Kieltyka Roxanne, Englebienne Pablo, Moitessier Nicolas, Sleiman Hanadi
Department of Chemistry, McGill University, Montreal, QC, Canada.
Methods Mol Biol. 2010;608:223-55. doi: 10.1007/978-1-59745-363-9_14.
Telomerase inhibition through guanine quadruplex sequestration by small-molecule drugs is of great current interest as an anticancer strategy. G-quadruplexes (GQs) can be formed at the guanine-rich sequences found at the end of the telomere. They possess a large electron-rich pi-surface which is favorable for the binding of electron-poor small molecules. Small molecules binding to GQs can sequester the telomere ends and inhibit the enzyme telomerase, which is expressed in cancer cells and absent in normal somatic cells. Transition-metal complexes present a myriad of geometries and numerous ligand coordination environments and allow for modular syntheses for development of compound libraries to target GQs. We have demonstrated the size of the pi-surface, binding selectivity and affinity of phenanthroimidazole platinum (II) complexes PtPIX(en)2PF (6) (-) (X = naphthyl, phenyl and en = ethylenediamine) and metallosupramolecular complexes [Pt(4,4'-bpy)(en)] (4) (8+) 8PF (6) (-) (where bpy = bipyridine) to GQs can be readily tuned and assayed through a number of biophysical techniques.
通过小分子药物螯合鸟嘌呤四链体来抑制端粒酶，作为一种抗癌策略，目前备受关注。在端粒末端富含鸟嘌呤的序列处可形成鸟嘌呤四链体（GQs）。它们具有一个大的富电子π表面，有利于与缺电子小分子结合。与GQs结合的小分子可螯合端粒末端并抑制端粒酶，端粒酶在癌细胞中表达而在正常体细胞中不存在。过渡金属配合物呈现出多种几何形状和众多配体配位环境，并允许进行模块化合成以开发针对GQs的化合物库。我们已经证明，通过多种生物物理技术，可以很容易地调节和测定菲咯咪唑铂（II）配合物PtPIX(en)2PF(6)(-)（X = 萘基、苯基，en = 乙二胺）和金属超分子配合物Pt(4,4'-bpy)(en)(8+)8PF(6)(-)（其中bpy = 联吡啶）对GQs的π表面大小、结合选择性和亲和力。
