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

Eur J Med Chem. 2022 Oct 5:240:114575. doi: 10.1016/j.ejmech.2022.114575.

Huajian Zhu ¹, Lixue Lu ², Wenjian Zhu ¹, Yuchen Tan ¹, Yiping Duan ², Jie Liu ³, Wencai Ye ⁴, Zheying Zhu ⁵, Jinyi Xu ⁶, Shengtao Xu ⁷

Affiliations

1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
2 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China; Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
3 Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: cpu-jill@163.com.
4 College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, PR China.
5 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK.
6 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: jinyixu@china.com.
7 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: cpuxst@cpu.edu.cn.

PMID: 35803175 DOI: 10.1016/j.ejmech.2022.114575

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.

Keywords

23-Hydroxybetulinic acid; Antitumor; Indolequinone; NQO1; Prodrug.

Name
Email *

	Sorry, but the email address you supplied was invalid.