SPIRASTRELLOLIDES, ANTIMITOTIC MACROLIDES AND ANALOGUES; AND PHARMACEUTICAL COMPOSITIONS AND RESEARCH TOOLS THEREOF

摘要

A series of novel antimitotic macrolides based on the structure ofSpirastrellolide A, which was isolatedfrom the Caribbean marine sponge Spirastrella occinea, are described.Spirastrellolide A has a 47 carbonlinear polyketide backbone incorporated into a highly functionalized 38membered lactone containing atetrahydropyran and two spiro bispyran substructures embedded in themacrocycle and a side chainterminating in a carboxylic acid. Spirastrellolide A's structure waselucidated by detailed spectroscopicanalysis of its methyl ester. Spirastrellolide A methyl ester shows potentactivity in a cell-based assay thatdetects mitotic arrest, but it does not affect tubulin polymerization invitro. It has the unusual biologicalproperty of being able to accelerate entry of cells into mitosis from othercell-cycle stages, before it arreststhem in mitosis.