Solid phase nucleic acid synthesis

Reagent 206 has been prepared that allows disulfide cross-links to be introduced into nucleic acids during solid-phase synthesis. The disulfide is formed between thioalkyl tethers at the N-3-position of thymidines and stabilises the termini of nucleic acid helices. Disulfide linked triplexes have been studied. ... 

While no examples of automated solid-phase oligosaccharide synthesis had been reported until the work described here,2 automated oligosaccharide synthesis was predated by efficient methods for the synthesis of peptides3 and nucleic acids.4 Here we briefly discuss the general features of each method, with particular emphasis on the scale and efficiency of peptide and nucleic acid synthesis. 

Noncovalent Protection in Solid-Phase Rhodamine-Labeled Peptide Nucleic Acid Synthesis... 

Beausoleil, E., Truong, K.T., Kirshenbaum, K., and Zuckermann, R.N. Influence of monomer structural elements in hydrophilic peptoids. In Innovations and Perspectives in Solid Phase Synthesis and Combinatorial Libraries Peptides, Proteins, and Nucleic Acids, R. Epton (Ed.), 2001, Mayflower Scientific Press Kingswin-ford, UK, pp. 239-242. 

The synthesis and crystal structure of the peptide nucleic acid (PNA) monomer 25 having cyanuric acid as nucleobase have been described. Monomer 25 can be directly used for the solid phase synthesis of PNA oligomers . 

The application of solid-phase synthesis and automation has revolutionized much of the chemical and biochemical research related to peptides and nucleic acids.5 Thus, it is likely that successful methods to synthesize oligosaccharides and glycoconjugates... 

In a recent report, the divergent solid-phase synthesis of nucleic acid dendrimers was also reported and the purity assessed using PAGE [24], however, the details are not included here due to space constraints. 

The ability to synthesize chemically short sequences of single-stranded DNA (oligonucleotides) is an essential part of many aspects of genetic engineering. The method most frequently employed is that of solid-phase synthesis, where the basic philosophy is the same as that in solid-phase peptide synthesis (see Section 13.6.3). In other words, the growing nucleic acid is attached to a suitable solid support, protected nucleotides are supplied in the appropriate sequence, and each addition is followed by repeated coupling and deprotection cycles. 

Despite all of the activity in pyrimidine-based synthesis, only one study has emerged of solid-phase versions of these reactions <2003TL1267, 20030BC1909>. This chemistry was based upon condensation of dicarbonyl compounds with resin-bound pyrimidine-5,6-diamines through a 2-alkylthio link and oxidative cleavage as described in Section 10.18.7.2. The value of alkylthio substituents in the synthesis of complex substituted pterins has also been demonstrated in the synthesis of nucleic acid conjugates <2004OBC3588> (see Section 10.18.12.4). 

Other known oligonucleotide analogs include oligomers in which the heterocyclic bases have been modified [155] or replaced by other types of compound [156], Solid-phase syntheses of hybrids of DNA with peptides [157-163], with carbohydrates [164,165], and with PNA (peptide nucleic acids, see Section 16.4.1.2 [166-168]) have also been reported, and several strategies have been developed that enable the preparation of oligonucleotides with a modified 5 - or 3 -terminus [169-174] or of cyclic oligonucleotides [122,175], Various techniques for the parallel solid-phase synthesis of oligonucleotides have been developed for the preparation of compound libraries [176-181],... 

A supported sulfide source has been demonstrated by Zhang et al.16 to synthesize oligonucleotide phosphorothioates (entry 12). Aminodithiazole-thione attached to a methacrylate-ethyleneglycol copolymer is used to efficiently convert a nucleotide phosphite to a phosphorothioate. The product nucleotide possesses protecting groups suitable for solid-phase oligonucleotide synthesis and thus is a valuable building block for nucleic acid therapeutics. 

Welz et al. developed a procedure for synthesis of oligoribonucleotides based on application of tetrazole for activation of RNA phosphoramidites in automated solid-phase synthesis <2000MB934>. Ar-Benzoyl tetrazole has been developed as a mild and selective reagent for monobenzoylation of the exocyclic amino group in nucleic acid bases <1997TL8811>. An improved procedure is described for the efficient and high yield (76-91%) synthesis of... 

Epton R. (Ed.), Innovation and Perspectives in Solid Phase Synthesis-Peptides, Proteins and Nucleic Acids, Mayflower Worldwide, Kingswinford, UK, 1994. 

Zhang, L., Goldhammer, C., Henkel, B., et al. (1994) Peptides, proteins and nucleic acids. Biological and biomedical applications, in Innovation and Perspectives in Solid Phase Synthesis (Epton, R., ed.), Mayflower Worldwide Ltd, Birmingham, UK, pp. 711-716. 

McCairn MC, Hughes MD, Hine AV, Sutherland AJ. A platform for both solid-phase peptide nucleic acid oUgomer synthesis and subsequent in sim detection and quantificahon of nucleic acid 43. sequences. J. Comb. Chem. 2006 8 639-642. 

Christensen L, Fitzpatrick R, Gildea B, Petersen KH, Hansen HF, Koch T, Egholm M, Buchardt O, Nielsen PE, Coull J, Berg RH. Solid-phase synthesis of pephde nucleic acids. J. Pephde Sci. 1995 3 175-183. 

Building blocks such as compounds 18 and 19 can be used for solid-phase synthesis of peptide-nucleic acids. 

Solid-phase synthesis of nucleic acids. Precise sequences of nucleic acids can be synthesized de novo and used to identify or amplify other nucleic acids. 

Hyde, C. Johnson, T. Owen, D. Quibel, M. Sheppard, R. C., In Innovation and Perspectives in Solid Phase Peptide Synthesis Peptides, Proteins and Nucleic Acids, Biological and Biomedical Applications, Epton, R., Ed. Mayflower Worldwide Birmingham, UK,... 

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