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Calcitriol derivatives with two different side-chains at C-20. Part 4: further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2007 Jul 01; Vol. 15 (13), pp. 4444-55. Date of Electronic Publication: 2007 Apr 25. - Publication Year :
- 2007
-
Abstract
- Signaling of cell differentiation is one of the important physiological functions of the activated vitamin D receptor (VDR). Activation of the VDR can be achieved not only by 1alpha,25-dihydroxyvitamin D(3) (1,25D), the natural ligand, but also by a large number of its analogs. These include a category containing two side chains emanating at C-20, generally referred to as Gemini. The introduction of a cyclopropyl moiety as part of the pro-R side chain provides modified Gemini compounds with increased steric requirement and decreased chain flexibility; the biological consequences of this novel structural variant are subject of this investigation. In general, the resulting 1alpha,25-dihydroxy-(4-hydroxy-4-methyl-pentyl)-21,22-cis-cyclo-cholecalciferols reduced had differentiation and transcriptional potency and induced cell cycle arrest less efficiently, as shown by a decrease in G1/S ratio, when compared to 1,25D. Modifying their calcitriol side chain in the form of a 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropent-2-ynyl moiety, however, resulted in pronounced induction of differentiation in 1,25D-sensitive and moderate level of differentiation in 1,25D-resistant leukemia cells.
- Subjects :
- Biomarkers
Cell Cycle drug effects
Cell Differentiation drug effects
HL-60 Cells
Humans
Indicators and Reagents
Models, Molecular
Oxidation-Reduction
Reverse Transcriptase Polymerase Chain Reaction
Structure-Activity Relationship
Transcription, Genetic drug effects
Calcitriol analogs & derivatives
Calcitriol pharmacology
Leukemia pathology
Monocytes drug effects
Receptors, Calcitriol drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 15
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17485214
- Full Text :
- https://doi.org/10.1016/j.bmc.2007.04.034