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首页> 美国卫生研究院文献>ACS Omega >Indolizine-Based Scaffolds as Efficient and VersatileTools: Application to the Synthesis of Biotin-Tagged AntiangiogenicDrugs
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Indolizine-Based Scaffolds as Efficient and VersatileTools: Application to the Synthesis of Biotin-Tagged AntiangiogenicDrugs

机译：高效高效的基于吲哚嗪的支架工具：在合成生物素标记的抗血管生成中的应用毒品

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摘要

We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug–biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug–protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223-interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheseson the mode of action of this antiangiogenic drug.
机译：我们描述了基于荧光吲哚嗪核心与各种正交基团（胺，酯，肟，炔烃等）衍生的多功能支架的设计和优化。为了展示一种在生物学中作为工具的应用，该支架被用于制备药物-生物素结合物，然后将其固定在亲和素-琼脂糖上进行亲和层析。更具体地说，选择了其作用机理尚不清楚的抗血管生成药物COB223作为概念验证药物。通过亲和柱洗脱细胞裂解物后观察到的对蛋白质的药物选择性区分，该结合物被具有生物活性的COB223或与结构相关的非活性类似物（COB236）进行了功能化，明确表明吲哚利嗪核心的存在并不限制药物-蛋白质相互作用，并证实了吲哚利嗪支架的有用性。此外，从人胎盘提取物中分离出与COB223相互作用的蛋白质，揭示了属于调控RNA结合蛋白家族的意外蛋白靶标，这为新的假设开辟了道路这种抗血管生成药物的作用方式。

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