Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Bioorganic Research Institute, Suntory Foundation for Life Sciences (SUNBOR), 8-1-1 Seikadai, Seika, Soraku, Kyoto, 619-0284, Japan.
Angew Chem Int Ed Engl. 2018 Nov 19;57(47):15405-15409. doi: 10.1002/anie.201808054. Epub 2018 Oct 25.
DNA-DNA cross-linking agents constitute an important family of chemotherapeutics that non-specifically react with endogenous nucleophiles and therefore exhibit undesirable side effects. Here we report a cationic Sondheimer diyne derivative "DiMOC" that exhibits weak, reversible intercalation into duplex DNA (K =15 μm) where it undergoes tandem strain-promoted cross-linking of azide-containing DNA to give DNA-DNA interstrand crosslinks (ICLs) with an exceptionally high apparent rate constant k =2.1×10 m s . This represents a 21 000-fold rate enhancement as compared the reaction between DIMOC and 5-(azidomethyl)-2'-deoxyuridine (AmdU) nucleoside. As single agents, 5'-bispivaloyloxymethyl (POM)-AmdU and DiMOC exhibited low cytotoxicity, but highly toxic DNA-DNA ICLs were generated by metabolic incorporation of AmdU groups into cellular DNA, followed by treatment of the cells with DiMOC. These results provide the first examples of intercalation-enhanced bioorthogonal chemical reactions on DNA, and furthermore, the first strain-promoted double click (SPDC) reactions inside of living cells.
DNA-DNA 交联剂是一类重要的化疗药物，它们非特异性地与内源性亲核试剂反应，因此表现出不良的副作用。在这里，我们报告了一种阳离子 Sondheimer 二炔衍生物“DiMOC”，它弱而可逆地插入双链 DNA 中（K = 15 μm），在其中它经历串联应变促进的含叠氮化物的 DNA 的交联，从而产生具有异常高的表观速率常数 k = 2.1×10 m s 的 DNA-DNA 链间交联（ICLs）。与 DIMOC 和 5-(叠氮甲基)-2'-脱氧尿苷（AmdU）核苷之间的反应相比，这代表了 21000 倍的速率增强。作为单剂，5'-双特戊酰氧甲基（POM）-AmdU 和 DiMOC 表现出低细胞毒性，但通过将 AmdU 基团代谢掺入细胞 DNA 中，然后用 DiMOC 处理细胞，可产生高度有毒的 DNA-DNA ICLs。这些结果提供了在 DNA 上进行的增强型生物正交化学反应的第一个实例，并且是活细胞内的第一个应变促进双点击（SPDC）反应。
