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-b enzoyladenine or propargyl alcohol, respectively, followed by phosphorylati on and deprotection. NMR spectroscopy and a molecular dynamics simulation i ndicated that the 5'-6 "-tether induces a conformational change from 2'-end o/syn in 1 to 3'-endol/anti in 14. The unexpected small loss of Ca2+-releas ing potency of cyclophostin 14, which is reflected by the low EC50/IC50 rat io in comparison with cycloribophostin 15, suggests that the interaction of the adenine with IP3R plays a decisive role in determining the high activi ty of adenophostin A (1). (C) 2000 Elsevier Science Ltd. All rights reserve d.