Premium
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‐oxopropyl Protections from the Internucleosidic Phosphodiester and Phosphorothioate Linkages
Author(s) -
Poijärvi Päivi,
Mäki Esa,
Tomperi Jussi,
Ora Mikko,
Oivanen Mikko,
Lönnberg Harri
Publication year - 2002
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(200207)85:7<1869::aid-hlca1869>3.0.co;2-w
Subject(s) - chemistry , hydroxymethyl , thiophosphate , stereochemistry , malonate , hydrolysis , leaving group , nucleotide , cleavage (geology) , protecting group , carboxylate , medicinal chemistry , organic chemistry , catalysis , biochemistry , geotechnical engineering , fracture (geology) , engineering , gene , alkyl
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′‐dimethoxytrityl)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. The 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 25°, 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.