Heme-catalyzed Endogenous Activation of N-oxide Prodrugs
- 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation Institute of Materia Medica
- 2Chinese Academy of Medical Sciences & Peking Union Medical College
- 3Institute of Medicinal Biotechnology
Abstract
N-oxides are prominent functionalities in bioorthogonal prodrugs activated by exogenous stimuli such as boron reagents, X-ray, and ultrasound. However, N-oxide optical probes that are activated by endogenous heme and hemoproteins are recently reported, which has caused the existence of endogenous activation mechanism of N-oxide prodrugs to be overlooked or remain disputed. Here, we report a systemic study to examine the endogenous activation of N-oxide prodrugs in vitro, in liver microsomes, and in mice. We prepared four N-oxide prodrugs based on the synthetic molecule IOX5 and natural product derivative SN-38 with stable N-oxide moieties. We found that all the prodrugs could be catalytically reduced by heme and hemoproteins in vitro. The pharmacokinetics results indicated that all prodrugs could release the parent drugs in liver microsomes and animals. Notably, N-oxide prodrugs of SN-38, 7-1 and 8-40, exhibited dramatically improved oral bioavailability (23.3% and 18.7% for released SN-38) compared to SN-38 itself (0.07%). In the acute myeloid leukemia mice, oral administration of 7‑1 markedly reduced the leukemia burden and the percentage of leukemia stem cells, significantly prolonging the survival rate of leukemia mice. Overall, this study not only discloses that N-oxide prodrugs could be activated by endogenous heme, without any exogenous reagent or specific physiological condition, but also provides a modular and promising prodrug strategy to improve the oral bioavailability of poorly water-soluble drugs.
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BibTeX
@misc{ha2026hemecatalyzed,
title = {{Heme-catalyzed Endogenous Activation of N-oxide Prodrugs}},
author = {Si Ha and Tingyu Guo and Feng Wang and Ke Li and Chong-Jing Zhang},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008394/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008394/v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Heme-catalyzed Endogenous Activation of N-oxide Prodrugs
AU - Si Ha
AU - Tingyu Guo
AU - Feng Wang
AU - Ke Li
AU - Chong-Jing Zhang
PY - 2026
DA - 2026/09/07
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008394/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008394/v1
AB - N-oxides are prominent functionalities in bioorthogonal prodrugs activated by exogenous stimuli such as boron reagents, X-ray, and ultrasound. However, N-oxide optical probes that are activated by endogenous heme and hemoproteins are recently reported, which has caused the existence of endogenous activation mechanism of N-oxide prodrugs to be overlooked or remain disputed. Here, we report a systemic study to examine the endogenous activation of N-oxide prodrugs in vitro, in liver microsomes, and in mice. We prepared four N-oxide prodrugs based on the synthetic molecule IOX5 and natural product derivative SN-38 with stable N-oxide moieties. We found that all the prodrugs could be catalytically reduced by heme and hemoproteins in vitro. The pharmacokinetics results indicated that all prodrugs could release the parent drugs in liver microsomes and animals. Notably, N-oxide prodrugs of SN-38, 7-1 and 8-40, exhibited dramatically improved oral bioavailability (23.3% and 18.7% for released SN-38) compared to SN-38 itself (0.07%). In the acute myeloid leukemia mice, oral administration of 7‑1 markedly reduced the leukemia burden and the percentage of leukemia stem cells, significantly prolonging the survival rate of leukemia mice. Overall, this study not only discloses that N-oxide prodrugs could be activated by endogenous heme, without any exogenous reagent or specific physiological condition, but also provides a modular and promising prodrug strategy to improve the oral bioavailability of poorly water-soluble drugs.
ER -