2. Academic Validation
  3. Design, synthesis, and biological evaluation of NAD(P)H: Quinone oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation

Design, synthesis, and biological evaluation of NAD(P)H: Quinone oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation

  • Eur J Med Chem. 2017 May 26:132:310-321. doi: 10.1016/j.ejmech.2017.03.055.
Shengtao Xu 1,  Hong Yao 1,  Lingling Pei 1,  Mei Hu 1,  Dahong Li 2,  Yangyi Qiu 1,  Guangyu Wang 1,  Liang Wu 3,  Hequan Yao 1,  Zheying Zhu 4,  Jinyi Xu 5
Affiliations

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; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wen Hua Road, Shenyang 110016, PR China.
  • 3 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: wul2004@hotmail.com.
  • 4 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK. Electronic address: Zheying.Zhu@nottingham.ac.uk.
  • 5 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.
PMID: 28395199 DOI: 10.1016/j.ejmech.2017.03.055
Abstract

The Enzyme NQO1 is a potential target for selective Cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic Diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC50 = 0.263-2.904 μM), while NQO1-defficient lung adenosquamous carcinoma cells (H596) were less sensitive to these compounds, among which, compound 29h exhibited the most potent antiproliferative activity against both A549 and HT-29 cells, with IC50 values of 0.386 and 0.263 μM, respectively. Further HPLC and docking studies demonstrated that 29h is a good substrate of NQO1. Moreover, the investigation of Anticancer mechanism showed that the representative compound 29h affected cell cycle and induced NQO1 dependent Apoptosis through an oxidative stress triggered mitochondria-related pathway in A549 cells. Besides, the antitumor activity of 29h was also verified in a liver Cancer xenograft mouse model. Biological evaluation of these compounds concludes that there is a strong correlation between NQO1 Enzyme and induction of Cancer cell death. Thus, this suggests that some of the target compounds activated by NQO1 are novel prodrug candidates potential for selective Anticancer therapy.

Keywords

Antitumor; Hypoxia-selective; Indolequinone; NQO1; Oridonin.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z