7-Deazapurin-2,6-diamine and 7-deazaguanine: Synthesis and property of 7-substituted nucleosides and oligonucleotides

Article abstract of DOI:10.1081/NCN-200060319

The synthesis of 7-substituted 7-deazaguanine and 7-deazaadenine ribonucleosides 1-2, the incorporation of 3a-d into oligonucleotides, and the stability of the corresponding duplexes and base discrimination are described. The pK_a values of 3-4

Full text of DOI:10.1081/NCN-200060319

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7-DEAZAPURIN-2,6-DIAMINE AND 7-DEAZAGUANINE:
SYNTHESIS AND PROPERTY OF 7-SUBSTITUTED
NUCLEOSIDES AND OLIGONUCLEOTIDES
Frank Seela a b , Xiaohua Peng a b & Xin Ming a b
a Laboratorium für Organische und Bioorganische Chemie , Institut für Chemie, Universitat
Osnabrück , Osnabrück, Germany
b Center for Nanotechnology (CeNTech) , Münster, Germany
Published online: 15 Nov 2011.
To cite this article: Frank Seela , Xiaohua Peng & Xin Ming (2005) 7-DEAZAPURIN-2,6-DIAMINE AND 7-DEAZAGUANINE:
SYNTHESIS AND PROPERTY OF 7-SUBSTITUTED NUCLEOSIDES AND OLIGONUCLEOTIDES, Nucleosides, Nucleotides and Nucleic
Acids, 24:5-7, 839-841, DOI: 10.1081/NCN-200060319
To link to this article: http://dx.doi.org/10.1081/NCN-200060319
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):839–841, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060319
7-DEAZAPURIN-2,6-DIAMINE AND 7-DEAZAGUANINE:
SYNTHESIS AND PROPERTY OF 7-SUBSTITUTED
NUCLEOSIDES AND OLIGONUCLEOTIDES
5
Frank Seela, Xiaohua Peng, and Xin Ming
Laboratorium fu¨r Organische und
Bioorganische Chemie, Institut fu¨r Chemie, Universita¨t Osnabru¨ck, Osnabru¨ck, Germany and
Center for Nanotechnology (CeNTech), Mu¨nster, Germany
5
The synthesis of 7-substituted 7-deazaguanine and 7-deazaadenine ribonucleosides 1–2, the
incorporation of 3a–d into oligonucleotides, and the stability of the corresponding duplexes and base
discrimination are described. The pKa values of 3–4 are determined.
Keywords 7-Deazapurine, 7-Substituents, Nucleosides, Oligonucleotides, Base-Pairing
INTRODUCTION
The frequent occurrence and unusual biological properties of 7-deazapurine
nucleosides have promoted studies towards the synthesis, biological activity
and incorporation into oligonucleotides of their chemically designed analogs.[1]
Earlier, the 7-halogenated 7-deazapurin-nucleosides related to dA or dG were
described and their base-pairing properties in oligonucleotides were studied. It
was shown that the 7-halogeno substituents enhance the DNA-duplex stability
compared to the unmodified counterparts.[2,3] Also, the 7-substituted nucleosides
1--4 as well as the phosphoramidites 5a--d and 6b--c were synthesized.[4,5]
Now, the synthesis of 1b--g and 2e--g is described, oligonucleotides containing
3a--d were prepared and their stability was studied in duplex DNA (Schemes 1
and 2).
Address correspondence to Frank Seela, Laboratorium fu¨r Organische und Bioorganische Chemie, Institut
fu¨r Chemie, Universit¨at Osnabru¨ck, Barbarastr. 7, Osnabru¨ck 49069, Germany.
839
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840
F. Seela, X. Peng, and X. Ming
SCHEME 1 Structure of nucleosides 1--6.
SCHEME 2 Synthesis of guanosine analogs 1b--d.
SCHEME 3 Palladium-catalyzed Sonogashira cross coupling reaction.
RESULTS AND DISCUSSION
Nucleobase-anion glycosylation reaction[6,7] was employed for the synthesis of
7-halogenated 7-deazaguanosines 1b--d. The 7-halogenated nucleobases 7a--c
served as starting materials[5] Glycosylation of 7a--c with halogenose 8 gave 7-
halogenated 7-deazapurine ribonucleosides 9a--c in 58--62% yield, which were
deprotected and treated with 2N NaOH to yield guanosine analogs 1b--d. The

F. Seela, X. Peng, and X. Ming
841
TABLE 1 Tm Values of Oligonucleotides Containing 3a--da
Duplex
Tm (°C)
5’-d(TAGGTCAATACT)-3’(11)
3’-d(ATCCAGTTATGA)-5’(12)
5’-d(TAGGTC3aATACT)-3’(13)
3’-d(ATCC3aGTT3aTGA)-5’(14)
5’-d(TAGGTC3bATACT)-3’(15)
3’-d(ATCC3bGTT3bTGA)-5’(16)
5’-d(TAGGTC3cATACT)-3’(17)
3’-d(ATCC3cGTT3cTGA)-5’(18)
5’-d(TAGGTC3dATACT)-3’(19)
3’-d(ATCC3dGTT3dTGA)-5’(20)
47
47
55
56
54
aMeasured in 0.1 M NaCl, 10 mM MgCl2, and 10 mM Na-
cacodylate buffer, pH 7.0, with 5 mM + 5 mM single-strand
concentration.
synthesis of 7-alkynyl-7-deazapurine nucleosides 1e--g and 2e--g was accom-
plished by palladium-catalyzed Sonogashira cross coupling reaction using the 7-
iodo-nucleoside 1d or 2d[8] as precursors (Scheme 3).
The synthesis of oligonucleotides containing 7-deazapurin-2,6-diamine nucleo-
sides 3a--d using the protocol of phosphoramidite chemistry was performed on an
ABI 392-08 synthesizer. The phosphoramidites 5a--d were used, which were
prepared as described.[5] The replacement of the dA residues by non-functionalized
nucleoside 3a has no influence on the duplex stability, while the incorporation of
the 7-halogenated derivatives 3b--d causes a significant increase of the Tm-values
(duplexes 15Á16, 17Á18 and 19Á20) (Table 1). For the standard duplex 11 Á 12
compounds 3b--d show a similar stabilizing effect. The Tm increase corresponds to
2.3--2.7°C per modification. A tridentate base pair is suggested for the 3a--d/dT
pair (motif I) (see Figure 1).
Hybridization experiments of oligonucleotides having 3a--d incorporated
opposite to the four canonical nucleosides show that nucleoside 3a forms rather
stable base pairs with dC and dG (duplexes 21Á14 and 22Á14) (Table 2),[9] while
the incorporation of 7-halogenated analogs 3b--d enhance the base discrimina-
tion. A bidentate base pair motif II is suggested for the mismatches 3a--d/dC
(see Figure 1).
FIGURE 1 Base-pair motifs related to dA-dT and mismatches dA-dC.