作者:Yasmin Mawani、Jacqueline F. Cawthray、Stanley Chang、Kristina Sachs-Barrable、David M. Weekes、Kishor M. Wasan、Chris Orvig
DOI:10.1039/c2dt32373g
日期:——
Lanthanide ions, Ln(III), are of interest in the treatment of bone density disorders because they are found to accumulate preferentially in bone (in vivo), have a stimulatory effect on bone formation, and exhibit an inhibitory effect on bone degradation (in vitro), altering the homeostasis of the bone cycle. In an effort to develop an orally active lanthanide drug, a series of 3-hydroxy-4-pyridinone ligands were synthesized and eight of these ligands (H1 = 3-hydroxy-2-methyl-1-(2-hydroxyethyl)-4-pyridinone, H2 = 3-hydroxy-2-methyl-1-(3-hydroxypropyl)-4-pyridinone, H3 = 3-hydroxy-2-methyl-1-(4-hydroxybutyl)-4-pyridinone, H4 = 3-hydroxy-2-methyl-1-(2-hydroxypropyl)-4-pyridinone, H5 = 3-hydroxy-2-methyl-1-(1-hydroxy-3-methylbutan-2-yl)-4-pyridinone, H6 = 3-hydroxy-2-methyl-1-(1-hydroxybutan-2-yl)-4-pyridinone, H7 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H8 = 1-carboxyethyl-3-hydroxy-2-methyl-4-pyridinone) were coordinated to Ln3+ (Ln = La, Eu, Gd, Lu) forming stable tris-ligand complexes (LnL3, L = 1−, 2−, 3−, 4−, 5−, 6−, 7− and 8−). The dissociation (pKan) and metal ligand stability constants (log βn) of the 3-hydroxy-4-pyridinones with La3+ and Gd3+ were determined by potentiometric titrations, which demonstrated that the 3-hydroxy-4-pyridinones form stable tris-ligand complexes with the lanthanide ions. One phosphinate-EDTA derivative (H5XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was also synthesized and coordinated to Ln3+ (Ln = La, Eu, Lu), forming the potassium salt of [Ln(XT)]2−. Cytotoxicity assays were carried out in MG-63 cells; all the ligands and metal complexes tested were observed to be non-toxic to this cell line. Studies to investigate the toxicity, cellular uptake and apparent permeability (Papp) of the lanthanide ions were conducted in Caco-2 cells where it was observed that [La(XT)]2− had the greatest cell uptake. Binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral hydroxyapatite (HAP) are high, as well as moderate to strong for the free ligand with the bone mineral depending on the functional group.
镧系离子Ln(III)在治疗骨密度紊乱方面具有研究价值,因为它们在体内优先积累于骨组织中,对骨形成有刺激作用,并在体外表现出对骨降解的抑制作用,从而改变骨周期的稳态。为了开发一种口服活性的镧系药物,合成了一系列3-羟基-4-吡啶酮配体,其中的八个配体(H1 = 3-羟基-2-甲基-1-(2-羟基乙基)-4-吡啶酮,H2 = 3-羟基-2-甲基-1-(3-羟基丙基)-4-吡啶酮,H3 = 3-羟基-2-甲基-1-(4-羟基丁基)-4-吡啶酮,H4 = 3-羟基-2-甲基-1-(2-羟基丙基)-4-吡啶酮,H5 = 3-羟基-2-甲基-1-(1-羟基-3-甲基丁烷-2-基)-4-吡啶酮,H6 = 3-羟基-2-甲基-1-(1-羟基丁烷-2-基)-4-吡啶酮,H7 = 1-羧甲基-3-羟基-2-甲基-4-吡啶酮,H8 = 1-羧乙基-3-羟基-2-甲基-4-吡啶酮)与Ln3+(Ln = La, Eu, Gd, Lu)配位,形成了稳定的三配体复合物(LnL3,L = 1−, 2−, 3−, 4−, 5−, 6−, 7− 和 8−)。通过电位滴定法测定了3-羟基-4-吡啶酮与La3+和Gd3+的解离(pKan)和金属配体稳定常数(log βn),结果表明3-羟基-4-吡啶酮与镧系离子形成了稳定的三配体复合物。同时,合成了一种磷酸酯-EDTA衍生物(H5XT = 双[[双(羧甲基)氨基]甲基]磷酸酯),并与Ln3+(Ln = La, Eu, Lu)配位,形成了[Ln(XT)]2−的钾盐。在MG-63细胞中进行了细胞毒性实验,结果显示所有测试的配体和金属复合物对这种细胞系均无毒性。在Caco-2细胞中研究了镧系离子的毒性、细胞摄取和表观渗透性(Papp),观察到[La(XT)]2−具有最大的细胞摄取量。自由镧系离子(Ln = La, Gd 和 Lu)、金属复合物以及自由3-羟基-4-吡啶酮与骨矿物质羟基磷灰石(HAP)的结合亲和力都很高,而自由配体与骨矿物质的结合亲和力则取决于功能团,表现为中等到强。