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Formaldehyde-activated WEHI-150 induces DNA interstrand crosslinks with unique structural features.
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2019-12-14 , DOI: 10.1016/j.bmc.2019.115260
Paul P Pumuye 1 , Benny J Evison 1 , Shyam K Konda 2 , J Grant Collins 2 , Celine Kelso 3 , Jelena Medan 4 , Brad E Sleebs 5 , Keith Watson 6 , Don R Phillips 1 , Suzanne M Cutts 1
Affiliation  

Mitoxantrone is an anticancer anthracenedione that can be activated by formaldehyde to generate covalent drug-DNA adducts. Despite their covalent nature, these DNA lesions are relatively labile. It was recently established that analogues of mitoxantrone featuring extended side-chains terminating in primary amino groups typically yielded high levels of stable DNA adducts following their activation by formaldehyde. In this study we describe the DNA sequence-specific binding properties of the mitoxantrone analogue WEHI-150 which is the first anthracenedione to form apparent DNA crosslinks mediated by formaldehyde. The utility of this compound lies in the versatility of the covalent binding modes displayed. Unlike other anthracenediones described to date, WEHI-150 can mediate covalent adducts that are independent of interactions with the N-2 of guanine and is capable of adduct formation at novel DNA sequences. Moreover, these covalent adducts incorporate more than one formaldehyde-mediated bond with DNA, thus facilitating the formation of highly lethal DNA crosslinks. The versatility of binding observed is anticipated to allow the next generation of anthracenediones to interact with a broader spectrum of nucleic acid species than previously demonstrated by the parent compounds, thus allowing for more diverse biological activities.

中文翻译:

甲醛激活的WEHI-150诱导具有独特结构特征的DNA链间交联。

米托蒽醌是一种抗癌蒽酮,可以被甲醛激活以产生共价药物-DNA加合物。尽管它们具有共价性质,但这些DNA损伤相对不稳定。最近确定的是,具有延长的侧链终止于伯氨基的米托蒽醌类似物在被甲醛激活后通常可产生高水平的稳定DNA加合物。在这项研究中,我们描述了米托蒽醌类似物WEHI-150的DNA序列特异性结合特性,它是第一个形成甲醛介导的明显DNA交联的蒽二酮。该化合物的用途在于所显示的共价结合模式的多功能性。与迄今为止描述的其他炭疽病不同,WEHI-150可以介导不依赖于与鸟嘌呤N-2相互作用的共价加合物,并且能够在新的DNA序列上形成加合物。此外,这些共价加合物与DNA结合了一个以上的甲醛介导的键,从而促进了高致死性DNA交联的形成。预期所观察到的结合的多功能性将使下一代蒽二酮能与先前由母体化合物证明的更广泛的核酸种类相互作用,从而允许更多样化的生物学活性。
更新日期:2019-12-17
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