Characterization of five 19-nor-analogs of 1alpha,25(OH)2-Vitamin D3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties
| Autor: | June E. Bishop, Craig M. Bula, Christopher J. Olivera, Percy S. Manchand, Anthony W. Norman, Luciano Adorini, Milan R. Uskokovic |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Stereochemistry
Protein Conformation Endocrinology Diabetes and Metabolism medicine.medical_treatment Clinical Biochemistry Ligands Biochemistry DNA-binding protein Calcitriol receptor Mice Endocrinology Calcitriol In vivo Transcription (biology) medicine Animals Receptor Molecular Biology Chemistry Cell Biology Ligand (biochemistry) Mice Inbred C57BL Steroid hormone Nuclear receptor COS Cells Molecular Medicine Receptors Calcitriol Calcium Female Protein Binding |
| Zdroj: | The Journal of steroid biochemistry and molecular biology. (1-5) |
| ISSN: | 0960-0760 |
| Popis: | The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect