2'-O-METHYL-CIS-ADENOSINE 3',5'-CYCLIC METHYL MONOPHOSPHATE, A NEW MODEL SYSTEM FOR CAMP - ASPECTS OF STRUCTURE AND REACTIVITY

This study is focussed on 2'-O-methyl-cis-adenosine 3',5'-cyclic methy l monophosphate (cis-4; cis describes the relationship between OMe (bo und to phosphorus) and the adenine base), which is regarded a model fo r enzyme-bound cyclic adenosine monophosphate (cAMP). In this complex the negative phosphate charge is shielded in part via complexation wit h cationic sites on the enzyme surface. We report synthesis, crystal s tructure, solution conformation (400 MHz H-1 NMR), and kinetic-mechani stic aspects of the alkaline hydrolysis of cis-4. The methanol solvate of cis-4 crystallizes in the orthorhombic space group P2(1)2(1),2(1) and the cell dimensions are a = 8.170(2) angstrom, b = 9.249(1) angstr om, c = 23.699(4) angstrom; V = 1788.5(6) angstrom3; Z = 4 molecules p er cell. Least-squares refinement converged at R = 0.062 for 2006 obse rved reflections. The adenine bases are linked via N6-H ... N1 and N6- H ... N7 hydrogen bonds in such a way that infinite one-dimensional ch ains are formed. This hydrogen bond scheme is very similar to that obs erved in the structure of 2'-deoxy-3',5'-di-O-acetyl adenosine. An add itional hydrogen bond is formed between methanol, incorporated in the crystal structure, and the adenine base. The conformational preference s of the cis-4 dissolved in methanol have been determined with 400 MHz H-1 NMR. It is found that the conformations observed in the solid and solution states are practically the same. Hydrolysis of the title com pound yields two acyclic phosphate diesters (a 3'- and a 5'-phosphate diester). The intermediates formed during the hydrolysis reaction are most likely five-coordinated phosphorus (P(v)) compounds with a trigon al bipyramidal geometry and an equatorial-axial located 3',5'-dioxapho sphorinane ring.