通过与 G-四链体配体偶联重新编程苯丁酸氮芥的作用机制,Journal of the American Chemical Society

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通过与 G-四链体配体偶联重新编程苯丁酸氮芥的作用机制
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2014-04-08 , DOI: 10.1021/ja5014344
Marco Di Antonio ₁ , Keith I E McLuckie , Shankar Balasubramanian

Affiliation

氮芥苯丁酸氮芥 (Chl) 与双螺旋 DNA 产生共价加合物并抑制细胞增殖。在这些加合物中，链间交联 (ICL) 毒性最大，因为它们通过产生 DNA 双链断裂 (DSB) 来阻止复制。相反，由 Chl 产生的链内交联可通过专用的核苷酸切除修复 (NER) 酶进行有效修复。我们合成了一种将 Chl 与 G-四链体 (G4) 配体 PDS (PDS-Chl) 结合的新型交联剂。我们证明了 PDS-Chl 在低 μM 浓度下烷基化 G4 结构，对双链或单链 DNA 没有反应性。由于分子内 G4 来自单条 DNA 链，我们推断此类结构的优先烷基化可能会阻止 ICL 的产生，同时有利于链内交联。我们观察到 PDS-Chl 选择性地损害 NER 基因缺陷细胞的生长，但对参与双链断裂修复的修复基因 BRCA2 没有表现出任何敏感性。我们的研究结果表明，这种临床上重要的烷化剂的 G4 靶向改变了整体作用机制。这些见解可能会为干预以 NER 遗传损伤为特征的疾病（例如皮肤癌和睾丸癌）提供新的机会。

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Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a G-Quadruplex Ligand

The nitrogen mustard Chlorambucil (Chl) generates covalent adducts with double-helical DNA and inhibits cell proliferation. Among these adducts, interstrand cross-links (ICLs) are the most toxic, as they stall replication by generating DNA double strand breaks (DSBs). Conversely, intrastrand cross-links generated by Chl are efficiently repaired by a dedicated Nucleotide Excision Repair (NER) enzyme. We synthesized a novel cross-linking agent that combines Chl with the G-quadruplex (G4) ligand PDS (PDS-Chl). We demonstrated that PDS-Chl alkylates G4 structures at low μM concentrations, without reactivity toward double- or single-stranded DNA. Since intramolecular G4s arise from a single DNA strand, we reasoned that preferential alkylation of such structures might prevent the generation of ICLs, while favoring intrastrand cross-links. We observed that PDS-Chl selectively impairs growth in cells genetically deficient in NER, but did not show any sensitivity to the repair gene BRCA2, involved in double-stranded break repair. Our findings suggest that G4 targeting of this clinically important alkylating agent alters the overall mechanism of action. These insights may inspire new opportunities for intervention in diseases specifically characterized by genetic impairment of NER, such as skin and testicular cancers.

更新日期：2014-04-08

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