Papi Francesco, Bazzicalupi Carla, Ferraroni Marta, Massai Lara, Bertrand Benoît, Gratteri Paola, Colangelo Donato, Messori Luigi
Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino (FI, Italy.
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco, Salute del Bambino (NEUROFARBA), Laboratory of Molecular Modeling Cheminformatics & QSAR, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI, Italy.
Chemistry. 2017 Oct 4;23(55):13784-13791. doi: 10.1002/chem.201702854. Epub 2017 Sep 6.
Physicochemical methods have been used to investigate interactions occurring in solution between the dicarbene gold(I) complex [Au(9-methylcaffein-8-ylidene) ]BF (AuNHC) and a human telomeric DNA sequence, namely Tel23. Circular dichroism measurements allow identification of the conformational changes experienced by Tel23 upon interaction with AuNHC, and the respective binding stoichiometries and constants were determined. Computational studies provide a good link between previous crystallographic results of the same system and the present solution data, offering an exhaustive description of the inherent noncovalent metallodrug-DNA interactions. Remarkably, we found that a preformed AuNHC/Tel23 adduct is capable of producing strong and selective inhibition of the enzyme telomerase. The latter feature is mechanistically relevant and might account for the conspicuous in vitro anticancer properties of the investigated dicarbene gold(I) complex.
物理化学方法已被用于研究二卡宾金（I）配合物[Au(9-甲基咖啡因-8-亚基)]BF（AuNHC）与人类端粒DNA序列Tel23在溶液中发生的相互作用。圆二色性测量能够识别Tel23与AuNHC相互作用时所经历的构象变化，并确定各自的结合化学计量和常数。计算研究在同一体系先前的晶体学结果与当前的溶液数据之间建立了良好的联系，对固有的非共价金属药物 - DNA相互作用进行了详尽描述。值得注意的是，我们发现预先形成的AuNHC/Tel23加合物能够对端粒酶产生强烈且选择性的抑制作用。后一特性在机制上具有相关性，可能解释了所研究的二卡宾金（I）配合物显著的体外抗癌特性。
