Jacobs Claire S, Dervan Peter B
Division of Chemistry and Chemical Engineering, The California Institute of Technology, 1200 E California Boulevard, Mail Code 164-30, Pasadena, California 91125, USA.
J Med Chem. 2009 Dec 10;52(23):7380-8. doi: 10.1021/jm900256f.
Pyrrole-imidazole (Py-Im) hairpin polyamides are a class of small molecule DNA minor groove binding compounds that have been shown to modulate endogenous gene expression in cell culture. Gene regulation by polyamides requires efficient cellular uptake and nuclear localization properties for candidate compounds. To further optimize Py-Im polyamides for enhanced potency in cell culture, a focused library of polyamides possessing various modifications at the C-terminus was synthesized and tested. Comparison of polyamide biological activity in two cell lines revealed tolerance for structural modifications and agreement in activity trends between cell lines. The use of an oxime linkage between the polyamide and an aromatic functionality on the C-terminus resulted in a approximately 20-fold increase in the potency of polyamides targeted to the androgen response element (ARE) in LNCaP cells by measuring AR-activated PSA expression.
吡咯-咪唑(Py-Im)发夹型聚酰胺是一类小分子DNA小沟结合化合物,已证实在细胞培养中可调节内源性基因表达。聚酰胺对基因的调控要求候选化合物具备高效的细胞摄取和核定位特性。为了进一步优化Py-Im聚酰胺以增强其在细胞培养中的效力,合成并测试了一个在C端具有各种修饰的聚酰胺聚焦文库。对两种细胞系中聚酰胺生物活性的比较揭示了对结构修饰的耐受性以及细胞系之间活性趋势的一致性。通过测量AR激活的PSA表达,在聚酰胺和C端的芳香官能团之间使用肟键,使得靶向LNCaP细胞中雄激素反应元件(ARE)的聚酰胺效力提高了约20倍。