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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Flow Cytometric Evaluation of Novel 12,3,4-Tetrahydroisoquinoline Conformationally Constrained Analogues of Nitrobenzylmercaptopurine Riboside (NBMRP) Designed for Probing Its Conformation When Bound to the es Nucleoside Transporter
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Synthesis and Flow Cytometric Evaluation of Novel 12,3,4-Tetrahydroisoquinoline Conformationally Constrained Analogues of Nitrobenzylmercaptopurine Riboside (NBMRP) Designed for Probing Its Conformation When Bound to the es Nucleoside Transporter

机译：硝基苄基巯基嘌呤核糖核苷（NBMRP）的新型12,3,4-四氢异喹啉构象约束类似物的合成及流式细胞术评价，旨在结合到核苷转运蛋白上探索其构象

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摘要

Novel regioisomers of conformationally constrained analogues of the potent es nucleoside transporter ligand, nitrobenzylmercaptopurine riboside (NBMPR), designed for probing its bound (bioactive) conformation, were synthesized and evaluated as es transporter ligands by flow cytometry. Purine 6-position 5,6,7, or 8-nitro-1,2,3,4-tetrahydroisoquinolypurine ribosides, in which the nitrobenzyl moiety in NBMPR has been locked into the nitro-1,2,3,4-tetrahydroisoquinoline system, were synthesized by reaction of the appropriate nitro-1,2,3,4-tetrahydroisoquinoline with 6-chloropurine ribosinde. Flow cytometry was performed using 5-(SAENTA)-X8-fluorescein as the competitive ligand. A high degree of variation in the es transporter binding capacity of the target compounds was observed, with the K_i values ranging from 0.45 nM for the most tightly bound compound (4) to 300 nM for the least tightly bound compound (5). The K_i of NBMPR was 0.70 nM, a little higher than that of compound 4. Compound 4 is the isomer that has the nitro group in the best orientation at the es transporter binding site compared to the other three compounds, 2, 3 and 5.
机译：合成了有效的es核苷转运蛋白配体的构象受约束类似物的新型区域异构体，硝基硝基巯基嘌呤核糖核苷（NBMPR），用于探测其结合的（生物活性）构象，并通过流式细胞术评估为es转运蛋白配体。嘌呤6位5,6,7或8-硝基-1,2,3,4-四氢异喹啉嘌呤核苷，其中NBMPR中的硝基苄基部分已被锁定在硝基1,2,3,4-四氢异喹啉系统中通过适当的硝基-1,2,3,4-四氢异喹啉与6-氯嘌呤核糖苷的反应合成α-，。使用5-（SAENTA）-X8-荧光素作为竞争性配体进行流式细胞术。观察到目标化合物的es转运蛋白结合能力发生高度变化，K_i值范围从最紧密结合的化合物（4）的0.45 nM到最不紧密结合的化合物（5）的300 nM。 NBMPR的K_i为0.70 nM，略高于化合物4的K_i。与其他三个化合物2、3和5相比，化合物4是在es转运蛋白结合位点具有最佳取向硝基的异构体。

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