Synthesis and biological evaluation of cyclophostin:: A 5′,6"-tethered analog of adenophostin A

The synthesis, conformational analysis and biological evaluation of 5'-6 "-tethered adenophostin A, so-called cyclophostin 14, and its de-adeninylated analog 15 are described. They are prepared via ring-closing metathesis of diolefin 28, consecutive coupling of the central building block 33 to 6-N-benzoyladenine or propargyl alcohol, respectively, followed by phosphorylation and deprotection. NMR spectroscopy and a molecular dynamics simulation indicated that the 5'-6 "-tether induces a conformational change from 2'-endo/syn in 1 to 3'-endol/anti in 14. The unexpected small loss of Ca2+-releasing potency of cyclophostin 14, which is reflected by the low EC50/IC50 ratio in comparison with cycloribophostin 15, suggests that the interaction of the adenine with IP3R plays a decisive role in determining the high activity of adenophostin A (1). (C) 2000 Elsevier Science Ltd. All rights reserved.