Document Detail


Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase.
MedLine Citation:
PMID:  22133546     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)(2)D(3) analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner-Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80-1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)(2)D(3), further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)(2)D(3) and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1.
Authors:
Grazia Chiellini; Simona Rapposelli; Jinge Zhu; Ilaria Massarelli; Marilena Saraceno; Anna Maria Bianucci; Lori A Plum; Margaret Clagett-Dame; Hector F DeLuca
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-11-25
Journal Detail:
Title:  Steroids     Volume:  77     ISSN:  1878-5867     ISO Abbreviation:  Steroids     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-18     Completed Date:  2012-05-11     Revised Date:  2014-01-13    
Medline Journal Info:
Nlm Unique ID:  0404536     Medline TA:  Steroids     Country:  United States    
Other Details:
Languages:  eng     Pagination:  212-23     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
25-Hydroxyvitamin D3 1-alpha-Hydroxylase / antagonists & inhibitors
Amino Acid Sequence
Animals
Calcifediol / analogs & derivatives,  chemical synthesis,  chemistry
Calcium / chemistry
Cell Differentiation
Cyclopropanes / chemical synthesis,  chemistry
Enzyme Activation
Enzyme Inhibitors / chemical synthesis*,  chemistry,  pharmacology
HL-60 Cells
Half-Life
Humans
Hydroxycholecalciferols / chemistry
Magnetic Resonance Spectroscopy
Mice
Molecular Sequence Data
Osteoblasts / drug effects
Rats
Sequence Homology, Amino Acid
Steroid Hydroxylases / antagonists & inhibitors*
Transcriptional Activation
Vitamin D / analogs & derivatives*,  chemistry
Grant Support
ID/Acronym/Agency:
P41 GM066326/GM/NIGMS NIH HHS; P41 RR002301/RR/NCRR NIH HHS; P41GM66326/GM/NIGMS NIH HHS; P41RR02301/RR/NCRR NIH HHS; RR02781/RR/NCRR NIH HHS; RR08438/RR/NCRR NIH HHS; S10 RR002781-01/RR/NCRR NIH HHS; S10 RR008438-01/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Cyclopropanes; 0/Enzyme Inhibitors; 0/Hydroxycholecalciferols; 0/N-cyclopropyl-2-methylene-19,25,26,27-tetranor-25-aza-1-hydroxyvitamin D; 1406-16-2/Vitamin D; 8PR8XTH1X1/cyclopropylamine; EC 1.14.-/25-Hydroxyvitamin D3 1-alpha-Hydroxylase; EC 1.14.-/Steroid Hydroxylases; EC 1.14.13.126/vitamin D 24-hydroxylase; P6YZ13C99Q/Calcifediol; SY7Q814VUP/Calcium
Comments/Corrections

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