Synthesis and biological evaluation of a des-C,D-analog of 2-methylene-19-nor-1alpha,25-(OH)2D3.
Structure-activity studies directed at novel Vitamin D compounds of potential therapeutic value has long attracted an attention of numerous research groups. To date more than 3000 analogs of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1) have been synthesized and tested. As a continuation of our studies on 19-norvitamin D compounds we have obtained (20S)-des-C,D-2-methylene-1alpha,25-dihydroxy-19-norvitamin D(3) (6) and examined its biological activity. This Vitamin D compound was efficiently prepared in a convergent synthesis. The "upper" fragment was synthesized starting with methyl (R)-(-)-3-hydroxy-2-methylpropionate (9). The key synthetic step involved Lythgoe type Wittig-Horner coupling of the protected hydroxy aldehyde 19 with the phosphine oxide 20. The prepared Vitamin D analog 6 exhibited limited binding ability to the rat intestinal Vitamin D receptor being ca. 80 times less potent when compared to the natural hormone 1. Although the analog 6 did retain some cell differentiating and transcriptional activities, preliminary in vivo tests do not show any activity of this analog in animals.
Plonska-Ocypa
Katarzyna
K
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland.
Grzywacz
Pawel
P
Sicinski
Rafal R
RR
Plum
Lori A
LA
DeLuca
Hector F
HF
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
C468519:2-methylene-1,25-dihydroxy-19-norvitamin D3; D000447:Aldehydes; D008024:Ligands; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D002117:Calcitriol