结合三联体识别的最佳特性：BQQ-新霉素共轭物的合成与核酸结合

Combining the best in triplex recognition: synthesis and nucleic acid binding of a BQQ-neomycin conjugate.

作者信息

Arya Dev P, Xue Liang, Tennant Paul

机构信息

Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, USA.

出版信息

J Am Chem Soc. 2003 Jul 9;125(27):8070-1. doi: 10.1021/ja034241t.

DOI:10.1021/ja034241t

PMID:12837054

Abstract

Synthesis of a BQQ-neomycin conjugate is reported. The conjugate combines two ligands, one known to intercalate triplexes (BQQ) and another known to bind in the triplex groove (neomycin). The conjugate stabilizes T.A.T, as well as mixed base DNA triplex, better than neomycin, BQQ, or a combination of both. The conjugate selectively stabilizes the triplex (in the presence of physiological salt concentrations), with as little as 4 muM of the ligand leading to a DeltaTm of >60 degrees C. Competition dialysis studies show a clear preference for the drug binding to triplex DNA/RNA over the duplex/single strand structures. Modeling studies suggest a structure of neomycin bound to the larger W-H (Watson-Hoogsteen) groove with BQQ intercalated between the triplex bases.

摘要

报道了一种BQQ-新霉素缀合物的合成。该缀合物结合了两种配体，一种已知可嵌入三链体（BQQ），另一种已知可结合在三链体凹槽中（新霉素）。与新霉素、BQQ或两者的组合相比，该缀合物能更好地稳定T.A.T以及混合碱基DNA三链体。该缀合物（在生理盐浓度存在下）能选择性地稳定三链体，低至4 μM的配体就能导致ΔTm >60℃。竞争透析研究表明，该药物明显更倾向于结合三链体DNA/RNA而非双链/单链结构。建模研究表明，新霉素的结构是结合在较大的W-H（沃森-霍格施泰因）凹槽中，BQQ嵌入在三链体碱基之间。