2,2-disubstituted analogues of the natural hormone 1α,25-dihydroxyvitamin D3:: Chemistry and biology

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. (C) 2002 Elsevier Science Ltd. All rights reserved.