Huajian Zhu
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
Authors
Lixue Lu
Wenjian Zhu
Yuchen Tan
Yiping Duan
Jie Liu
Wencai Ye
ZHEYING ZHU Zheying.Zhu@nottingham.ac.uk
Associate Professor in International Pharmacy and Traditional Medicines
Jinyi Xu
Shengtao Xu
Abstract
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.
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 |
DOI | https://doi.org/10.1016/j.ejmech.2022.114575 |
Keywords | Organic Chemistry; Drug Discovery; Pharmacology; General Medicine |
Public URL | https://nottingham-repository.worktribe.com/output/9584110 |
Publisher URL | https://www.sciencedirect.com/science/article/abs/pii/S0223523422004779 |
Files
23-HBA NQO1 Manuscript-Revised
(1.5 Mb)
PDF
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