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New tetrahydroisoquinoline-based P-glycoprotein modulators: decoration of the biphenyl core gives selective ligands†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-04-03 00:00:00 , DOI: 10.1039/c8md00075a Marialessandra Contino 1, 2, 3, 4 , Stefano Guglielmo 4, 5, 6, 7 , Maria Grazia Perrone 1, 2, 3, 4 , Roberta Giampietro 1, 2, 3, 4 , Barbara Rolando 4, 5, 6, 7 , Antonio Carrieri 1, 2, 3, 4 , Daniele Zaccaria 1, 2, 3, 4 , Konstantin Chegaev 4, 5, 6, 7 , Vanessa Borio 4, 5, 6, 7 , Chiara Riganti 4, 8, 9, 10 , Katarzyna Zabielska-Koczywąs 11, 12, 13, 14, 15 , Nicola A. Colabufo 1, 2, 3, 4, 16 , Roberta Fruttero 4, 5, 6, 7
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-04-03 00:00:00 , DOI: 10.1039/c8md00075a Marialessandra Contino 1, 2, 3, 4 , Stefano Guglielmo 4, 5, 6, 7 , Maria Grazia Perrone 1, 2, 3, 4 , Roberta Giampietro 1, 2, 3, 4 , Barbara Rolando 4, 5, 6, 7 , Antonio Carrieri 1, 2, 3, 4 , Daniele Zaccaria 1, 2, 3, 4 , Konstantin Chegaev 4, 5, 6, 7 , Vanessa Borio 4, 5, 6, 7 , Chiara Riganti 4, 8, 9, 10 , Katarzyna Zabielska-Koczywąs 11, 12, 13, 14, 15 , Nicola A. Colabufo 1, 2, 3, 4, 16 , Roberta Fruttero 4, 5, 6, 7
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P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several regions of our body. It plays a crucial defense role as it mediates the efflux of hundreds of potentially toxic substances. However, P-gp is one of the main causes of failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication concerns the correlation between P-gp expression impairment and the onset of several central nervous system pathologies such as Alzheimer's and Parkinson's diseases. In view of these considerations, in the present study, a new series of P-gp modulators have been designed, synthesized and evaluated for their activity towards P-gp and two other sister proteins (BCRP and MRP1). The compounds, structurally correlated to the potent but non-selective P-gp inhibitor MC70 [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds 5a, 5d and 12d proved capable of restoring doxorubicin toxicity in resistant cancer cells.
中文翻译：
新的基于四氢异喹啉的P-糖蛋白调节剂：联苯核心的修饰产生选择性配体†
P-糖蛋白（P-gp，MDR1）是在我们身体的多个区域表达的膜转运蛋白。它起着至关重要的防御作用，因为它介导了数百种潜在有毒物质的外排。但是，P-gp是癌症化疗失败的主要原因之一，因为许多化学治疗剂都是P-gp底物。另一个有趣的含义涉及P-gp表达障碍与多种中枢神经系统疾病（例如阿尔茨海默氏病和帕金森氏病）的发作之间的相关性。考虑到这些考虑因素，在本研究中，已经设计，合成和评估了一系列新的P-gp调节剂对P-gp和另外两个姊妹蛋白（BCRP和MRP1）的活性。这些化合物[4'-（6,7-二甲氧基-3,4-二氢-1 H-异喹啉-2-基甲基）联苯-4-醇]被证明对P-gp具有相当的选择性，其效力在微摩尔范围内。证明化合物5a，5d和12d能够恢复抗性癌细胞中的阿霉素毒性。
更新日期：2018-04-03
中文翻译：
新的基于四氢异喹啉的P-糖蛋白调节剂：联苯核心的修饰产生选择性配体†
P-糖蛋白（P-gp，MDR1）是在我们身体的多个区域表达的膜转运蛋白。它起着至关重要的防御作用，因为它介导了数百种潜在有毒物质的外排。但是，P-gp是癌症化疗失败的主要原因之一，因为许多化学治疗剂都是P-gp底物。另一个有趣的含义涉及P-gp表达障碍与多种中枢神经系统疾病（例如阿尔茨海默氏病和帕金森氏病）的发作之间的相关性。考虑到这些考虑因素，在本研究中，已经设计，合成和评估了一系列新的P-gp调节剂对P-gp和另外两个姊妹蛋白（BCRP和MRP1）的活性。这些化合物[4'-（6,7-二甲氧基-3,4-二氢-1 H-异喹啉-2-基甲基）联苯-4-醇]被证明对P-gp具有相当的选择性，其效力在微摩尔范围内。证明化合物5a，5d和12d能够恢复抗性癌细胞中的阿霉素毒性。
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