Structural and solution chemistry of gold(I) and silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents
Structural and solution chemistry of gold(I) and silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents
复制标题
DOI：
10.1016/s0010-8545(99)00039-9
复制
发表时间：
1999-05-01
影响因子：
20.6
通讯作者：
McKeage, MJ
中科院分区：
文献类型：
--
作者：
Berners-Price, SJ;Bowen, RJ;McKeage, MJ
本文合成了Ag（I）和Au（I）与1，2-双（二-n-吡啶膦基）乙烷（dnpype）（n = 2，3，4）的1：2加合物，并用多核核磁共振、谱学表征了其溶液性质。该配合物是亲脂性Au（I）抗肿瘤配合物[Au（dppe）（2）]（+）的亲水性类似物，亲水性程度关键取决于N原子在吡啶环中的位置。d3型和d4型的配合物是简单的单体[M（d3型）（2）]（+）和[M（d4型）（2）]（+）物质，其具有比2-吡啶基配合物高得多的水溶性，2-吡啶基配合物在固态下结晶为二聚体[{M（d2型）（2）}（2）]（2+）。在溶液中，这些1：2的M：d 2型物质以单体、二聚体和三聚体（AE）或四聚体（Au）簇的平衡混合物的形式存在。已经评价了Au（I）和Ag（I）吡啶基膦络合物对一组培养的人卵巢癌细胞系的抗肿瘤活性。结果表明，化合物具有有效和选择性活性，IC 50值范围为0.18至1500 μ M。在抗肿瘤选择性程度和辛醇/水分配系数之间存在相关性，对于最亲水的络合物[Au（d4pype）（2）] Cl，发现具有最大的选择性（500倍范围）。母体化合物[Au（dppe）（2）]（+）的临床开发因肝毒性而停止，当暴露于分离的大鼠肝细胞时，亲水性吡啶基膦类似物的毒性显著低于[Au（dppe）（2）]（+）。本文还介绍了双齿吡啶基膦d2pype、d3pype和d4pype的简便合成方法。(C)1999年Elsevier Science S.A. All rights reserved.
The 1:2 adducts of Ag(I) and Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype) for n = 2, 3 and 4 have been synthesised and solution properties characterised by multinuclear NMR, spectroscopy. The complexes are hydrophilic analogs of the lipophilic Au(I) antitumour complex [Au(dppe)(2)](+) and the degree of hydrophilicity depends critically on the position of the N atom in the pyridyl ring. The complexes of d3pype and d4pype are simple monomeric [M(d3pype)(2)](+) and [M(d4pype)(2)](+) species which have a much higher water solubility than the 2-pyridyl complexes which crystallise in the solid state as dimeric [{M(d2pype)(2)}(2)](2+). In Solution these 1:2 M:d2pype species exist as equilibrium mixtures of monomeric,:dimeric and trimeric (AE) or tetrameric (Au) clusters, The Au(I) and Ag(I)pyridyl phosphine complexes have been evaluated for antitumour activity against a panel of cultured human ovarian carcinoma cell lines. The results show both potent and selective activity for the compounds with IC50 values ranging from 0.18 to 1500 mu M. There is a correlation between the degree of antitumour selectivity and the octanol/water partition coefficients with the greatest selectivity (500-fold range) found for the most hydrophilic complex [Au(d4pype)(2)]Cl. Clinical development of the parent compound [Au(dppe)(2)](+) was halted by liver toxicity and the hydrophilic pyridylphosphine analogs are significantly less toxic than [Au(dppe)(2)](+) when exposed to isolated rat hepatocytes. Convenient synthetic routes to the bidentate pyridyl phosphines d2pype, d3pype and d4pype are also described. (C) 1999 Elsevier Science S.A. All rights reserved.