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Synthesis, extracorporeal nephrotoxicity, and 3D‐QSAR of andrographolide derivatives
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-09-18 , DOI: 10.1111/cbdd.13796 Lili Gu 1 , Jiaqi Lu 1 , Qin Li 1 , Wenhai Huang 1 , Ningzi Wu 1 , Qingqing Yu 2 , Hong Lu 2 , Xinyue Zhang 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-09-18 , DOI: 10.1111/cbdd.13796 Lili Gu 1 , Jiaqi Lu 1 , Qin Li 1 , Wenhai Huang 1 , Ningzi Wu 1 , Qingqing Yu 2 , Hong Lu 2 , Xinyue Zhang 1
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Andrographolide is a traditional Chinese medicine monomer with many pharmacological activities, but has potential nephrotoxicity. Here, we aim to investigate the relationship between modification of andrographolide structure and its nephrotoxicity. Twenty‐three andrographolide derivatives were synthesized, and their structures were confirmed by 1H‐NMR and HRMS. Nephrotoxicity of these compounds against human renal tubular epithelial (HK‐2) cells was evaluated using the MTT assay. The results indicated that most of them had significantly reduced nephrotoxicity, especially compounds III, V, and IXc, with IC50 values of 1,985, 1,300, and 806.9 μmol/L, respectively, which were obviously superior to andrographolide (IC50 30.60 μmol/L). However, compounds Ia–If (IC50 values < 30 μmol/L), the 14‐OH derivatives of andrographolide, showed higher nephrotoxicity than that of andrographolide. Three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models of COMFA and COMSIA were established (COMFA: q2 = 0.639, r2 = 0.951; COMSIA: q2 = 0.569, r2 = 0.857). This model allowed proposing five new compounds with lower theoretical nephrotoxicity, which would be worthwhile to synthesize and evaluate. We believe that predicted models will help us to understand the structural modification requirements of andrographolide to reduce the nephrotoxicity, and further investigations will be needed to determine the mechanism involved in the effect of less nephrotoxic compounds.
中文翻译：
穿心莲内酯衍生物的合成、体外肾毒性和 3D-QSAR
穿心莲内酯是一种中药单体，具有多种药理活性，但具有潜在的肾毒性。在这里，我们旨在研究穿心莲内酯结构的修饰与其肾毒性之间的关系。合成了 23 种穿心莲内酯衍生物，其结构经1 H-NMR 和 HRMS 确证。使用 MTT 测定评估这些化合物对人肾小管上皮 (HK-2) 细胞的肾毒性。结果表明，它们中的大多数具有显着降低的肾毒性，尤其是化合物III、V和IX c，IC 50值分别为1,985、1,300和806.9 μmol/L，明显优于穿心莲内酯（IC 50 30.60 μmol/L）。然而，化合物I a – I f (IC 50值 < 30 μmol/L)，穿心莲内酯的 14-OH 衍生物，表现出比穿心莲内酯更高的肾毒性。建立了COMFA和COMSIA的三维定量构效关系（3D-QSAR）模型（COMFA：q 2 = 0.639，r 2 = 0.951；COMSIA：q 2 = 0.569，r 2 = 0.857）。该模型允许提出五种具有较低理论肾毒性的新化合物，这些化合物值得合成和评估。我们相信预测模型将帮助我们了解穿心莲内酯降低肾毒性的结构修饰要求，并且需要进一步研究以确定肾毒性较小化合物的作用机制。
更新日期：2020-09-18
中文翻译：
穿心莲内酯衍生物的合成、体外肾毒性和 3D-QSAR
穿心莲内酯是一种中药单体，具有多种药理活性，但具有潜在的肾毒性。在这里，我们旨在研究穿心莲内酯结构的修饰与其肾毒性之间的关系。合成了 23 种穿心莲内酯衍生物，其结构经1 H-NMR 和 HRMS 确证。使用 MTT 测定评估这些化合物对人肾小管上皮 (HK-2) 细胞的肾毒性。结果表明，它们中的大多数具有显着降低的肾毒性，尤其是化合物III、V和IX c，IC 50值分别为1,985、1,300和806.9 μmol/L，明显优于穿心莲内酯（IC 50 30.60 μmol/L）。然而，化合物I a – I f (IC 50值 < 30 μmol/L)，穿心莲内酯的 14-OH 衍生物，表现出比穿心莲内酯更高的肾毒性。建立了COMFA和COMSIA的三维定量构效关系（3D-QSAR）模型（COMFA：q 2 = 0.639，r 2 = 0.951；COMSIA：q 2 = 0.569，r 2 = 0.857）。该模型允许提出五种具有较低理论肾毒性的新化合物，这些化合物值得合成和评估。我们相信预测模型将帮助我们了解穿心莲内酯降低肾毒性的结构修饰要求，并且需要进一步研究以确定肾毒性较小化合物的作用机制。
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