Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 4, Pages 1756-1760Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.12.137
Keywords
Vitamin D; Carborane; Pharmacophore; Cell differentiation
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan [21790110, 19201044, 19689004]
- Takeda Science Foundation
- Mitsubishi Foundation
- Grants-in-Aid for Scientific Research [21790110, 24590137, 19201044, 23790128, 22136013, 19689004] Funding Source: KAKEN
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Vitamin D receptor (VDR) is a nuclear receptor for 1 alpha, 25-dihydroxyvitamin D-3 (1 alpha, 25(OH)(2)D-3), and is an attractive target for multiple clinical applications. We recently developed novel non-secosteroidal VDR ligands bearing a hydrophobic p-carborane cage, thereby establishing the utility of this spherical hydrophobic core structure for development of VDR ligands. Here, we synthesized two series of novel non-secosteroidal VDR ligands with different spherical hydrophobic cores, that is, bicyclo[2.2.2] octane derivatives and p-carborane derivatives, and compared their biological activities in order to examine the difference between the interactions of the C-H hydrocarbon surface and the B-H carborane surface with the receptor. Carborane derivatives exhibited more potent differentiation-inducing activity toward HL-60 cells than did the corresponding bicyclo[2.2.2] octane derivatives. These results suggest that the hydrophobic carborane cage may interact more efficiently than the hydrocarbons with the hydrophobic surface of VDR. This finding further supports the view that carborane structure is a promising option for drug development. (C) 2012 Elsevier Ltd. All rights reserved.
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