新型结合物双[（（4-溴苯基）氨基）喹唑啉]，一种EGFR-TK配体，具有荧光Ru（II）-联吡啶复合物，在线粒体中具有特定的亚细胞定位。,Molecular Pharmaceutics

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新型结合物双[（（4-溴苯基）氨基）喹唑啉]，一种EGFR-TK配体，具有荧光Ru（II）-联吡啶复合物，在线粒体中具有特定的亚细胞定位。
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-09-25 , DOI: 10.1021/acs.molpharmaceut.9b00608
Rashid Ilmi ₁ , Eleni Tseriotou , Panayiota Stylianou ₁ , Yiota A Christou ₁ , Iakovia Ttofi , Nikolas Dietis , Costas Pitris , Andreani D Odysseos ₁ , Savvas N Georgiades

Affiliation

表皮生长因子受体（EGFR）是抗癌研究的关键目标，其在恶性肿瘤中的异常功能与关键细胞过程中的严重异常有关，包括细胞周期进程，增殖，分化和存活。跨膜或易位至线粒体和/或细胞核的EGFR突变体通常表现出对EGFR抑制剂的抗性。无创成像和定量EGFR的能力为EGFR相关恶性肿瘤的检测，监测和治疗提供了新颖的方法。当前的研究旨在提供一种新型的治疗剂，该试剂结合了荧光成像特性和EGFR抑制作用。这是通过结合内部开发的突变型EGFR-TK的（（4-溴苯基）氨基）喹唑啉抑制剂实现的，选自聚焦氨基喹唑啉文库，具有[Ru（bipyridine）3] 2+荧光团。使用具有（+）-可电离位点的三乙二醇衍生的二氨基接头来连接两个功能部分，从而提供两个空前的Ru偶联物，其Ru络合物的化学计量为1：1和2：1的氨基喹唑啉与Ru络合物（mono-quinazoline-Ru-conjugate）和双喹唑啉-Ru-共轭物）。通过荧光成像发现保留必不可少的抑制活性的双-喹唑啉-Ru-共轭物被Uppsala 87恶性神经胶质瘤（IV级恶性神经胶质瘤）细胞有效摄取。荧光成像研究和时间分辨的荧光共振能量转移研究表明，结合物的特定亚细胞分布与靶向线粒体的染料相符，提示偶联物的线粒体定位以及与线粒体易位形式的EGFR的潜在关联。在线粒体分离测定中，通过特定浓度的双喹唑啉-Ru偶联物进一步证实了线粒体的定位。

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A Novel Conjugate of Bis[((4-bromophenyl)amino)quinazoline], a EGFR-TK Ligand, with a Fluorescent Ru(II)-Bipyridine Complex Exhibits Specific Subcellular Localization in Mitochondria.

The epidermal growth factor receptor (EGFR) is a key target in anticancer research, whose aberrant function in malignancies has been linked to severe irregularities in critical cellular processes, including cell cycle progression, proliferation, differentiation, and survival. EGFR mutant variants, either transmembrane or translocated to the mitochondria and/or the nucleus, often exhibit resistance to EGFR inhibitors. The ability to noninvasively image and quantify EGFR provides novel approaches in the detection, monitoring, and treatment of EGFR-related malignancies. The current study aimed to deliver a new theranostic agent that combines fluorescence imaging properties with EGFR inhibition. This was achieved via conjugation of an in-house-developed ((4-bromophenyl)amino)quinazoline inhibitor of mutant EGFR-TK, selected from a focused aminoquinazoline library, with a [Ru(bipyridine)3]2+ fluorophore. A triethyleneglycol-derived diamino linker featuring (+)-ionizable sites was employed to link the two functional moieties, affording two unprecedented Ru conjugates with 1:1 and 2:1 stoichiometry of aminoquinazoline to the Ru complex (mono-quinazoline-Ru-conjugate and bis-quinazoline-Ru-conjugate, respectively). The bis-quinazoline-Ru-conjugate, which retains an essential inhibitory activity, was found by fluorescence imaging to be effectively uptaken by Uppsala 87 malignant glioma (grade IV malignant glioma) cells. The fluorescence imaging study and a time-resolved fluorescence resonance energy transfer study indicated a specific subcellular distribution of the conjugate that coincides with that of a mitochondria-targeted dye, suggesting mitochondrial localization of the conjugate and potential association with mitochondria-translocated forms of EGFR. Mitochondrial localization was further documented by the specific concentration of the bis-quinazoline-Ru-conjugate in a mitochondrial isolation assay.

更新日期：2019-09-26

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