Synthesis and biological activity of two C-7 methyl analogues of vitamin D.
Two novel vitamin D analogues of the hormone 1α,25-(OH)2D3 modified at C-7, namely, 7-methyl-1α,25-(OH)2D3 (12) and 7-methyl-1α,25-(OH)2-19-nor-D3 (26), were synthesized and biologically evaluated to gain further insights into the structure-function relationships of vitamin D. Key steps in the synthesis of 12 include the functionalization at C-7 by an efficient regioselective hydrostannylation of an allene precursor, and the construction of the triene framework by a palladium-catalyzed intramolecular cyclization-Suzuki-Miyaura coupling cascade. Since the calcitriol analogue 12 was prone to conversion into its previtamin D form by thermal equilibration, the corresponding 19-nor-compound 26 was also synthesized. The diene moiety of compound 26 was constructed by a modified Julia coupling. UV data as well as X-ray analysis indicate that introduction of the methyl group at C-7 results in a significant deviation from planarity of the 5,7-diene moiety. The new vitamin D analogues 12 and 26 retained good VDR binding ability.
†Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Katarzyna
K
Sokolowska
‡Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Diego
D
Carballa
§Departamento de Fisiología, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Samuel
S
Seoane
§Departamento de Fisiología, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Román
R
Pérez-Fernández
‡Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Antonio
A
Mouriño
†Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Rafal R
RR
Sicinski
D008958:Models, Molecular; D008968:Molecular Conformation; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D018167:Receptors, Calcitriol; D014807:Vitamin D