Syntheses of 5-formyl- and 5-carboxyl-dC containing DNA oligos as potential oxidation products of 5-hydroxymethylcytosine in DNA - PubMed (original) (raw)

. 2011 Jul 1;13(13):3446-9.

doi: 10.1021/ol201189n. Epub 2011 Jun 7.

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Syntheses of 5-formyl- and 5-carboxyl-dC containing DNA oligos as potential oxidation products of 5-hydroxymethylcytosine in DNA

Qing Dai et al. Org Lett. 2011.

Abstract

To investigate the potential oxidation products of 5-hydroxymethylcytosine (5-hmC)-containing DNA, we present here efficient syntheses of 5-formyl- and 5-methoxycarbonyl-2'-deoxycytidine phosphoramidites. The 5-formyl group in III was easy to introduce and was compatible with phosphoramidite and DNA syntheses. An additional treatment of ODN1 with NaBH(4) produced the corresponding ODN2 quantitatively. Phosphoramidite V was also incorporated into DNA, and the methyl ester could be hydrolyzed under mild basic conditions to afford ODN3.

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Figures

Figure 1

Figure 1

A possible demethylation pathway of 5-mC through 5-hmC, 5-fC, and 5-caC

Figure 2

Figure 2

Structures of phosphoramidites for synthesis of DNA or RNA containing 5-fC or 5-caC modifications

Figure 3

Figure 3

(A) ODN1 was deprotected by treatment of 0.1 M K2CO3 in MeOH/H2O (1:1 v/v) at r.t. for 2 h. Peak a is the fully deprotected 5mer, [MH]+=1491. (B) ODN1 was deprotected by treatment of NH4OH at r.t. for 2 h, peak b is the proposed imine intermediate. (C) ODN1 obtained in the same way as (B) was dissoved in H2O and allowed to stand overnight at r.t., after which peak b disappeared. (D) ODN2 was deprotected by treatment of 0.1 M K2CO3 in MeOH/H2O (1:1 v/v) at r.t. for 2 h, peak c is the fully deprotected 5mer, [MH]+=1493. (E) ODN2 was deprotected by NH4OH at r.t. for 2 h. (F) ODN3 made from phoshoramidite IV was deprotected by treatment of 0.1 M K2CO3 in MeOH/H2O (1:1 v/v) at r.t. overnight. Peak d is the fully deprotected 5mer, [MH]+=1507; peak e is the 5mer with 5-trifluoroethoxycarbonyl-dC modification, [MH]+=1589. (G) ODN3 made from phoshoramidite V was deprotected by treatment of 0.1 M K2CO3 in MeOH/H2O (1:1 v/v) at r.t. overnight. (H) ODN3 made from phoshoramidite V was treated with NH4OH at r.t. for 2 h. Peak f is the 5mer with a 5-formamide modification, [MH]+=1506; peak g is the 5mer with a 5-methoxycarbonyl-dC modification, [MH]+ =1521.

Scheme 1

Scheme 1

Synthesis of phosphoramidite III

Scheme 2

Scheme 2

Synthesis of phosphoramidite V

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