Structure-activity relationships and DNA binding properties of apoptosis inducing cytotoxic rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS3
Structure-activity relationships and DNA binding properties of apoptosis inducing cytotoxic rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS3
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DOI：
10.1016/j.jinorgbio.2009.01.008
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发表时间：
2009-05-01
影响因子：
3.9
通讯作者：
Sheldrick, William S.
中科院分区：
文献类型：
--
作者：
Bieda, Ruth;Ott, Ingo;Sheldrick, William S.
通过用适当的多吡啶配体（pp）处理RhCl_3中心点~ 3 H（2）O，然后用1，4，7-三硫杂环壬烷（tap）处理双吡啶并[3，2-d：2 '，3'-f]喹喔啉（dpq），双吡啶并[2，3-a：2 '，3'-c]吩嗪（dppz），制备了[RhCl（pp）（[9]aneS（3））]（2+）[（pp）= 2，2 '-bpy（bpy），2，2'-b嘧啶（bpm），1，10-菲咯啉（phen），1，10-菲咯啉（phen）]型Rh（Ⅲ）多吡啶配合物。通过CD和UV/可见光谱以及凝胶电泳研究了多吡啶配合物与DNA的相互作用。dpq复合物6在黑暗中切割DNA，但需要UV照射来诱导bpy复合物2的核酸酶活性。而2[IC 50值：12.8（+/- 0.2）和4.4（+/-0.1）μ M]对MCF-7和HT-29细胞的细胞毒性显著高于4 [IC 50值：36.3（+/-6.0）和72.2（+/-8.0）]，系列4/6/7的络合物的活性与多吡啶配体的大小直接相关，如它们对HT-29细胞的各自的IC 50值72.2（+/-8.0）、20.9（+/-2.8）和7.4（+/-2.2）所证明的。富氮配体bpm（3）[IC 50值：1.7（+/-0.5）和1.9（+/-0.1）μ M]和tap（5）[IC 50值：11.5（+/-0.6）和7.6（+/-4.8）μ M]的络合物比它们的bpy和phen对应物2和4有效得多。淋巴瘤（BJAB）细胞孵育1小时后乳酸脱氢酶释放的测量表明，对于最具活性的化合物3和7，非特异性坏死可忽略不计。在72小时孵育后检测到BJAB细胞通过DNA片段化的特异性细胞死亡凋亡，并且淋巴瘤细胞中线粒体膜电位的显著损失表明参与了内在途径。(C)2009 Elsevier Inc. All rights reserved.
The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS(3))](2+) [(pp) = 2,2'-bipyridine (bpy), 2,2'-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), dipyrido[2,3-a:2',3'-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl3 center dot 3H(2)O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2[IC50 values: 12.8 (+/- 0.2) and 4.4 (+/-0.1) mu M] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC50 values: 36.3 (+/-6.0) and 72.2 (+/-8.0)], the activity of complexes it) the series 4/6/7 correlates directly with the size of the polypyricly] ligand, as documented by their respective IC50 values of 72.2 (+/-8.0), 20.9 (+/-2.8) and 7.4 (+/-2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC50 values: 1.7 (+/-0.5) and 1.9 (+/-0.1) mu M] and tap (5) [IC50 values: 11.5 (+/-0.6) and 7.6 (+/-4.8) mu M] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1 h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved. (C) 2009 Elsevier Inc. All rights reserved.