Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3

Chem Biol. 1999 May;6(5):265-75. doi: 10.1016/S1074-5521(99)80072-6.


Background: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries.

Results: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3.

Conclusions: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biological Transport
  • Breast Neoplasms / pathology
  • Calcitriol / pharmacology
  • Calcium / metabolism*
  • Calcium Channel Agonists / pharmacology
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Female
  • HL-60 Cells
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Ketones / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Male
  • Mice
  • Molecular Mimicry
  • Phenyl Ethers / pharmacology
  • Prostatic Neoplasms / pathology
  • Rats
  • Receptors, Calcitriol / metabolism
  • Receptors, Calcitriol / physiology*
  • Transcriptional Activation
  • Vitamin D / analogs & derivatives
  • Vitamin D / chemical synthesis
  • Vitamin D / pharmacology*
  • Vitamin D-Binding Protein / metabolism


  • Antineoplastic Agents
  • Calcium Channel Agonists
  • Ketones
  • Phenyl Ethers
  • Receptors, Calcitriol
  • Vitamin D-Binding Protein
  • Vitamin D
  • Calcitriol
  • Calcium