Redesigning the DNA-targeted chromophore in platinum-acridine anticancer agents: a structure-activity relationship study.
Redesigning the DNA-targeted chromophore in platinum-acridine anticancer agents: a structure-activity relationship study.
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DOI：
10.1002/chem.201404845
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发表时间：
2014-12-01
影响因子：
4.3
通讯作者：
Bierbach, Ulrich
中科院分区：
文献类型：
--
作者：
Pickard, Amanda J.;Liu, Fang;Bartenstein, Thomas F.;Haines, Laura G.;Levine, Keith E.;Kucera, Gregory L.;Bierbach, Ulrich
铂-吖啶杂合药物在耐药非小细胞肺癌（NSCLC）中显示出低纳摩尔效力，但在体内具有高全身毒性。为了减少这些药物的混杂遗传毒性并改善其药理学性质，使用模块化构建点击筛选方法来评估含有不同碱度的截短和延长发色团的20种杂合药物的小文库。选择的衍生物进行再合成，并在五个NSCLC细胞系代表大细胞，鳞状细胞和腺癌进行测试。7-氨基苯并[c]吖啶被鉴定为混合剂（P1-B1）中有前途的支架，其在几种DNA修复熟练和p53突变癌症模型中保持亚微摩尔活性，同时与母体铂-吖啶（P1-A1）相比，在小鼠中显示出32倍的耐受性改善。研究了基于吖啶和苯并[c]吖啶的类似物在NCI-H460细胞中产生的分布和DNA/RNA加合物水平（共聚焦显微镜，ICP-MS），以及它们结合G-四链体形成DNA序列的能力（CD光谱，HR-ESMS）。与P1-A1相比，P1-B1是一种遗传毒性更低、耐受性更好、靶点选择性更强的杂合药物。
Platinum–acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1–A1.
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影响因子：
7.3
作者：
Ding, Song;Qiao, Xin;Kucera, Gregory L.;Bierbach, Ulrich
通讯作者：
Bierbach, Ulrich
影响因子：
5.3
作者：
Fujii, Tetsuya;Toyooka, Shinichi;Date, Hiroshi
通讯作者：
Date, Hiroshi
DOI：
10.1111/j.1349-7006.1992.tb01959.x
发表时间：
1992-05
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Akaboshi M;Kawai K;Maki H;Akuta K;Ujeno Y;Miyahara T
通讯作者：
Miyahara T
影响因子：
15
作者：
Dai, Jixun;Carver, Megan;Hurley, Laurence H.;Yang, Danzhou
通讯作者：
Yang, Danzhou
影响因子：
2.9
作者：
Ghosh, Saptaparni;Kar, Anirban;Dasguptat, Dipak
通讯作者：
Dasguptat, Dipak