Conjugating glucosamine to triptolide to enhance its protective effect against renal ischemia-reperfusion injury and reduce its toxicity

Purpose: This study examined whether a triptolide-glucosamine conjugate (TPG) would show better renal accumulation and few side effects than triptolide (TP) on its own, thereby improving the drug's protective effects against renal ischemia-reperfusion (I/R) injury. Methods: TP was coupled via carbamate bond to 2-glucosamine to generate TPG. The TPG and TP were compared in terms of their in vitro stability, cytotoxicity, in vivo biodistribution, protective effects against renal I/R injury and toxicity. Results: Successful synthesis of TPG was confirmed by H-1 nuclear magnetic resonance (NMR), 13 C NMR, UV spectroscopy and mass spectrometry. After intravenous injection in mice, TPG showed a renal concentration 44.7-fold higher than that of TP at 60 min ( p < 0.01), and the area under the curve (AUC) for TPG in kidneys was 3.29-fold higher than that for TP ( p < 0.01). TPG also ameliorated the progression of renal I/R injury more effectively than TP did. TPG was associated with less toxicity to the liver, male reproductive system and immune system than was TP. Conclusion: TPG shows greater efficacy and lower toxicity than TP alone in mice and rats, suggesting that it merits further study in clinical trials as a potential next-generation treatment for immunological renal diseases.