The first locked side-chain analogues of calcitriol (1alpha,25-dihydroxyvitamin D3) induce vitamin D receptor transcriptional activity.

[structure: see text]. We describe the synthesis of the first locked side-chain analogues of the natural hormone 1alpha,25-(OH)2-D3 and their effects on gene transcription in human colon cancer cells. Analogue 2 was more potent than 1alpha,25-(OH)2-D3 at inducing vitamin D receptor (VDR) transcriptional activity. Analogues 3a and 3b show potency similar to that of 1alpha,25-(OH)2-D3, whereas 3c was less active. The novel analogues efficiently bind VDR in vivo to induce transcription from a consensus vitamin D responsive element (VDRE).