Jones G B, Davey C L, Jenkins T C, Kamal A, Kneale G G, Neidle S, Webster G D, Thurston D E
Division of Medicinal Chemistry, School of Pharmacy and Biomedical Sciences, Portsmouth Polytechnic, UK.
Anticancer Drug Des. 1990 Aug;5(3):249-64.
A series of 15 pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones has been synthesized and evaluated for in vitro DNA binding by thermal denaturation and fluorescence quenching studies with calf thymus (CT) DNA. The results indicate that two compounds of the series, 7 and 8, elevate the melting point of DNA by 2.9 +/- 0.6 and 3.3 +/- 0.8 K, respectively. Similarly, a significant quenching of the fluorescence of the dihydroxy analogue 8 was observed upon interaction with CT-DNA. As controls, the dihydroxy isomer 9 with the reverse stereochemistry at C2 and the non-substituted parent dilactam 12, failed to increase the DNA melting point or exhibit significant quenching upon interaction with DNA. In addition, preliminary experiments with GC- and AT-rich polymers suggest some sequence-dependent properties for dilactams 7 and 8. Overall, these results indicate a highly specific structural requirement for DNA binding. Molecular modelling with d(GTAGATC), d(GCAGATC) and d(GCGTAGC) duplex sequences has provided a model based on hydrogen bonding between the dihydroxy dilactam 8 and DNA, that rationalizes some of the results obtained. It is possible that the observed interactions represent the non-covalent (binding) component of the interaction of covalently-bonding anthramycin-type anti-tumour antibiotics with DNA.
已合成了一系列15种吡咯并[2,1-c][1,4]苯并二氮杂卓-5,11-二酮，并通过热变性和与小牛胸腺（CT）DNA的荧光猝灭研究对其体外DNA结合能力进行了评估。结果表明，该系列中的两种化合物，即7号和8号，分别使DNA的熔点升高了2.9±0.6K和3.3±0.8K。同样，在与CT-DNA相互作用时，观察到二羟基类似物8的荧光有显著猝灭。作为对照，在C2处具有相反立体化学的二羟基异构体9和未取代的母体双内酰胺12，在与DNA相互作用时未能提高DNA熔点或表现出显著猝灭。此外，用富含GC和AT的聚合物进行的初步实验表明，双内酰胺7和8具有一些序列依赖性特性。总体而言，这些结果表明DNA结合具有高度特异性的结构要求。用d(GTAGATC)、d(GCAGATC)和d(GCGTAGC)双链序列进行的分子建模提供了一个基于二羟基双内酰胺8与DNA之间氢键的模型，该模型使所获得的一些结果合理化。观察到的相互作用可能代表了共价结合的蒽环类抗肿瘤抗生素与DNA相互作用的非共价（结合）成分。
