Issue 5, 2011

Structure–function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097

Abstract

Derivatives of vitamin D3 containing a second side-chain emanating at C-20 are known as gemini and act as vitamin D receptor agonists. Recently, two of these, namely Gemini-0072 and the epimeric Gemini-0097, were selected for further studies in view of their high biological activities and lack of hypercalcemic effects. We now show that the two analogs recruit coactivator SRC-1 better than the parental gemini and act as VDR superagonists. The crystal structures of complexes of zVDR with Gemini-0072 and Gemini-0097 indicate that these ligands induce an extra cavity within the ligand-binding pocket similar to gemini and that their superagonistic activity is due to an increased stabilization of helix H12.

Graphical abstract: Structure–function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097

Supplementary files

Article information

Article type
Concise Article
Submitted
31 Dec 2010
Accepted
28 Feb 2011
First published
17 Mar 2011

Med. Chem. Commun., 2011,2, 424-429

Structure–function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097

T. Huet, H. Maehr, H. J. Lee, M. R. Uskokovic, N. Suh, D. Moras and N. Rochel, Med. Chem. Commun., 2011, 2, 424 DOI: 10.1039/C1MD00059D

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