TY - JOUR
T1 - 2,2-Disubstituted analogues of the natural hormone 1α,25-dihydroxyvitamin D3
T2 - Chemistry and biology
AU - Posner, Gary H.
AU - Woodard, Benjamin T.
AU - Crawford, Kenneth R.
AU - Peleg, Sara
AU - Brown, Alex J.
AU - Dolan, Patrick
AU - Kensler, Thomas W.
N1 - Funding Information:
We thank the NIH for support of this work (CA 44530 to G.H.P. and TWK and DK 50583 to S.P.). We thank Prof. K. Afarinkia (Kings College, UK) for early work at Johns Hopkins on the Diels–Alder cycloaddition in Scheme 1 , and Dr. Milan Uskokovic for a generous gift of 15 .
PY - 2002
Y1 - 2002
N2 - Six new 2,2-disubstituted analogues of the natural hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels-Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues 8. Analogues 7a and 8a are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2-3 times more active transcriptionally than calcitriol, whereas dimethylated analogue 8a is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue 8a is considerably less calcemic than calcitriol. Dimethylated analogue 8a strongly suppresses parathyroid hormone (PTH) secretion.
AB - Six new 2,2-disubstituted analogues of the natural hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels-Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues 8. Analogues 7a and 8a are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2-3 times more active transcriptionally than calcitriol, whereas dimethylated analogue 8a is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue 8a is considerably less calcemic than calcitriol. Dimethylated analogue 8a strongly suppresses parathyroid hormone (PTH) secretion.
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U2 - 10.1016/S0968-0896(02)00058-5
DO - 10.1016/S0968-0896(02)00058-5
M3 - Article
C2 - 11983533
AN - SCOPUS:0036241999
SN - 0968-0896
VL - 10
SP - 2353
EP - 2365
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 7
ER -