Synthesis, DNA-binding and antiproliferative properties of diarylquinolizinium derivatives.
Synthesis, DNA-binding and antiproliferative properties of diarylquinolizinium derivatives.
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DOI：
10.1039/d0ob02298e
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发表时间：
2021-01
影响因子：
3.2
通讯作者：
Roberta Bortolozzi;H. Ihmels;R. Schulte;C. Stremmel;G. Viola
中科院分区：
文献类型：
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作者：
Roberta Bortolozzi;H. Ihmels;R. Schulte;C. Stremmel;G. Viola
合成了10个2，7-和2，8-二芳基喹啉类化合物，并研究了它们的DNA结合和细胞毒活性。除了一个硝基取代的衍生物外，所有的二芳基喹啉离子都与DNA有足够的亲和力(2×104M-1-2×105M-1)。光度、荧光、旋光滴定和Flow-LD分析表明，配体主要以插层方式与双链DNA结合，但根据配体与DNA的比例，也观察到与某些衍生物的沟槽结合和主链缔合。通过对非肿瘤细胞和选定的癌细胞的细胞毒性和抗增殖性能的测试，以及细胞周期分析和Annexin-V检测，进一步研究了该化合物的生物活性。值得注意的是，在苯基的4位上携带给体官能团的底物显示出很强的抗增殖活性，在某些情况下，通过在白血病和实体瘤中非常低的微摩尔甚至亚微摩尔水平的生长抑制GI50来量化。
A series of ten 2,7- and 2,8-diarylquinolizinium derivatives was synthesized and their DNA-binding and cytotoxic properties were investigated. Except for one nitro-substituted derivative all tested diarylquinolizinium ions bind to DNA with sufficient affinity (2 × 104 M-1-2 × 105 M-1). It was shown with photometric, fluorimetric and polarimetric titrations as well as with flow-LD analysis that the ligands bind mainly by intercalation to duplex DNA, however, depending on the ligand-DNA ratio, groove binding and backbone association were also observed with some derivatives. The biological activity was further investigated with tests of cytotoxicity and antiproliferative properties towards non-tumor cells and selected cancer cells, along with cell cycle analysis and an annexin-V assay. Notably, substrates that carry donor-functionalities in the 4-position of the phenyl substituents revealed a strong, and in some cases selective, antiproliferative activity as quantified by the growth inhibition, GI50, at very low micromolar and even submicromolar level both in leukemia and solid tumors.