A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
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
Tekijät: Poijarvi P, Maki E, Tomperi J, Ora M, Oivanen M, Lonnberg H
Kustantaja: WILEY-V C H VERLAG GMBH
Julkaisuvuosi: 2002
Lehti:: Helvetica Chimica Acta
Tietokannassa oleva lehden nimi: HELVETICA CHIMICA ACTA
Lehden akronyymi: HELV CHIM ACTA
Vuosikerta: 85
Numero: 7
Aloitussivu: 1869
Lopetussivu: 1876
Sivujen määrä: 8
ISSN: 0018-019X
DOI: https://doi.org/10.1002/1522-2675(200207)85:7<1869::AID-HLCA1869>3.0.CO;2-W
Tiivistelmä
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.
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