both the hydroxide and metal ion concentration, and it proceeds by inversion of configuration at phosphorus, consistent with an in-line displacement mechanism. The isomerization and desulfurization are much less susceptible to metal ion catalysis: 6.4- and 7.7-fold accelerations were observed with Zn2+, respectively. Gd3+ does not promote these reactions at all. The isomerization proceeds by retention of configuration at phosphorus, consistent with formation of a pentacoordinated thiophosphorane intermediate having the entering 2′-hydroxy group apical and the leaving 3′-hydroxy equatorial, and subsequent pseudorotation posing the leaving group apical. The hydrolysis of 2′,3′-cUMPS is accelerated by metal ions slightly more efficiently than the cleavage of 3′,5′-Up(s)U to 2′,3′-cUMPS. In striking contrast to the reactions of 3′,5′-Up(s)U, the hydrolytic desulfurization to 2′,3′-cUMP is accelerated as efficiently as its endocyclic hydrolysis to uridine 2′and 3′-phosphoromonothioates [2′- and 3′-UMPS]. Somewhat unexpectedly, the latter compounds were observed to undergo metal-ion-promoted cyclization/desulfurization to 2′,3′-cUMP. The hydrolysis of 2′- or 3′-UMPS to uridine was, in turn, observed to be retarded by metal ions. The mechanisms of the partial reactions are discussed.
