Topologically constrained bifunctional intercalators: DNA intercalation by a macrocyclic bisacridine
Topologically constrained bifunctional intercalators: DNA intercalation by a macrocyclic bisacridine
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拓扑约束双功能嵌入剂：大环双吖啶嵌入 DNA
DOI：
10.1021/ja00199a047
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发表时间：
1989
影响因子：
15
通讯作者：
T. Fairley
中科院分区：
文献类型：
--
作者：
S. Zimmerman;C. Lamberson;M. Cory;T. Fairley
合成了一种拓扑结构新颖的DNA双功能嵌入剂4，并将其与单嵌入剂9-氨基吖啶（6）和精胺双吖啶（5）的DNA结合进行了比较。以4-溴甲基-9-氯吖啶为原料，与7V，7V ′-双（2-巯基乙基）琥珀酰胺和碱反应，合成了水溶性大环双吖啶4。将所得二氯化物转化为相应的双（9-苯氧基吖啶），其与精胺四盐酸盐反应形成大环双吖啶4。在4与小牛胸腺DNA磷酸盐的1：10比例下，测量到> 40 ° C的Δ Tm，这表明高结合亲和力。使用超声处理的小牛胸腺DNA的螺旋延伸的粘度分析给出了化合物4和5的斜率，其远大于6的斜率。加入DNA后，在4的吸收光谱中观察到异色性位移。这些异染性位移与在相同条件下5和6所示的类似。添加4到封闭的环状超螺旋质粒DNA（1 - 6）删除和逆转的超螺旋测量的粘度性质的变化的质粒。大环化合物4和已知的双嵌入剂精胺双吖啶（5）的结合数据的相似性表明，前者也作为双功能嵌入剂与DNA结合。十多年来，人们一直致力于DNA多嵌体的合成和研究，主要是基于它们作为有效抗肿瘤剂的潜力。此外，这些化合物可以作为探测DNA结构的实验工具。已经发表了超过100种DNA双嵌入剂的研究，它们的结构在长度、刚性和连接链的电荷以及嵌入发色团本身上不同。2 34在这些双插层中不变的是它们的拓扑结构。这些合成的DNA“受体”都是非大环结构的
A topologically novel DNA bifunctional intercalator, 4, has been synthesized and its DNA binding compared with the binding of the monointercalator 9-aminoacridine (6) and spermine bisacridine (5), a known bisintercalator. Water-soluble macrocyclic bisacridine 4 was synthesized by reaction of 4-(bromomethyl)-9-chloroacridine with 7V, 7V'-bis (2-mercaptoethyl) succinamide and base. The resulting dichloride was converted to the corresponding bis (9-phenoxyacridine), which reacted with spermine tetrahydrochloride to form macrocyclic bisacridine 4. At a 1: 10 ratio of 4 to calf thymus DNA phosphate, a ATm of> 40 C was measured, which indicates a high binding affinity. Viscometric analysis of helix extension using sonicated calf thymus DNA gave slopes for compounds 4 and 5 that were much greater than that for 6. Metachromic shifts were observed in the absorption spectra of 4 upon addition of DNA. These metachromic shifts were similar to those shown by 5 and 6 under the same conditions. Additions of 4 to closed circular supercoiled plasmid DNA (1 6) removed and reversed the supercoiling as measured by the changes in the viscometric properties of the plasmid. Thesimilarities in binding data obtained for macrocycle 4 and the knownbisintercalator spermine bisacridine (5) indicate that the former also binds to DNA as a bifunctional intercalator.For more than a decade extensive effort has been directed toward the synthesis and study of DNA polyintercalators, primarily based on their potential as effective antitumor agents. 1 Additionally, these compounds can serve as experimental tools to probe DNA structure. Studies of more than 100 DNA bis-intercalators have been published, their structures differing in length, rigidity, and charge of the linking chain and by the intercalating chromophore itself. 2 34What is invariant in these bis-intercalators is their topology. These synthetic “receptors” for DNA have been exclusively of the nonmacrocyclic structure