A simplified analog of debromoaplysiatoxin lacking the B-ring of spiroketal moiety retains protein kinase C-binding and antiproliferative activities

Abstract

A simplified analog (3) of aplysiatoxin was synthesized. Compound 3 has only one tetrahydropyran ring at positions 3-7, the A-ring of the spiroketal moiety, which is the conformation-controlling unit for the macrolactone ring. Nuclear magnetic resonance (NMR) analysis and density functional theory (DFT) calculations indicated that 3 existed as an equilibrium mixture of two conformers arising from inversion of the chair conformation of the 2,6-trans-tetrahydropyran ring. The des-B-ring analog 3 binds protein kinase C isozymes and exhibits antiproliferative activity toward human cancer cell lines, comparable to 18-deoxy-aplog-1 with a spiroketal moiety.

Keywords: Antiproliferative activity; Aplysiatoxin; Conformer; Isozyme selectivity; Molecular dynamics simulation; Protein kinase C; Simplified analog.