Effect of substituents of alloxazine derivatives on the selectivity and affinity for adenine in AP-site-containing DNA duplexes.

Using the DNA duplex containing an AP site (5'-TCC AGX GCA AC-3'/3'-AGG TCN CGT TG-5', X = AP site, N = A, T, C, or G), we have found that 2-amino-4-hydroxypteridine (pterin) selectively binds to guanine (G), and that the enhanced binding affinity for G is obtained by its methylated derivative 2-amino-6,7-dimethyl-4-hydroxypteridine (diMe pteridine). Similarly, among the cytosine (C)-selective ligands, i.e. derivatives of 2-amino-1,8-naphthyridine, a trimethyl-substituted derivative (2-amino-5,6,7-trimethyl-1,8-naphthyridine) selectively binds to C with a strong binding affinity of 1.9 × 10(7) M(-1). In the case of lumazine derivatives, pteridine-2,4(1H,3H)-dione (lumazine) binds to adenine (A), and its methylated derivative, 6,7-dimethylpteridine-2,4(1H,3H)-dione (diMe lumazine) strongly binds to A with enhanced binding affinity, keeping the same base-selectivity. On the other hand, the benzo-annelated (with phenyl ring, 2.4 Å) derivative of lumazine, benzo[g]pteridine-2,4(1H,3H)-dione (alloxazine), can bind to A selectively, whereas its methylated ligand, 7,8-dimethylbenzo[g]pteridine-2,4(1H,3H)-dione (lumichrome) selectively binds to thymine (T) over A, C and G. Methyl-substituted lumichrome derivatives show moderate binding affinities for target nucleobases. The changes in the base-selectivity and binding affinities are discussed in detail with respect to the substituents of these ligands, considering hydrogen-bonding patterns, size of AP site and stacking interactions.

Citation

Burki Rajendar, Arivazhagan Rajendran, Zhiqiang Ye, Eriko Kanai, Yusuke Sato, Seiichi Nishizawa, Marek Sikorski, Norio Teramae. Effect of substituents of alloxazine derivatives on the selectivity and affinity for adenine in AP-site-containing DNA duplexes. Organic & biomolecular chemistry. 2010 Nov 7;8(21):4949-59

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PMID: 20820650

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