Department of Chemistry, Georgia State University, PO Box 4098, Atlanta, GA 30302, USA.
Eur J Med Chem. 2012 Aug;54:647-59. doi: 10.1016/j.ejmech.2012.06.017. Epub 2012 Jun 21.
Protein arginine methylation regulates multiple biological processes. Deregulation of protein arginine methyltransferase (PRMT) activities has been observed in many disease phenotypes. Small molecule probes that target PRMTs with strong affinity and selectivity can be used as valuable tools to dissect biological mechanisms of arginine methylation and establish the role of PRMT proteins in a disease process. In this work, we report synthesis and evaluation of a class of carbocyanine compounds containing indolium, benz[e]indolium or benz[c,d]indolium heterocyclic moieties that bind to the predominant arginine methyltransferase PRMT1 and inhibit its methyltransferase activity at low micromolar potencies. In particular, the developed molecules have long wavelength colorimetric and fluorometric photoactivities, which can be used for optical and near-infrared fluorescence imaging in cells or biological tissues. Together, these new chemical probes have potential application in PRMT studies both as enzyme inhibitors and as fluorescent dyes for microscope imaging.
蛋白质精氨酸甲基化调控多种生物学过程。在许多疾病表型中，观察到蛋白质精氨酸甲基转移酶（PRMT）活性失调。对 PRMT 具有强亲和力和选择性的小分子探针可用作有价值的工具，用于剖析精氨酸甲基化的生物学机制，并确定 PRMT 蛋白在疾病过程中的作用。在这项工作中，我们报告了一类含有吲哚鎓、苯并[e]吲哚鎓或苯并[c,d]吲哚鎓杂环部分的碳菁化合物的合成和评价，这些化合物与主要的精氨酸甲基转移酶 PRMT1 结合，并以低微摩尔效力抑制其甲基转移酶活性。特别是，所开发的分子具有长波长比色和荧光光活性，可用于细胞或生物组织中的光学和近红外荧光成像。总之，这些新的化学探针具有作为酶抑制剂和显微镜成像荧光染料在 PRMT 研究中的潜在应用。
