Synthesis, DNA binding, and cytotoxicity of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates

被引：40

作者：

Hsin, Ling-Wei ^{[1
]}

Wang, Hui-Po ^{[2
]}

Kao, Pi-Hung ^{[1
]}

Lee, On ^{[1
]}

Chen, Wan-Ru ^{[1
]}

Chen, Hung-Wei ^{[1
]}

Guh, Jih-Hwa ^{[1
]}

Chan, Ya-Ling ^{[1
]}

His, Chin-Ping ^{[1
]}

Yang, Ming-Show ^{[2
]}

Li, Tsai-Kun ^{[3
,4
]}

Lee, Chieh-Hua ^{[3
,4
]}

机构：

[1] Natl Taiwan Univ, Coll Med, Inst Pharmaceut Sci, Taipei 10018, Taiwan

[2] Chang Gung Univ, Inst Nat Prod, Tao Yuan 333, Taiwan

[3] Natl Taiwan Univ, Coll Med, Dept Microbiol, Taipei 10018, Taiwan

[4] Natl Taiwan Univ, Coll Med, Grad Inst Microbiol, Taipei 10018, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 02期

关键词：

anthraquinone; DNA binding; DNA affinity; conjugate; cytotoxicity;

D O I：

10.1016/j.bmc.2007.10.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1006 / 1014

页数：9

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