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

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.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.Successful synthesis of TPG was confirmed by 1H nuclear magnetic resonance (NMR), 13C 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.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.