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-κB signaling, suggesting a possible induction of apoptosis through the regulation of NF-κB 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.

中文翻译：

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发现1H-吡咯并[1,2-c]咪唑-1-酮的稠合双环衍生物作为VDR信号调节剂。

VDR信号的调节在调节肿瘤相关信号转导和保护免受微生物感染中很重要。在这项研究中，我们通过萤光素酶报告基因检测发现，在钙三醇的帮助下，几种1H-吡咯并[1,2-c]咪唑-1-酮的稠合双环衍生物可导致VDR启动子活性增加多达三倍。20种化合物的初步SAR结果表明，这些化合物的理想VDR信号调节剂是由多种因素的最佳组合建立的。蛋白质印迹分析表明，ZD-3，ZD-4和ZD-5化合物不仅显着上调p62和LC3-II，而且还提高了LC3-II / LC3-I的比例，这可能导致活化的自噬。所有这五种化合物还显着下调p65和上调p-p65，ZD-3是NF-κB信号最活跃的一种，表明可能通过调节VDR信号转导的NF-κB信号转导来诱导凋亡。ZD-3，ZD-4和ZD-5化合物可显着抵消VDR shRNA的干扰，其中ZD-3获得了最高的VDR表达补偿和最高的LC3-II / LC3-I比值，表明ZD- 3很可能激活VDR介导的自噬。综上所述，这些1H-吡咯并[1,2-c]咪唑-1-酮衍生物可以调节VDR信号传导，可能导致某些信号通路的调节，从而诱导自噬和细胞凋亡。ZD-4和ZD-5显着抵消了VDR shRNA的干扰，其中ZD-3获得了最高的VDR表达补偿和最高的LC3-II / LC3-I比值，这表明ZD-3很可能会激活VDR-介导的自噬。综上所述，这些1H-吡咯并[1,2-c]咪唑-1-酮衍生物可以调节VDR信号传导，可能导致某些信号通路的调节，从而诱导自噬和细胞凋亡。ZD-4和ZD-5显着抵消了VDR shRNA的干扰，其中ZD-3获得了最高的VDR表达补偿和最高的LC3-II / LC3-I比值，这表明ZD-3很可能会激活VDR-介导的自噬。综上所述，这些1H-吡咯并[1,2-c]咪唑-1-酮衍生物可以调节VDR信号传导，可能导致某些信号通路的调节，从而诱导自噬和细胞凋亡。