Synthesis and Cytotoxicity Evaluation of Denitroaristolochic Acids: Structural Insights and Mechanistic Implications in Nephrotoxicity
Jianfei Gao, Mengtong Zhao, Jianhua Su, Yi Gao, Xiaofeng Zhang, Yongzhao Ding, Xiaoping Liu, Yang Luan, Chun Hu
TL;DR
This study explores the synthesis and toxicity of denitroaristolochic acids, revealing how structural changes affect their harmful effects on kidney cells.
Contribution
The paper introduces a novel synthetic strategy and reveals new insights into the cytotoxic mechanisms of denitroaristolochic acids.
Findings
Denitroaristolochic acids III and IV showed reduced cytotoxicity compared to the nitro-containing prototype.
The absence of a nitro group does not eliminate toxicity, suggesting alternative mechanisms like oxidative stress.
DAA-II and DAA-V showed no detectable cytotoxicity, indicating reduced toxicological impact.
Abstract
The efficient synthetic routes and evaluates cytotoxic profiles of denitroaristolochic acids II–V (DAA-II–V) were demonstrated in this study. Based on retrosynthetic analysis, a modular synthetic strategy was developed through Suzuki–Miyaura coupling, Wittig reaction, and bismuth triflate-catalyzed intramolecular Friedel–Crafts cyclization to efficiently construct the phenanthrene core. Process optimization significantly improved yields: aryl bromide intermediate A reached 50.8% yield via bromination refinement, while arylboronic ester intermediate B overcame selectivity limitations. Combining Darzens condensation with Wittig reaction enhanced throughput, achieving 88.4% yield in the key cyclization. Structures were confirmed by NMR and mass spectra. CCK-8 cytotoxicity assays in human renal proximal tubular epithelial cells revealed distinct toxicological profiles: DAA-III and DAA-IV…
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Taxonomy
TopicsNephrotoxicity and Medicinal Plants · Garlic and Onion Studies · Phytochemistry and biological activities of Ficus species