Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes.
Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes.
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DOI：
10.1016/j.jinorgbio.2012.10.007
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发表时间：
2013-02
影响因子：
3.9
通讯作者：
A. P. Neves;Michelle X.G. Pereira;E. Peterson;R. Kipping;Maria D. Vargas;F. Silva-Jr;J. Carneiro;Nicholas P. Farrell
中科院分区：
文献类型：
--
作者：
A. P. Neves;Michelle X.G. Pereira;E. Peterson;R. Kipping;Maria D. Vargas;F. Silva-Jr;J. Carneiro;Nicholas P. Farrell
研究了几种对癌细胞具有中高细胞毒性的2-羟基-3-（氨基甲基）-1,4-萘醌曼尼希碱HL的氯基和氨基Pt2+配合物，探讨了它们的DNA结合模式、体外DNA链断裂、拓扑异构酶（Topo I）抑制机制和细胞积累。DNA模型碱基研究表明，复合物1a [Pt(HL1)Cl2]能够与9-乙基鸟嘌呤（9-EtG）和5 ' -GMP共价结合。1H NMR和质谱研究表明，两种氯化物都被9-EtG配体取代，而5 ' -GMP由于位阻作用只能取代一个氯基配体。氯离子Pt2+复合物[Pt(HL)Cl2]在前列腺（PC-3）和黑色素瘤（MDA-MB-435）细胞系中高度积累，能够在体外诱导DNA链断裂，并通过催化模式抑制Topo I。另一方面，游离的2-羟基-3-（氨基甲基）-1,4-萘醌HL和氨基Pt2+配合物[Pt(L−)(NH3)2] no3既不会导致DNA链断裂，也不会表现出强烈的DNA相互作用，但后者也被发现是Topo I在100μM范围内的催化抑制剂。因此，Mannich碱HL与“PtCl2”片段的配位极大地影响了前配体的化学和生物物理性质，从而改善了它们的DNA结合特性，并产生了切割DNA和催化抑制Topo i的化合物。最后，游离（未配合的）2-羟基-3-（氨基甲基）-1,4-萘醌所表现出的高细胞毒性可能与它们在溶液中的分解有关，这在Pt2+配合物中没有观察到。
Several chlorido and amino Pt2+complexes of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases HL exhibiting moderate to high cytotoxicity against cancer cell lines were studied in order to investigate their modes of DNA binding, in vitro DNA strand breaks, mechanism of topoisomerase (Topo I) inhibition and cellular accumulation. DNA model base studies have shown that complex 1a [Pt(HL1)Cl2] was capable of binding covalently to 9-ethylguanine (9-EtG) and 5′-GMP.1H NMR and mass spectrometry studies have shown that both chlorides were substituted by 9-EtG ligands, whereas 5′-GMP was able to replace only one chlorido ligand, due to steric hindrance. The chlorido Pt2+complexes [Pt(HL)Cl2] highly accumulate in prostate (PC-3) and melanoma (MDA-MB-435) cell lines, being able to induce DNA strand breaks in vitro and inhibit Topo I by a catalytic mode. On the other hand, the free 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones HL and the amino Pt2+complexes [Pt(L−)(NH3)2]NO3neither cause DNA strand breakage nor exhibit strong DNA interaction, nevertheless the latter were also found to be catalytic inhibitors of Topo I at 100μM. Thus, coordination of the Mannich bases HL to the “PtCl2” fragment substantially affects the chemical and biophysical properties of the pro-ligands, leading to an improvement of their DNA binding properties and generating compounds that cleave DNA and catalytically inhibit Topo I. Finally, the high cytotoxicity exhibited by the free (uncomplexed) 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones might be associated with their decomposition in solution, which is not observed for the Pt2+complexes.