New findings in the study on the intercalation of bisdaunorubicin and its monomeric analogues with naked and nucleus DNA
New findings in the study on the intercalation of bisdaunorubicin and its monomeric analogues with naked and nucleus DNA
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DOI：
10.1016/s0009-2797(03)00061-9
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发表时间：
2003-06-15
影响因子：
5.1
通讯作者：
Garnier-Suillerot, A
中科院分区：
文献类型：
--
作者：
Haj, HTB;Salerno, M;Garnier-Suillerot, A
DNA是蒽环类抗癌药物的靶分子。我们使用了新的蒽环类化合物，双柔红霉素(WP631)及其单体类似物(WP700系列)，看看药物与裸DNA和细胞内细胞核的结合亲和力是否与其细胞毒性有关。用圆二色谱(CD)和荧光光谱跟踪了蒽环类化合物与裸DNA和细胞核的相互作用。WP631与DNA以两种不同的化学计量比相互作用，即6：1和3：1碱基对(BP)/WP631分子(每个蒽环3：1和1.5：1)。单体柔红霉素(DNR)的氨基糖N结合在氨基和硝基取代的苯基上，代表WP631双嵌入器中存在的对二甲苯基连接物，与DNA的结合比DNR或WP631强得多。这些发现得到了K562细胞核结合药物的研究的支持。约70%的WP700在稳态时嵌入到细胞核DNA中，而DNR只有45%嵌入到细胞内。K562细胞对WP631的结合效率更低(接近20%)。WP700化合物在与DNA的结合、自缔合和细胞聚集方面非常相似，但在细胞毒性方面却有很大的不同。最有效的化合物是WP700系列的氨基-苄基衍生物。硝基-苄基化合物的毒性很低。即使它们与DNA结合的能力与氨基衍生物相似。所有数据的比较清楚地表明，药物的细胞毒性与其嵌入DNA的能力之间没有关系。(C)2003爱思唯尔爱尔兰科学有限公司。保留所有权利。
DNA is a target molecule for anthracycline anticancer drugs. We have used new anthracycline derivatives, bisdaunorubicin (WP631) and its monomeric analogues (WP700 serie), and look if there was a relation between the drug binding affinity to naked DNA and to cell nucleus in the cell with its cytotoxicity. Circular dichroism (CD) and fluorescence were used to follow the interaction of anthracycline derivatives with naked DNA and cell nuclei. WP631 interacts with DNA at two distinct stoichiometries, 6:1 and 3:1 base pair (bp)/WP631 molecule (3:1 and 1.5:1 per anthracycline rings). Monomeric daunorubicin (DNR) with its amino sugar N-bound to amino- and nitro-substituted benzyl moiety, representing p-xylenyl linker present in WP631 bisintercalator, is much more binding to DNA than DNR or WP631. These findings are supported by the study of drug binding by nuclei of K562 cells. Around 70% of WP700 intercalate to nucleus DNA in the steady-state, while only 45% of DNR intercalate DNA in the cell. The binding of WP631 by K562 cells is even less effective (similar to20%). WP700 compounds, which are very similar to each other in their binding to DNA, self-association and cell accumulation, differ very distinctly in their cytotoxicity power. The most effective compounds are amino-benzyl derivatives of WP700 series. The nitro-benzyl compounds have very low toxicity. even if they bind to DNA with similar power with that of the amino derivatives. The comparison of the all data clearly indicates no relation between cytotoxicity of the drug and its ability to intercalate DNA. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.