The vitamin D₃ receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential molecular target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC₅₀ values in the submicromolar-concentration range. In addition, 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities determined by dual-luciferase-reporter assays and human-leukemia-cell-line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy.

中文翻译：

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非甾体维生素D受体调节剂的苯基-吡咯烷戊烷系列作为抗癌剂的进一步发展

属于核受体超家族的维生素D ₃受体（VDR）是抗癌药物发现的潜在分子靶标。在这项研究中，合成了一系列具有苯基-吡咯基戊烷骨架的非甾族维生素D模拟物，在癌症治疗中具有治疗潜力。其中，11b和11g被认为是降低四种癌细胞系（尤其是乳腺癌细胞系）活力的最有效药物，IC ₅₀值在亚微摩尔浓度范围内。另外11b和11g拥有VDR结合亲和力，并显示出显着的部分VDR激动活性，该活性由双荧光素酶报告基因测定法和人白血病细胞系（HL-60）分化测定法确定。此外，11b和11g通过抑制细胞增殖和诱导细胞凋亡来抑制原位乳腺肿瘤模型中的肿瘤生长。更重要的是，11b和11g在体内表现出良好的药代动力学行为，并且不会增加血清钙水平或引起任何其他明显的副作用。总之，11b和11g可以作为新型VDR调节剂，并且有望成为癌症化疗的有前途的候选药物。