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Discovery of fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one as VDR signaling regulators
Bin Xu1; Mo-Yu Ding2,3; Zhibing Weng1; Zheng-Qing Li2,3; Feng Li1; Xia Sun1; Qiu-Ling Chen2,3; Yi-Tao Wang2,3; Ying Wang2,3; Guo-Chun Zhou1

The modulation of VDR signaling is important in regulating tumor-related signal transduction and protecting from microorganismal infection. In this study we discovered by luciferase reporter assay that several fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one with the assistance of calcitriol result in up to three-fold increases of VDR promoter activity. Preliminary SAR results from 20 compounds disclose that ideal VDR signaling regulators of these compounds are built up by the optimal combination of multiple factors. Western blot analysis indicates that compounds of ZD-3, ZD-4 and ZD-5 not only significantly upregulate p62 and LC3-II but also elevate the ratio of LC3-II/LC3-I, which possibly leads to activated autophagy. All of five compounds also significantly downregulate p65 and upregulate p-p65 and ZD-3 is the most active one to NF-kappa B signaling, suggesting a possible induction of apoptosis through the regulation of NF-kappa B signal transduction mediated by VDR signaling. Compounds of ZD-3, ZD-4 and ZD-5 significantly counteract the interference by VDR shRNA, in which ZD-3 gets the highest compensation of VDR expression and the highest ratio of LC3-II/LC3-I, indicating that ZD-3 very likely activates VDR-mediated autophagy. Taken together, these 1H-pyrrolo[1,2-c]imidazol-1-one derivatives can modulate VDR signaling, possibly resulting in the regulation of some signal pathways to induce autophagy and apoptosis.

Keyword1h-pyrrolo[1,2-c]Imidazol-1-one Vitamin d Receptor (Vdr) Autophagy Apoptosis
Indexed BySCIE
WOS Research AreaBiochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
WOS IDWOS:000477773100014
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorYing Wang; Guo-Chun Zhou
Affiliation1.School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu 211816, China
2.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao
3.[ 3 ] Univ Macau, Inst Chinese Med Sci, Ave Univ, Taipa, Macao, Peoples R China
Corresponding Author AffilicationInstitute of Chinese Medical Sciences;  University of Macau
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GB/T 7714
Bin Xu,Mo-Yu Ding,Zhibing Weng,et al. Discovery of fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one as VDR signaling regulators[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2019,27(17):3879-3888.
APA Bin Xu,Mo-Yu Ding,Zhibing Weng,Zheng-Qing Li,Feng Li,Xia Sun,Qiu-Ling Chen,Yi-Tao Wang,Ying Wang,&Guo-Chun Zhou.(2019).Discovery of fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one as VDR signaling regulators.BIOORGANIC & MEDICINAL CHEMISTRY,27(17),3879-3888.
MLA Bin Xu,et al."Discovery of fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one as VDR signaling regulators".BIOORGANIC & MEDICINAL CHEMISTRY 27.17(2019):3879-3888.
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