Spectroscopic and calorimetric studies on the DNA recognition of pyrrolo[2,1-c][1,4]benzodiazepine hybrids
Spectroscopic and calorimetric studies on the DNA recognition of pyrrolo[2,1-c][1,4]benzodiazepine hybrids
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DOI：
10.1016/j.bmc.2008.11.033
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发表时间：
2009-01-15
影响因子：
3.5
通讯作者：
Weisz, Klaus
中科院分区：
文献类型：
--
作者：
Rettig, Michael;Kamal, Ahmed;Weisz, Klaus
用DNA熔解实验、紫外和荧光滴定、圆二色性光谱和等温滴定量热法研究了两个由烷基化吡咯并[2，1-c][1，4]苯并二氮杂卓（PBD）与萘酰亚胺或苯基苯并咪唑生色团组成的杂合配体与DNA的结合.两种杂交体的结合导致显著的热稳定性，对于双链体，DNA解链温度增加高达40 ° C，这允许PBD部分共价连接到其小沟中的鸟嘌呤碱基。CD光谱测量表明，药物的萘酰亚胺部分通过嵌入相互作用。相比之下，PBD-苯并咪唑杂合物结合在DNA小沟中，偏好（A，T）（4）G序列。而这两个配体的结合是双稳态驱动的，并与负熵相关联，苯并咪唑杂合物表现出一个不太有利的结合焓，这是由一个更有利的熵项相平衡时，相比的萘二甲酰亚胺杂合物。(C)2008爱思唯尔有限公司保留所有权利。
DNA binding of two hybrid ligands composed of an alkylating pyrrolo[2,1-c][1,4] benzodiazepine (PBD) moiety tethered to either a naphthalimide or a phenyl benzimidazole chromophore was studied by DNA melting experiments, UV and fluorescence titrations, CD spectroscopy and isothermal titration calorimetry (ITC). Binding of both hybrids results in a remarkable thermal stabilization with an increase of DNA melting temperatures by up to 40 degrees C for duplexes that allow for a covalent attachment of the PBD moiety to guanine bases in their minor groove. CD spectroscopic measurements suggest that the naphthalimide moiety of the drug interacts through intercalation. In contrast, the PBD-benzimidazole hybrid binds in the DNA minor groove with a preference for (A, T)(4)G sequences. Whereas the binding of both ligands is enthalpy-driven and associated with a negative entropy, the benzimidazole hybrid exhibits a less favourable binding enthalpy that is counterbalanced by a more favourable entropic term when compared to the naphthalimide hybrid. (C) 2008 Elsevier Ltd. All rights reserved.