Synthesis and Properties of Nonpolar DNA (Arylalkyl)phosphonates

• Published in: Helvetica chimica acta Vol. 85; no. 8; pp. 2503 - 2517
• Main Authors: Amberg, Stefan, Engels, Joachim W.
• Format: Journal Article
• Language: English
• Published: Basel WILEY-VCH Verlag 01.08.2002; WILEY‐VCH Verlag; Wiley
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; OLIGODEOXYNUCLEOTIDES; STACKING; DESIGN; ACID; STABILITY; RESIDUE; BACKBONE; ANTISENSE OLIGONUCLEOTIDES; EXPRESSION; BINDING
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/1522-2675(200208)85:8<2503::AID-HLCA2503>3.0.CO;2-I

The eight (arylalkyl)‐modified phosphoramidites (=(arylalkyl)phosphonamidites) 1–8 (Fig. 2) were synthesized (Schemes 1–3) and incorporated at different positions into 2′‐deoxyoligonucleotides. The [P(R)]‐ and [P(S)]‐diastereoisomers of the hexanucleotides 32–39 (Table 1) and of the dodecanucleotides 41–45 (Table 2) obtained were separated by means of reversed‐phase HPLC. UV, CD, and fluorescence spectroscopy were used to investigate the thermal stability (Tm) and the structural changes of their DNA duplexes with 5′‐d(CGCGCG)‐3′ and 5′‐d(ATGATTGACCTG)‐3′, respectively. The Tm values significantly depend on the place of modification (Table 2). A dangling‐end effect is observed when the [3‐(anthracen‐9‐yl)propyl]‐modified 8 is attached at the 5′‐terminus (see duplex with 45c). In the case of the incorporation of aromatic moieties tethered via a methylene linker to the P‐atom (benzyl‐ and (naphthalen‐1‐ylmethyl)‐modified 1 and 6, resp.), the duplexes with the [P(R)]‐oligonucleotides are more stable than those with the [P(S)]‐isomers, whereas in the case of longer alkyl chains at the P‐atom (see 2–5), the Tm values show the reverse tendency. The observed Tm differences are assigned to changes in base stacking (Figs. 6 and 7).