Collect. Czech. Chem. Commun. 1987, 52, 2572-2588

Synthesis of phosphonylmethyl analogues of diribonucleoside monophosphates containing modified internucleotide bond

Ivan Rosenberg and Antonín Holý

Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, 166 10 Prague 6


Two types of (2'-5')- and (3'-5')-isomers of analogues of diribonucleoside monophosphates derived from O-phosphonylmethyl derivatives of ribonucleosides, differing in the position of the methylene group in the internucleotide bond (type A, B, C, and D) have been synthesized. The compounds were prepared from methyl esters of O-phosphonylmethylribonucleosides I and XVII by a procedure analogous to the phosphotriester method of oligonucleotide synthesis. The phosphonate moiety was protected with the methyl group. After protection of the hydroxyl or amino groups, the compounds I or XVII were condensed with protected ribonucleosides VIII, XI, XIV, XXIII to afford the neutral diesters IX, XII, XV, XXIV, XXVI, and XXVIII which were isolated by short column chromatography on silica gel. Deprotection, ion-exchange chromatography, and semipreparative HPLC gave (2'-5')- and (3'-5')-isomers of both types of O-phosphonylmethyl analogues of diribonucleoside monophosphates (X, XIII and XXV, XXVII). All these compounds are resistant towards cleavage with ribonucleases A and T2 and with snake venom exonuclease. Under conditions of alkaline hydrolysis of RNA, the analogues of the type A and B are completely stable whereas compounds of the type C and D are degraded to form 2'- or 3'-O-phosphonylmethylribonucleosides and 3'-terminal ribonucleosides.