title: 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.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Garay
authors.forename: Pawel
authors.initials: P
authors.lastname: Jankowski
authors.forename: Paulo
authors.initials: P
authors.lastname: Lizano
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Marczak
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Milan R
authors.initials: MR
authors.lastname: Uskokovic
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D015415:Biomarkers; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007202:Indicators and Reagents; D007938:Leukemia / Q000473:pathology*; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects*; D010084:Oxidation-Reduction; D018167:Receptors, Calcitriol / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015415:Biomarkers; D007202:Indicators and Reagents; D018167:Receptors, Calcitriol; D002117:Calcitriol