Asymmetric catalytic ene-cyclization approach to 2-fluoro-19-nor-1,25-dihydroxyvitamin D-3 A-ring analog with significant transactivation activity

1 alpha ,25-Dihydroxyvitamin D-3 (1 alpha ,25(OH)(2)D-3) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for the treatment of ca ncer and psoriasis. However, little information has been available on the b inding conformation of the 1 alpha ,25(OH)(2)D-3 molecule and its analogs w ith the vitamin D receptor (VDR). Therefore, we synthesized 2 alpha -fluori nated A-ring analogs of 19-nor-1 alpha ,25(OH)(2)D-3 in order to investigat e the VDR-binding conformation of the A-rings on the basis of the F-19 NMR analysis. The 2 alpha -fluoro-19-nor-1 alpha ,25-dihydroxyvitamin D-3 A-rin g analog thus synthesized via a asymmetric catalytic carbonyl-ene cyclizati on, shows significant activity in transactivation. Chirality 13:366-371, 20 01. (C) 2001 Wiley-Liss, Inc.