1. Academic Validation
  2. Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents

Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents

  • J Med Chem. 2018 Apr 12;61(7):3059-3075. doi: 10.1021/acs.jmedchem.8b00106.
Meixi Hao 1 Siyuan Hou 1 Lingjing Xue 1 Haoliang Yuan 1 Lulu Zhu 1 Cong Wang 1 Bin Wang 1 Chunming Tang 1 Can Zhang 1
Affiliations

Affiliation

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery , China Pharmaceutical University , 24 Tong Jia Xiang , Nanjing 210009 , China.
Abstract

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.

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