Evaluation of new migrastatin and dorrigocin congeners unveils cell migration inhibitors with dramatically improved potency.
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.
Ju
Jianhua
J
Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705-2222, USA.
Rajski
Scott R
SR
Lim
Si-Kyu
SK
Seo
Jeong-Woo
JW
Peters
Noël R
NR
Hoffmann
F Michael
FM
Shen
Ben
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D018942:Macrolides; D010881:Piperidones; C089606:dorrigocin A; C418199:migrastatin; C077633:lactimidomycin; C007864:glutarimide