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.
Publication/Presentation Date
7-1-2007
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.
Volume
15
Issue
13
First Page
4444
Last Page
4455
ISSN
0968-0896
Published In/Presented At
Garay, E., Jankowski, P., Lizano, P., Marczak, S., Maehr, H., Adorini, L., Uskokovic, M. R., & Studzinski, G. P. (2007). 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. Bioorganic & medicinal chemistry, 15(13), 4444–4455. https://doi.org/10.1016/j.bmc.2007.04.034
Disciplines
Medicine and Health Sciences
PubMedID
17485214
Department(s)
Department of Medicine
Document Type
Article