Design and synthesis of a new class of membrane-permeable triazaborolopyridinium fluorescent probes.
Design and synthesis of a new class of membrane-permeable triazaborolopyridinium fluorescent probes.
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DOI：
10.1021/ja2005175
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发表时间：
2011-05-04
影响因子：
15
通讯作者：
Arterburn, Jeffrey B.
中科院分区：
文献类型：
--
作者：
Hapuarachchige, Sudath;Montano, Gilbert;Ramesh, Chinnasamy;Rodriguez, Delany;Henson, Lauren H.;Williams, Casey C.;Kadavakkollu, Samuel;Johnson, Dennis L.;Shuster, Charles B.;Arterburn, Jeffrey B.
由 2-肼基吡啶 (HPY) 腙合成了一类新型荧光三氮杂硼并吡啶化合物，并评估其作为活细胞成像应用的潜在染料。 HPY 染料体积小，吸收/发射特性可通过吡啶基或腙取代基的变化进行调节，并提供良好的光物理特性，具有大斯托克斯位移和对溶剂或 pH 值通常不敏感的特点。 HPY缀合物的中性电荷、细胞膜渗透性以及对水溶性的有利相对影响与现有荧光染料互补，并为受体靶向小分子探针的开发提供了优势。通过开发一类新型半胱氨酸衍生的 HPY 结合显像剂来评估这种潜力，该显像剂用于驱动蛋白纺锤体蛋白 (KSP)，该蛋白在有丝分裂过程中在细胞质中表达，是一个有前途的化疗靶点。使用生化和基于细胞的表型测定以及活细胞成像对具有中性 HPY 或带电 AlexaFluor 染料的缀合物进行比较，这些缀合物可作为 KSP 马达的有效选择性变构抑制剂。这些结果证明了 HPY 染料部分作为细胞内蛋白质靶标探针组分的有效性，并强调了染料结构在确定细胞进入途径中的重要性，以及小分子缀合物作为成像剂的整体性能。
A new class of fluorescent triazaborolopyridinium compounds was synthesized from hydrazones of 2-hydrazinylpyridine (HPY) and evaluated as potential dyes for live cell imaging applications. The HPY dyes are small, absorption/emission properties are tunable through variation of pyridyl or hydrazone substituents, and offer favorable photophysical characteristics featuring large Stokes shifts and general insensitivity to solvent or pH. The neutral charge, cell membrane permeability and favorable relative influences on the water solubility of HPY conjugates are complementary to existing fluorescent dyes, and offer advantages for the development of receptor-targeted small molecule probes. This potential was assessed through the development of a new class of cysteine-derived HPY-conjugate imaging agents for the kinesin spindle protein (KSP) that is expressed in the cytoplasm during mitosis, and is a promising chemotherapeutic target. Conjugates possessing the neutral HPY or charged AlexaFluor dyes that function as potent, selective allosteric inhibitors of the KSP motor were compared using biochemical and cell-based phenotypic assays, and live-cell imaging. These results demonstrate the effectiveness of the HPY dye moiety as components of probes for an intracellular protein target, and highlight the importance of dye structure in determining the pathway of cell-entry, and the overall performance of small molecule conjugates as imaging agents.
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