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

Article abstract of DOI:10.1016/S0040-4020(00)00480-4

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'-endolsyn 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). (C) 2000 Elsevier Science Ltd.