38 活性型ビタミンDの作用発現と立体構造(口頭発表の部)

抄録

Hydroxyl groups play a major role in binding to a receptor protein. To clarify the side chain conformation of 1,25(OH)_2D_3 (1) to bind to VDR, we analyzed the mobility of the side chain of 1 and its 20-epimer (2) in terms of the spatial region accessible by the 25-hydroxyl group and the results were displayed as a dot map. The dot map indicates that each vitamin D has two major densely populated regions: A and G for 1 and EA and EG for 2. We designed six 22-substituted analogs of active vitamin D, 3-8, whose side chain hydroxyl is restricted to occupy one of the four spatial regions defined above and the analogs were classified into group A, G, EA, and EG accordingly. Syntheses of analogs, 3-8, were performed via diastereoselective conjugate addition of alkyl cuprate to steroidal (E)-and (Z)-22-en-24-ones (12 and 13) and -22-en-24-oates (16, 17, 20 and 21) as the key step. The activity of the analogs, 3-8, to bind to VDR was examined in compared with 1. It is apparent that the members of A ( 4 and 6) and EG (7) group analogs show much higher activity than the others, G(3, 5) and EA (8). The contrasting activities of the two 22-methyl analogs (3 and 4) are especially outstanding: VDR binding (3:4:1=1/50:1/3:1); differentiation of HL-60 cells (3:4:1=1/70:1:1). The results suggest that the conformation of 1,25(OH)_2D_3 (1) involved in binding to VDR and responsible for activity is the C(17,20,22,23)-anti form and the region where the 25-hydroxyl group occupies is the A.