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Triple-Helix Formation by Pyrimidine Oligonucleotides Containing Nonnatural Nucleosides with Extended Aromatic Nucleobases: Intercalation from the major groove as a method for recognizing C·G and T·A base pairs

Lehmann, Thomas E. and Greenberg, William A. and Liberles, David A. and Wada, Carol K. and Dervan, Peter B. (1997) Triple-Helix Formation by Pyrimidine Oligonucleotides Containing Nonnatural Nucleosides with Extended Aromatic Nucleobases: Intercalation from the major groove as a method for recognizing C·G and T·A base pairs. Helvetica Chimica Acta, 80 (6). pp. 2002-2022. ISSN 0018-019X. https://resolver.caltech.edu/CaltechAUTHORS:20160510-100445777

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Abstract

The sequence-specific recognition of double-helical DNA by oligonucleotide-directed triple helix formation is limited primarily to purine tracts. To identify potential lead compounds which are able to extend the sequence repertoire of triple helical complexes, we designed two carbocyclic nucleosides with nucleobases attached via amide bonds. N5-[(1R, 2S, 3R, 4R)-3-hydroxy-4-(hydroxymethyl)-2-methoxycyclopentyl]-2-{[(1H-pyrrol-2-yl)carbonyl]-amino}thiazole-5-carboxamide (L1) and 2-benzamido-N^5-[(1R, 2S, 3R, 4R)-3-hydroxy-4-(hydroxymethyl)-2-methoxycyclopentyl]thiazole-5-carboxamide (L2) were synthesized and incorporated into pyrimidine oligonucleotides. The 2-(trimethylsilyl)ethoxymethyl (SEM) protecting group for the 1H-pyrrole NH was found to be compatible with DNA solid-phase synthesis of pyrimidine Oligonucleotides. By quantitative DNase I footprinting analysis, both nonnatural nucleosides L1 and L2 showed preferential binding of pyrimidine over purine bases: L1/2·(C·G) ≈ L1/2·(T · A) > L1/2·(G·C) ≈ L1/2·(A · T). Comparison with the previously reported nonnatural nucleosides with extended aromatic nucleobases 1-(2-deoxy-β-d-ribofuranosyl)-4-(3-benzamidophenyl)-imidazole (D3) and N^4-[6-(benzamido)pyridin-2-yl]-2′-deoxycytidine (^(bz)M) suggests that the observed binding selectivity C · G ≈ T · A > G · C ≈ A · T for the nucleoside analogs L1, L2, D3, and ^(bz)M is derived from sequence-specific intercalation with preferential stacking of their nucleobases over pyrimidine · purine Watson-Crick base pairs.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/hlca.19970800618DOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/hlca.19970800618/abstractPublisherArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1997 Verlag GmbH & Co. KGaA, Weinheim. We are grateful for financial support from the Office of Naval Research, the National Institutes of Health, the Beckman Institute, and the Studienstiftung des deutschen Volkes for an BASF postdoctoral fellowship to T. E. L.
Funders:
Funding AgencyGrant Number
Office of Naval Research (ONR)UNSPECIFIED
NIHUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Studienstiftung des deutschen VolkesUNSPECIFIED
Issue or Number:6
Record Number:CaltechAUTHORS:20160510-100445777
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160510-100445777
Official Citation:Lehmann, T. E., Greenberg, W. A., Liberles, D. A., Wada, C. K. and Dervan, P. B. (1997), Triple-Helix Formation by Pyrimidine Oligonucleotides Containing Nonnatural Nucleosides with Extended Aromatic Nucleobases: Intercalation from the major groove as a method for recognizing C·G and T · A base pairs. HCA, 80: 2002–2022. doi: 10.1002/hlca.19970800618
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66870
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 20:23
Last Modified:26 Nov 2019 11:15

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