Evaluation of New Migrastatin and Dorrigocin Congeners Unveils Cell Migration Inhibitors with Dramatically Improved Potency

摘要

Lactimidomycin (LTM, >1), iso-migrastatin (iso-MGS, >2) and migrastatin (MGS, >3) are macrolide antitumor antibiotics differing in macrolide ring size but all bearing a glutarimide side chain. To further develop these natural products and related analogs as drug candidates we have produced and evaluated the biological activities of a small library of iso-MGS and LTM-derived agents; congeners evaluated bear either the MGS scaffold or related acyclic (dorrigocin) scaffolds. Scratch wound-healing (SWH) assays with 4T1 mouse and MDA-MB-231 human mammary tumor cell lines, respectively reveal structural elements crucial to inhibition of cell migration by these compounds. Moreover, two substances, >14 and >17, with activity far superior to that of MGS are unveiled by SWH assays.