Oligonucleosides with a Nucleobase-Including Backbone, Part 1, Concept, Force-Field Calculations, and Synthesis of Uridine-Derived Monomers and Dimers

Abstract

A new type of oligonucleosides has been devised to investigate the potential of oligonucleosides with a nucleobase-including backbone to form homo-and/or heteroduplexes (cf. Fig. 2). It is characterised by ethynyllinkages between C(5') and C(6) of uridine, and between C(5') and C(8) of adenosine. Force-field calculations and Maruzen model studies suggest that such oligonucleosides form autonomous pairing systems and hybridize with RNA. We describe the syntheses of uridine-derived monomers, suitable for the construction of oligomers, and of a dimer. Treatment of uridine-5'-carbaldehyde (2) with triethylsilyl acetylide gave the diastereoisomeric propargylic alcohols 6 and 7 (1 : 2, 80%; Scheme 1). Their configuration at C(5') was determined on the basis of NOE experiments and X-ray crystal-structure analysis. Iodination at C(6) of the (R)-configured alcohol 7 by treatment with lithium diisopropylamide (LDA) and N-iodosuccinimide (NIS) gave the iodide 17 (62%), which was silylated at OÀC(5') to yield 18 (89%; Scheme 2).

Oligonucleotide Analogues with a Nucleobase-Including Backbone, Part 5, 2′-Deoxy-8-(hydroxymethyl)adenosine- and 2′-Deoxy-6-(hydroxymethyl)uridine-Derived Phosphoramidites: Synthesis and Incorporation into 14-Mer DNA Strands

“…TLC: precoated silica-gel plates (Merck silica gel 60 F 254 ); detection by spraying with mostain (400 ml of 10% aq. H 2 SO 4 , 20 g of (NH 4 ) 6 2912m, 2877m, 1707m, 1612s, 1584m, 1503w, 1455s, 1413m, 1352w, 1329m, 1111m, 1091m, 1071m, 1006m. (17).…”

“…± We have conceived oligonucleotide analogues with a nucleobaseincluding backbone (Fig. 1, B); these compounds should allow us to answer the question of whether the structural differentiation between nucleobase and backbone in DNA, RNA, and their analogues 1 ) is a prerequisite for the formation of stable homoand/or heteroduplexes [6] [7].…”

Oligonucleosides with a Nucleobase-Including Backbone, Part 3, Synthesis of Acetyleno-Linked Adenosine Dimers

“…± We have designed oligonucleotide analogues in which the 3',5'-phosphodiester moiety between adenosine units is replaced by an 8,5'-acetylene link (I, Scheme 1) [1]. Calculations predict that such adenosine-derived analogues may form stable complexes with uridine oligonucleotides and with their 6,5'-acetyleno-linked analogues.…”

“…Calculations predict that such adenosine-derived analogues may form stable complexes with uridine oligonucleotides and with their 6,5'-acetyleno-linked analogues. We have reported the synthesis of uridine-and adenosine-derived monomers [1] [2] and of uridine-derived dimers [1], and we now describe the synthesis of protected and unprotected 8,5'-acetyleno-linked adenosine dimers I (n 0; Scheme 1).…”

“…In view of the low diastereoselectivity in the addition of [(trimethylsilyl)ethynyl]magnesium bromide to aldehydes of type IV, we have followed path B that takes advantage of working with monomers of established configuration [2]. Considering the sensitivity of the alkynylated adenosine derivatives to acid and base (as during deprotection), resulting in elimination of the propargylic OH group and degradation, we also planned to deoxygenate the alkynylated monomers and subject the products to cross-coupling with iodoadenosines of type V. In this context, we examined the dependence of the cross-coupling on the propargylic substituent at C (5') and also on the N-benzoyl group, preparing the eight dimers 14a ± d, 15b ± d, and 16 (the C(5'/I) 1 ) epimer of 14d) (cf. Schemes 4 and 5).…”