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′-endo/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).