Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates

Paul S. Miller, Junichi Yano, Emi Yano, Charles Carroll, Krishna Jayaraman, Paul O P Ts'o

Research output: Contribution to journalArticle

Abstract

A series of dideoxyribonucleoside methylphosphonate analogues, dNpN and dNpNp, which contain a nonionic 3′-5′ methylphosphonyl internucleoside linkage were prepared. The two diastereoisomers, designated isomers 1 and 2, of each dimer differ in configuration of the methylphosphonate group and were separated by column chromatography. The diastereoisomers of each dimer have different conformations in solution as shown by ultraviolet hypochromicity data and their circular dichroism spectra. For example, dApA. isomer 1 is more highly stacked than isomer 2, although both isomers are less stacked than the dinucleoside monophosphate, dApA. The circular dichroism spectrum of isomer 1 is very similar to that of dApA, while the CD spectrum of isomer 2 shows a loss of molecular ellipticity, [θ], at 270 nm and a greatly diminished [θ] at 250 nm. These results suggest that the stacked bases of dApA isomer 1 tend to orient in an oblique manner, while those in isomer 2 tend to orient in a parallel manner. This interpretation is verified by the 1H NMR study of these dimers (L. S. Kan, D. M. Cheng, P. S. Miller, J. Yano, and P. O. P. Ts'o, unpublished experiments). Both diastereoisomers of dApA form 2U:1A and 2T:1A complexes with poly(U) and poly(dT), respectively. The higher Tm (Tm of poly(U)-isomer 1, 15.4 °C; Tm of poly(U)-isomer 2, 19.8 °C; Tm of poly(dT)-isomer 1, 18.7 °C; Tm of poly(dT)-isomer 2, 18.4 °C) values of these complexes vs. those of the corresponding dApA-polynucleotide complexes (Tm of poly(U)-dApA, 7.0 °C; Tm of poly(dT)-dApA, 9.2 °C) result from decreased charge repulsion between the nonionic dimer backbone and the negatively charged polymer backbone. The difference in conformations between dApA isomer 1 and dApA isomer 2 is reflected in the Tm of the isomer 1-poly(U) complex which is 4.4 °C lower than that of the isomer 2-poly(U) complex. Since these nonionic oligonucleotide analogues are taken up by cells in culture, they show promise as molecular probes for the function and structure of nucleic acids inside living cells.

Original languageEnglish (US)
Pages (from-to)5134-5143
Number of pages10
JournalBiochemistry®
Volume18
Issue number23
StatePublished - 1979

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Poly U
Poly T
Isomers
Nucleic Acids
Circular Dichroism
Dinucleoside Phosphates
Molecular Probes
Polynucleotides
Dimers
Molecular Structure
Oligonucleotides
Chromatography
Polymers
Cell Culture Techniques
dideoxyribonucleoside methylphosphonates
Conformations
Column chromatography

ASJC Scopus subject areas

  • Biochemistry

Cite this

Miller, P. S., Yano, J., Yano, E., Carroll, C., Jayaraman, K., & Ts'o, P. O. P. (1979). Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates. Biochemistry®, 18(23), 5134-5143.

Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates. / Miller, Paul S.; Yano, Junichi; Yano, Emi; Carroll, Charles; Jayaraman, Krishna; Ts'o, Paul O P.

In: Biochemistry®, Vol. 18, No. 23, 1979, p. 5134-5143.

Research output: Contribution to journalArticle

Miller, PS, Yano, J, Yano, E, Carroll, C, Jayaraman, K & Ts'o, POP 1979, 'Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates', Biochemistry®, vol. 18, no. 23, pp. 5134-5143.
Miller PS, Yano J, Yano E, Carroll C, Jayaraman K, Ts'o POP. Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates. Biochemistry®. 1979;18(23):5134-5143.
Miller, Paul S. ; Yano, Junichi ; Yano, Emi ; Carroll, Charles ; Jayaraman, Krishna ; Ts'o, Paul O P. / Nonionic nucleic acid analogues. Synthesis and characterization of dideoxyribonucleoside methylphosphonates. In: Biochemistry®. 1979 ; Vol. 18, No. 23. pp. 5134-5143.
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abstract = "A series of dideoxyribonucleoside methylphosphonate analogues, dNpN and dNpNp, which contain a nonionic 3′-5′ methylphosphonyl internucleoside linkage were prepared. The two diastereoisomers, designated isomers 1 and 2, of each dimer differ in configuration of the methylphosphonate group and were separated by column chromatography. The diastereoisomers of each dimer have different conformations in solution as shown by ultraviolet hypochromicity data and their circular dichroism spectra. For example, dApA. isomer 1 is more highly stacked than isomer 2, although both isomers are less stacked than the dinucleoside monophosphate, dApA. The circular dichroism spectrum of isomer 1 is very similar to that of dApA, while the CD spectrum of isomer 2 shows a loss of molecular ellipticity, [θ], at 270 nm and a greatly diminished [θ] at 250 nm. These results suggest that the stacked bases of dApA isomer 1 tend to orient in an oblique manner, while those in isomer 2 tend to orient in a parallel manner. This interpretation is verified by the 1H NMR study of these dimers (L. S. Kan, D. M. Cheng, P. S. Miller, J. Yano, and P. O. P. Ts'o, unpublished experiments). Both diastereoisomers of dApA form 2U:1A and 2T:1A complexes with poly(U) and poly(dT), respectively. The higher Tm (Tm of poly(U)-isomer 1, 15.4 °C; Tm of poly(U)-isomer 2, 19.8 °C; Tm of poly(dT)-isomer 1, 18.7 °C; Tm of poly(dT)-isomer 2, 18.4 °C) values of these complexes vs. those of the corresponding dApA-polynucleotide complexes (Tm of poly(U)-dApA, 7.0 °C; Tm of poly(dT)-dApA, 9.2 °C) result from decreased charge repulsion between the nonionic dimer backbone and the negatively charged polymer backbone. The difference in conformations between dApA isomer 1 and dApA isomer 2 is reflected in the Tm of the isomer 1-poly(U) complex which is 4.4 °C lower than that of the isomer 2-poly(U) complex. Since these nonionic oligonucleotide analogues are taken up by cells in culture, they show promise as molecular probes for the function and structure of nucleic acids inside living cells.",
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N2 - A series of dideoxyribonucleoside methylphosphonate analogues, dNpN and dNpNp, which contain a nonionic 3′-5′ methylphosphonyl internucleoside linkage were prepared. The two diastereoisomers, designated isomers 1 and 2, of each dimer differ in configuration of the methylphosphonate group and were separated by column chromatography. The diastereoisomers of each dimer have different conformations in solution as shown by ultraviolet hypochromicity data and their circular dichroism spectra. For example, dApA. isomer 1 is more highly stacked than isomer 2, although both isomers are less stacked than the dinucleoside monophosphate, dApA. The circular dichroism spectrum of isomer 1 is very similar to that of dApA, while the CD spectrum of isomer 2 shows a loss of molecular ellipticity, [θ], at 270 nm and a greatly diminished [θ] at 250 nm. These results suggest that the stacked bases of dApA isomer 1 tend to orient in an oblique manner, while those in isomer 2 tend to orient in a parallel manner. This interpretation is verified by the 1H NMR study of these dimers (L. S. Kan, D. M. Cheng, P. S. Miller, J. Yano, and P. O. P. Ts'o, unpublished experiments). Both diastereoisomers of dApA form 2U:1A and 2T:1A complexes with poly(U) and poly(dT), respectively. The higher Tm (Tm of poly(U)-isomer 1, 15.4 °C; Tm of poly(U)-isomer 2, 19.8 °C; Tm of poly(dT)-isomer 1, 18.7 °C; Tm of poly(dT)-isomer 2, 18.4 °C) values of these complexes vs. those of the corresponding dApA-polynucleotide complexes (Tm of poly(U)-dApA, 7.0 °C; Tm of poly(dT)-dApA, 9.2 °C) result from decreased charge repulsion between the nonionic dimer backbone and the negatively charged polymer backbone. The difference in conformations between dApA isomer 1 and dApA isomer 2 is reflected in the Tm of the isomer 1-poly(U) complex which is 4.4 °C lower than that of the isomer 2-poly(U) complex. Since these nonionic oligonucleotide analogues are taken up by cells in culture, they show promise as molecular probes for the function and structure of nucleic acids inside living cells.

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