Discovery of novel nonsteroidal VDR agonists with novel diarylmethane skeleton for the treatment of breast cancer

被引：11
作者：
Wang, Cong [1 ,2 ]
Wang, Bin [1 ,2 ]
Hou, Siyuan [1 ,2 ]
Xue, Lingjing [1 ,2 ]
Kang, Zisheng [1 ,2 ]
Du, Junjie [1 ,2 ]
Li, Yanyi [1 ,2 ]
Liu, Xuwentai [1 ,2 ]
Wang, Qianqian [1 ,2 ]
Zhang, Can [1 ,2 ]
机构：
[1] China Pharmaceut Univ, State Key Lab Nat Med, Ctr New Drug Discovery, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, Peoples R China
[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Ctr New Drug Discovery, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, Peoples R China
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 163卷
基金：
中国国家自然科学基金;
关键词：
Breast cancer; Vitamin D receptor (VDR); Nonsecosteroidal; Hypercalcemia; Anti-Tumor activity; 1-ALPHA; 25-DIHYDROXYVITAMIN D-3; ANALOG EB1089; MAMMARY-GLAND; LIGANDS; CELLS;
D O I：
10.1016/j.ejmech.2018.12.024
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Vitamin D receptor (VDR) is recognized as a potential target for the treatment of breast cancer which is the most common malignancy among women in the world. In this study, a series of nonsecosteroidal VDR agonists with a novel diarylmethane skeleton was designed, synthesized and the anti-tumor activities of these compounds were determined. Compound 28 was identified as the most effective agents in reducing the viability of MCF-7 cells, with a low IC50 via the inhibition of cell cycle and induction of apoptosis by regulating the expression of p21, Bcl2 and Bax. In addition, compound 28 showed high VDR-binding affinity and displayed significant VDR-agonistic activities. Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators. In summary, these findings discovered novel VDR modulators as promising candidates for cancer chemotherapy. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码：787 / 803
页数：17
相关论文
共 24 条
[1]  
Albert Benedikt, 2014, Adv Exp Med Biol, V810, P329
[2]   Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3 [J].
Boehm, MF ;
Fitzgerald, P ;
Zou, AH ;
Elgort, MG ;
Bischoff, ED ;
Mere, L ;
Mais, DE ;
Bissonnette, RP ;
Heyman, RA ;
Nadzan, AM ;
Reichman, M ;
Allegretto, EA .
CHEMISTRY & BIOLOGY, 1999, 6 (05) :265-275
[3]   Mechanisms for the selective action of Vitamin D analogs [J].
Bouillon, R ;
Verlinden, L ;
Eelen, G ;
De Clercq, P ;
Vandewalle, M ;
Mathieu, C ;
Verstuyf, A .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2005, 97 (1-2) :21-30
[4]   Dual functions of autophagy in the response of breast tumor cells to radiation Cytoprotective autophagy with radiation alone and cytotoxic autophagy in radiosensitization by vitamin D3 [J].
Bristol, Molly L. ;
Di, Xu ;
Beckman, Matthew J. ;
Wilson, Eden N. ;
Henderson, Scott C. ;
Maiti, Aparna ;
Fan, Zhen ;
Gewirtz, David A. .
AUTOPHAGY, 2012, 8 (05) :739-753
[5]   VITAMIN-D RECEPTORS IN BREAST-CANCER CELLS [J].
BURAS, RR ;
SCHUMAKER, LM ;
DAVOODI, F ;
BRENNER, RV ;
SHABAHANG, M ;
NAUTA, RJ ;
EVANS, SRT .
BREAST CANCER RESEARCH AND TREATMENT, 1994, 31 (2-3) :191-202
[6]  
Gandini Sara, 2014, Adv Exp Med Biol, V810, P69
[7]   Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy [J].
Ge, Zhixin ;
Hao, Meixi ;
Xu, Meng ;
Su, Zhigui ;
Kang, Zisheng ;
Xue, Lingjing ;
Zhang, Can .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 107 :48-62
[8]   Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents [J].
Hao, Meixi ;
Hou, Siyuan ;
Xue, Lingjing ;
Yuan, Haoliang ;
Zhu, Lulu ;
Wang, Cong ;
Wang, Bin ;
Tang, Chunming ;
Zhang, Can .
JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (07) :3059-3075
[9]   Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitarnin D3: Genomic and non-genomic mechanisms [J].
Haussler, Mark R. ;
Jurutka, Peter W. ;
Mizwicki, Mathew ;
Norman, Anthony W. .
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, 2011, 25 (04) :543-559
[10]   Sulfonyl-containing phenyl-pyrrolyl pentane analogues: Novel non-secosteroidal vitamin D receptor modulators with favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity [J].
Kang, Zi-Sheng ;
Wang, Cong ;
Han, Xiao-Lin ;
Wang, Bin ;
Yuan, Hao-Liang ;
Hou, Si-Yuan ;
Hao, Mei-Xi ;
Du, Jun-Jie ;
Li, Yan-Yi ;
Zhou, An-Wei ;
Zhang, Can .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 157 :1174-1191
123