Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents.
10.1016/j.apsb.2019.07.007
- Author:
Senling FENG
1
;
Huifang ZHOU
2
;
Deyan WU
2
;
Dechong ZHENG
1
;
Biao QU
1
;
Ruiming LIU
1
;
Chen ZHANG
2
;
Zhe LI
2
;
Ying XIE
1
;
Hai-Bin LUO
2
Author Information
1. School of Pharmacy, State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.
2. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
- Publication Type:Journal Article
- Keywords:
Ac2O, acetic anhydride;
AcOH, acetic acid;
AcONa, sodium acetate;
BF3·Et2O, boron trifluoride diethyl etherate;
Cancer multidrug resistance;
DCE, dichloroethane;
DCM, dichloromethane;
DMF, N,N-dimethylformamide;
DMSO, dimethyl sulfoxide;
DOX, doxorubicin;
Et3N, triethylamine;
Flutax-2, a fluorescent taxol derivative;
MDR, multidrug resistance;
Mechanism;
NIS, N-iodosuccinimide;
NOB, nobiletin;
Nobiletin;
P-gp inhibition;
P-gp, P-glycoprotein;
PI, propidium iodide;
PTX, paclitaxel;
QND, quinidine;
Reversal agents;
Rho123, rhodamine 123;
SRB, sulforhodamine B;
Solubility;
TCA, trichloroacetic acid;
THF, tetrahydrofuran;
TLC, thin-layer chromatography;
Total synthesis;
Ver, verapamil;
t-BuOK, potassium tert-butylate
- From:
Acta Pharmaceutica Sinica B
2020;10(2):327-343
- CountryChina
- Language:English
-
Abstract:
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy . However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors P-gp inhibition. Moreover, Western blot experiments revealed that inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying of multiple mechanisms to reverse MDR in lung cancer.
