Synthesis of the Macrolactone of Migrastatin and Analogues with Potent Cell‐Migration Inhibitory Activity

Abstract

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

Migrastatin Analogues Inhibit Canine Mammary Cancer Cell Migration and Invasion

“…Since then, several more effective analogues of migrastatin have been synthesized and described as promising anti-metastatic drugs [8-13]. There have been efforts to generate further analogues for structure activity studies [14-17]. Importantly, simpler analogues of migrastatin, such as the macrolide MGSTA-8 (Figure 1), have shown activity ~1000 fold more active than migrastatin itself in tumour cell migration assays in vitro [9].…”

“…Truncated analogues such as MGSTA-4 and the macroketone MGSTA-5 and MGSTA-8 inhibit metastasis of highly metastatic tumour cells in mouse models [10,12]. However, inhibition of cell migratory ability considerably depends on the structure of the compounds and some acyclic analogues show activity [11,14,15]. …”

Stereoselective Synthesis of an Analogue of the Macrolactone of Isomigrastatin

“…Recently, our group developed an approach for the synthesis of the macrolactone of migrastatin and analogues. 2 Regarding the biological importance of these skeletons and taking into consideration that isomigrastatin analogues have not been explored yet, we decided to extend this strategy in the synthesis of an analogue of the macrolactone of isomigrastatin.…”

A Long‐Range Acting Dehydratase Domain as the Missing Link for C17‐Dehydration in Iso‐Migrastatin Biosynthesis

“…[6,9] Albeit moderate for the natural product, cell migration inhibition potency has been significantly improved by preparing analogs mimicking the 14-membered macrolide moiety of 6 . [10] Members of the 12-membered macrolides, such as 1 and 2 , exhibited potent cytotoxicity, although their inhibitory activities toward tumor cell migration remained controversial. [11] Although the detailed modes of action that dictate and differentiate cell-migrating inhibition from cytotoxicity remain elusive for this family of natural products, [9] the discoveries of actin-bundling protein fascin as the target for cell migration inhibitory activity of 6 [12] and of blocking the translocation step in initiation of eukaryotic protein translation as the mechanism for cytotoxicity of 1 [13] are exciting, serving as great inspiration for the development of this family of natural products as small molecule probes [13] or promising anticancer drug leads.…”