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

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.