Synthesis, structure, biological activity, and DNA binding of platinum(II) complexes of the type trans-[PtCl2(NH3)L] (L = planar nitrogen base).: Effect of L and cis/trans isomerism on sequence specificity and unwinding properties observed in globally platinated DNA
Synthesis, structure, biological activity, and DNA binding of platinum(II) complexes of the type trans-[PtCl2(NH3)L] (L = planar nitrogen base).: Effect of L and cis/trans isomerism on sequence specificity and unwinding properties observed in globally platinated DNA
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DOI：
10.1021/ic981181x
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发表时间：
1999-07-26
影响因子：
4.6
通讯作者：
Farrell, N
中科院分区：
文献类型：
--
作者：
Bierbach, U;Qu, Y;Farrell, N
为了建立反式铂几何结构的抗肿瘤活化的基本结构要求，已经合成了通式[PtCl 2（NH 3）L]（L =平面N供体）的络合物。反式异构体trans-[PtCl 2（NH3）（quinoline）]（3）、trans-[PtCl 2（NH3）（thiazole）]（5）、trans-[PtCl 2（NH3）（benzothiazole）]（7）和trans-[PtCl 2（NH3）（isoquinoline）]（8）以及顺式异构体cis-[PtCl 2（NH3）（quinoline）]（4）和cis-[PtCl 2（NH3）（thiazole）]（6）通过H-1 NMR和分析数据表征。此外，测定了3、5、7和8的晶体结构：3，单斜晶系，P2（1）/c，a = 8.414（1）埃，B = 12.373（3）埃，c = 21.266（3）埃，β = 96.78（1）度，V = 2198.3（6）埃（3），Z = 8; 5，单斜晶系，P2（1）/n，a = 8.815（4）埃，B = 19.917（8）埃，c = 14.498（5）埃，β = 103.30（3）度，V = 2477（2）埃（3），Z = 12; 7，单斜晶系，P2（1）/c，a = 8.150（4）埃，B = 23.196（9）埃，c = 11.297（7）埃，β = 90.94（4）度，V = 2135.3（2）埃（3），Z = 8; 8，单斜晶系，C2/c，a = 19.043（4）埃，B = 8.570（2）埃，c = 29.127（6）埃，β_ = 111.59（2）度，V = 4420（2）埃（3），Z = 16。在所有情况下，Pt配位平面和L相互扭曲，平面之间的角度为50-68度。庞大的喹啉在3产生分子内空间应变证明了一个短的，非键合Pt…2.77埃的H8（quin）接触和伴随的扭曲Pt-N-quin-C键角。反式配合物3、5、7和8在顺铂敏感的L1210白血病中显示出比反式-[PtCl 2（NH 3）（2）]（2）显著更高的细胞毒性，其中3和5与相应的顺式异构体4和6一样有效。此外，平面配体的存在极大地增强了所有化合物在对顺铂（cis-[PtCl 2（NH3）（2）]（1）具有抗性的细胞中的活性。复杂的几何形状和L在1-7与DNA的结合中起重要作用。对于合成的poly（dG）·poly（dC）和poly（dG-dC）·poly（dG-dC），结合亲和力的顺序（r（B），药物与核苷酸的比率）分别为2 > 1 > 6 > 5 > 4 > 7 > 3和5 > 6 > 7 > 3 > 2 > 1 > 4。此外，3和7，携带大的平面配体，是非常有效的解旋负超螺旋，封闭的环状pUC 19 DNA（φ = 15度和17度，分别）。L对靶DNA的结构影响的后果与可能的生物学后果进行了讨论。
In order to establish fundamental structural requirements for the antitumor activation of the trans-platinum geometry, complexes of the general formulas [PtCl2(NH3)L] (L = planar N donor) have been synthesized. The trans isomers, trans-[PtCl2(NH3)(quinoline)] (3), trans-[PtCl2(NH3)(thiazole)] (5), trans-[PtCl2(NH3)(benzothiazole)] (7), and trans-[PtCl2(NH3)(isoquinoline)] (8) and the cis isomers cis-[PtCl2(NH3)(quinoline)] (4) and cis-[PtCl2(NH3)(thiazole)] (6) were characterized by H-1 NMR and analytical data. In addition, the crystal structures of 3, 5, 7, and 8 were determined: 3, monoclinic, P2(1)/c, with a = 8.414(1) Angstrom, b = 12.373(3) Angstrom, c = 21.266(3) Angstrom, beta = 96.78(1)degrees, V = 2198.3(6) Angstrom(3), and Z = 8; 5, monoclinic, P2(1)/n, with a = 8.815(4) Angstrom, b = 19.917(8) Angstrom, c = 14.498(5) Angstrom, beta = 103.30(3)degrees, V = 2477(2) Angstrom(3), and Z = 12; 7, monoclinic, P2(1)/c, with a = 8.150(4) Angstrom, b = 23.196(9) Angstrom, c = 11.297(7) Angstrom, beta = 90.94(4)degrees, V = 2135.3(2) Angstrom(3), and Z = 8; 8, monoclinic, C2/c, with a = 19.043(4) Angstrom, b = 8.570(2) Angstrom, c = 29.127(6) Angstrom, beta_ = 111.59(2)degrees, V = 4420(2) Angstrom(3), and Z = 16. In all cases, the Pt coordination plane and L are mutually twisted with angles between planes of 50-68 degrees. Bulky quinoline in 3 produces intramolecular steric strain as evidenced by a short, nonbonding Pt ... H8(quin) contact of 2.77 Angstrom and concomitantly distorted Pt-N-quin-C bond angles. The trans complexes 3, 5, 7, and 8 showed a significantly higher cytotoxicity in cisplatin-sensitive L1210 leukemia than trans-[PtCl2(NH3)(2)] (2), with 3 and 5 being as potent as the corresponding cis isomers 4 and 6. In addition, the presence of the planar ligand greatly enhanced the activity of all of the compounds in cells resistant to cisplatin, cis-[PtCl2(NH3)(2)] (1). Complex geometry and L play an important role in the binding of 1-7 to DNA. For synthetic poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) the order of binding affinities (r(b), drug-to-nucleotide ratio) was 2 > 1 > 6 > 5 > 4 > 7 > 3 and 5 > 6 > 7 > 3 > 2 > 1 > 4, respectively. Furthermore, 3 and 7, carrying large planar ligands, were remarkably effective at unwinding negatively supercoiled, closed circular pUC19 DNA (phi = 15 degrees and 17 degrees, respectively). The consequences of structural effects caused by L on target DNA with respect to possible biological consequences are discussed.