Synthesis of the macrolactone of migrastatin and analogues with potent cell-migration inhibitory activity

摘要

The synthesis of the macrolactone core of migrastatin 2, its potent anti-metastasis analogue 34, and ester derivatives 35 and 38 are reported. The approach involves the use of a dihydroxylation reaction to establish the desired C-8 stereocenter followed by a metathesis cyclization reaction. The effects of the compounds on the migration and invasion of human breast cancer cells were evaluated by using the wound-healing and the Boyden-chamber cell-migration and cell-invasion assays. The results revealed a high potency of the macrolactones 2 and 34 and the ester analogues 35 and 38, which suggests they have potential as antimetastatic agents. The synthesis of macrolactones 2 and 34 as well as esters 35 and 38 proceeds in good overall yields. Macrolactone 34 and ester 38 are amongst the most active compoundsof the migrastatin family prepared so far and show good promise as anticancer compounds.