A1 Refereed original research article in a scientific journal
Towards nucleotide prodrugs derived from 2,2-bis(hydroxymethyl)malonate and its congeners: Hydrolytic cleavage of 2-cyano-2-(hydroxymethyl)-3-methoxy-3-oxopropyl and 3-(alkylamino)-2-cyano-2-(hydroxymethyl)-3-oxopropyI protections from the internucleosidic phosphodiester and phosphorothioate linkages
Authors: Poijarvi P, Maki E, Tomperi J, Ora M, Oivanen M, Lonnberg H
Publisher: WILEY-V C H VERLAG GMBH
Publication year: 2002
Journal:: Helvetica Chimica Acta
Journal name in source: HELVETICA CHIMICA ACTA
Journal acronym: HELV CHIM ACTA
Volume: 85
Issue: 7
First page : 1869
Last page: 1876
Number of pages: 8
ISSN: 0018-019X
DOI: https://doi.org/10.1002/1522-2675(200207)85:7<1869::AID-HLCA1869>3.0.CO;2-W
Abstract
Thymidylyl-(3'-->5')-thymidine (TpT) and its stereoisomeric phosphoromonothioate analogs [P(R)]- and [P(S)]-Tp(s)T having the phosphate or thiophosphate linkage protected with a 2-cyano-2-{[(4,4'-dimethoxy-trityl)oxy]methyl}-3-methoxy-3-oxopropyl group (see 5a,b), as well as [P(R)]-Tp(s)T bearing a S-(2-cyano-2-{[(4,4'-dimethoxytrityl)oxy]methyl}-3-oxo-3-[(2-phenylethyl)amino]propyl) protection (see 5c), were prepared. ne kinetics of the cleavage of the protecting group from the corresponding detritylated compounds 6a-c was studied over a pH range from 2 to 7. All compounds undergo a hydroxide-ion-catalyzed reaction that releases the unprotected TpT (7a) or Tp(s)T (7b), in all likelihood by departure of the hydroxymethyl group as formaldehyde and concomitant elimination of the phosphodiester or phosphorothioate from the resulting carbanion. The half-life for the deprotection of 6a and 6b is ca. 6 s at pH 7 and 25degrees, and that of 6c ca. 600 s. The reasonably fast release of Tp(s)T from 6c offers a novel method for temporary intrachain attachment of peptides to oligonucleotides to enhance the cellular uptake.
Thymidylyl-(3'-->5')-thymidine (TpT) and its stereoisomeric phosphoromonothioate analogs [P(R)]- and [P(S)]-Tp(s)T having the phosphate or thiophosphate linkage protected with a 2-cyano-2-{[(4,4'-dimethoxy-trityl)oxy]methyl}-3-methoxy-3-oxopropyl group (see 5a,b), as well as [P(R)]-Tp(s)T bearing a S-(2-cyano-2-{[(4,4'-dimethoxytrityl)oxy]methyl}-3-oxo-3-[(2-phenylethyl)amino]propyl) protection (see 5c), were prepared. ne kinetics of the cleavage of the protecting group from the corresponding detritylated compounds 6a-c was studied over a pH range from 2 to 7. All compounds undergo a hydroxide-ion-catalyzed reaction that releases the unprotected TpT (7a) or Tp(s)T (7b), in all likelihood by departure of the hydroxymethyl group as formaldehyde and concomitant elimination of the phosphodiester or phosphorothioate from the resulting carbanion. The half-life for the deprotection of 6a and 6b is ca. 6 s at pH 7 and 25degrees, and that of 6c ca. 600 s. The reasonably fast release of Tp(s)T from 6c offers a novel method for temporary intrachain attachment of peptides to oligonucleotides to enhance the cellular uptake.