Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy

Eur J Med Chem. 2016 Jan 1;107:48-62. doi: 10.1016/j.ejmech.2015.10.042. Epub 2015 Nov 3.


A series of nonsecosteroidal vitamin D3 receptor (VDR) ligands with phenyl-pyrrolyl pentane skeleton were synthesized for cancer therapy. In contrast to 1α,25-dihydroxyvitamin D3 (Calcitriol), these VDR ligands exhibited anti-proliferative activity without inducing hypercalcemia. These compounds were evaluated for vitamin D3-agonistic ability and anti-proliferative activity in vitro. Among them, compounds 5k and 5i exhibited equivalent vitamin D3-agonistic activity compared with Calcitriol. Meanwhile, compound 5k displayed promising inhibiting profile against MCF-7, HepG-2 and Caco-2 with IC50 values of 0.00586 μM, 0.176 μM, and 1.01 μM (Calcitriol: 5.58 μM, 80.83 μM and 4.46 μM) respectively. Compound 5i inhibited proliferation of PC-3 with IC50 value of 0.00798 μM (Calcitriol: 17.25 μM). Additionally, neither of these compounds significantly elevated serum calcium in rats.

Keywords: Anti-proliferation; Cancer therapy; Hypercalcemia; Nonsecosteroid; Phenyl-pyrrolyl pentane skeleton; VDR; Vitamin D(3)-agonistic activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Caco-2 Cells / drug effects
  • Calcitriol / adverse effects
  • Calcium / blood
  • Cell Proliferation / drug effects
  • Hep G2 Cells / drug effects
  • Humans
  • Hypercalcemia / chemically induced
  • Inhibitory Concentration 50
  • Ligands
  • MCF-7 Cells / drug effects
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Pentanes / chemistry
  • Rats
  • Receptors, Calcitriol / agonists*
  • Receptors, Calcitriol / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Ligands
  • Pentanes
  • Receptors, Calcitriol
  • pentane
  • Calcitriol
  • Calcium