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Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties

Zhu, Huajian; Lu, Lixue; Zhu, Wenjian; Tan, Yuchen; Duan, Yiping; Liu, Jie; Ye, Wencai; Zhu, Zheying; Xu, Jinyi; Xu, Shengtao


Huajian Zhu

Lixue Lu

Wenjian Zhu

Yuchen Tan

Yiping Duan

Jie Liu

Wencai Ye

Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu

Shengtao Xu


A series of NQO1 selectively activated prodrugs were designed and synthesized by introducing indolequinone moiety to the C-3, C-23 or C-28 position of 23-hydroxybetulinic acid (23-HBA) and its analogues. Among them, the representative compound 32j exhibited significant antiproliferative activities against NQO1-overexpressing HT-29 cells and A549 cells, with IC50 values of 1.87 and 2.36 μM, respectively, which were 20–30-fold more potent than those of parent compound 23-HBA. More importantly, it was demonstrated in the in vivo antitumor experiment that 32j effectively suppressed the tumor volume and largely reduced tumor weight by 72.69% with no apparent toxicity, which was more potent than the positive control 5-fluorouracil. This is the first breakthrough in the improvement of in vivo antitumor activities of 23-HBA derivatives. The further molecular mechanism study revealed that 32j blocked cell cycle arrest at G2/M phase, induced cell apoptosis, depolarized mitochondria and elevated the intracellular ROS levels in a dose-dependent manner. Western blot analysis indicated that 32j induced cell apoptosis by interfering with the expression of apoptosis-related proteins. These findings suggest that compound 32j could be considered as a potent antitumor prodrug candidate which deserves to be further investigated for personalized cancer therapy.


Zhu, H., Lu, L., Zhu, W., Tan, Y., Duan, Y., Liu, J., …Xu, S. (2022). Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties. European Journal of Medicinal Chemistry, 240, Article 114575.

Journal Article Type Article
Acceptance Date Jun 25, 2022
Online Publication Date Jun 30, 2022
Publication Date Oct 5, 2022
Deposit Date Aug 23, 2022
Publicly Available Date Jul 1, 2023
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 240
Article Number 114575
Keywords Organic Chemistry; Drug Discovery; Pharmacology; General Medicine
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