(23S)- and (23R)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone function as antagonists of vitamin D receptor-mediated genomic actions of 1α,25-dihydroxyvitamin D3

We synthesized various analogues of 1 alpha ,25-(OH)(2)D-3-26,23-lactone and examined the effects of them on HL-60 cell differentiation using the evaluation system of the genomic action of 1 alpha ,25-(OH)(2)D-3. We found that (23S)- and (23R)-25-dehydro-1 alpha -OH-D-3-26,23-lactone (TEI-9647 and TEI-9648) strongly bound to the VDR, but did not induce HL-60 cell differentiation. Intriguingly, TEI-9647 and TEI-9648 did inhibit that induced by 1 alpha ,25-(OH)(2)D-3,D- whereas they did not suppress that caused by retinoic acid or TPA. On the contrary, the similar 25-dehydrated 24-dehydro analogues, TEI-D1807 and TEI-D1808, weakly but significantly induced HL-60 cell differentiation, never showing inhibitory effect on HL-60 cell differentiation induced by 1 alpha .25-(OH)(2)D-3. In other experiments, TEI-9637 and TEI-9648 markedly suppressed 25-OH-D-3-24-hydroxylase gene expression induced by 1 alpha ,25-(OH)(2)D-3 in HL-60 cells. TEI-9647 also inhibited the heterodimer formation between VDR and RXR alpha, and the VDR interaction with co-activator SRC-1 according to the results obtained from the mammalian two-hybrid system in Saos-2 cells. Taking all these results into consideration, we reached a manifest conclusion that TEI-9647 and TEI-9648 are the specific and first antagonists of 1 alpha ,25-(OH)(2)D-3 action, specifically VDR-VDRE mediated genomic action. (C) 2001 Elsevier Science Inc. All rights reserved.