Synthesis, DNA binding, and cytotoxicity of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates
Synthesis, DNA binding, and cytotoxicity of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates
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DOI：
10.1016/j.bmc.2007.10.012
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发表时间：
2008-01-15
影响因子：
3.5
通讯作者：
Lee, Chieh-Hua
中科院分区：
文献类型：
--
作者：
Hsin, Ling-Wei;Wang, Hui-Po;Lee, Chieh-Hua
设计合成了两个系列的1,4-双（2-氨基乙胺）蒽醌-氨基酸偶联物（BACs），即阿美醌(AT)-氨基酸偶联物（AACs）和米托蒽醌(MX)-氨基酸偶联物（MACs）。通过DNA热变性实验评价bac与DNA的结合。在该系列中，蛋氨酸取代的BACs的DNA结合最弱，赖氨酸取代的BACs的T-m值最高。测定BACs对MCF-7、NCI-H460、SF-268和PC-3细胞系生长的抑制能力。L-Met-MAC 16和L-Lys-MAC 20是最有效的生长抑制剂。MAC 16的细胞毒性高于MX，但T-m明显低于MX。与MAC 16相比，L-Lys-MAC 20的T-m高于MX。这些数据表明met - bac具有不同的药理学特征，其中稳定DNA的能力与杀死癌细胞的能力不同，与AT和MX不同。mac16细胞毒性的主要机制可能是TOP2中毒。因此，mac16可能为新一代蒽醌类抗肿瘤药物的开发提供线索。(C) 2007 Elsevier Ltd.版权所有。
Two series of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates (BACs), ametantrone (AT)-amino acid conjugates (AACs) and mitoxantrone (MX)-amino acid conjugates (MACs), were designed and synthesized. The DNA binding of BACs was evaluated by DNA thermal denaturation experiment. In the series, the methionine-substituted BACs had the weakest DNA binding, while the lysine-substituted BACs had the highest T-m values. The abilities of BACs to inhibit the growth of MCF-7, NCI-H460, SF-268, and PC-3 cell lines were determined. L-Met-MAC 16 and L-Lys-MAC 20 were the most potent growth inhibitors. MAC 16 was more cytotoxic than MX, whereas the T-m of MAC 16 was much lower than that of MX In contrast to MAC 16, L-Lys-MAC 20 demonstrated higher T-m than MX. These data suggested that Met-BACs possessed a different pharmacological profile, in which the ability to stabilize DNA is not parallel to the ability to kill cancer cells, from that of AT and MX. The primary mechanism of cytotoxicity for MAC 16 was most likely through TOP2 poisoning. Therefore, MAC 16 may provide a lead for the development of novel generations of anthraquinone-type antitumor agents. (C) 2007 Elsevier Ltd. All rights reserved.