Synthesis and in vitro evaluation of side chain-unsaturated analogs of 24a,24b-dihomo-1,25-dihydroxycholecalciferol.
A synthesis and an in vitro evaluation of side chain-unsaturated analogs 3 and 4 of 24a, 24b-dihomo-1,25-dihydroxycholecalciferol (1) are described, Novel C23a, 24-vitamin D synthons (sulfone 10 and aldehyde 11) were used for the synthesis of analog 4 and for the efficient preparation of the parent compound 1. The synthetic approach developed allows the use of easily available side chain fragments, such as oxirane 12 or Wittig reagent 15 for the preparation of compound 1 and analog 4, respectively. Introduction of a 24aE double bond results in a selective, 1000-fold increase in the binding affinity of analog 4 for the vitamin D receptor, compared to the affinity of 1, whereas the affinity of 4 for the vitamin D-binding protein and the activity in stimulating the differentiation of human promyelocytic leukemia HL-60 cells remained largely unchanged.
Chodyński
M
M
Pharmaceutical Research Institute, Warsaw, Poland.
Wojciechowska
W
W
Halkes
S J
SJ
van de Velde
J P
JP
Kutner
A
A
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007536:Isomerism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014809:Vitamin D-Binding Protein / Q000097:blood / Q000187:drug effects / Q000378:metabolism
C108254:PRI 1901; C108253:PRI 2168; D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; C073347:24,24-dihomo-1,25-dihydroxycholecalciferol; D002117:Calcitriol; D002118:Calcium