Solid-Phase Chemical Synthesis of Phosphonoacetate and Thiophosphonoacetate Oligodeoxynucleotides

Phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides were prepared via a solid-phase synthesis strategy. Under Reformatsky reaction conditions, novel esterified acetic acid phosphinodiamidites were synthesized and condensed with appropriately protected 5‘-O-(4, 4‘-dimethoxytrityl)-2‘-deox...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2003-01, Vol.125 (4), p.940-950
Main Authors: Dellinger, Douglas J, Sheehan, David M, Christensen, Nanna K, Lindberg, James G, Caruthers, Marvin H
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Chromatography, High Pressure Liquid
Chromatography, Ion Exchange
Dna, deoxyribonucleoproteins
Fundamental and applied biological sciences. Psychology
Nuclear Magnetic Resonance, Biomolecular
Nucleic acids
Oligonucleotides - chemical synthesis
Organothiophosphates - chemical synthesis
Phosphonoacetic Acid - analogs & derivatives
Phosphonoacetic Acid - chemical synthesis
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Summary:Phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides were prepared via a solid-phase synthesis strategy. Under Reformatsky reaction conditions, novel esterified acetic acid phosphinodiamidites were synthesized and condensed with appropriately protected 5‘-O-(4, 4‘-dimethoxytrityl)-2‘-deoxynucleosides to yield 3‘-O-phosphinoamidite reactive monomers. These synthons when activated with tetrazole were used with an automated DNA synthesizer to prepare phosphonoacetic acid modified internucleotide linkages on controlled pore glass. The phosphinoacetate coupling products were quantitatively oxidized at each step with (1S)-(+)-(10-camphorsulfonyl)oxaziridine or 3H-1,2-benzodithiol-3-one-1,1-dioxide to produce mixed sequence phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides with an average per cycle coupling efficiency of greater than 97%. Completely deprotected, modified oligodeoxynucleotides were purified by reverse-phase HPLC and characterized by ion exchange HPLC, 31P NMR, and MALDI/TOF mass spectroscopy. Both analogues were stable toward hydrolysis with snake venom phosphodiesterase and stimulated RNase H1 activity.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja027983f