Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin Academic Article uri icon

Overview

MeSH Major

  • Lung Neoplasms
  • Macrolides
  • Neoplasm Metastasis
  • Piperidones

abstract

  • Migrastatin is a biologically active natural product isolated from Streptomyces that has been shown to inhibit tumor cell migration. Upon completion of the first total synthesis of migrastatin, a number of structurally simplified analogs were prepared. Following extensive in vitro screening, a new generation of analogs was identified that demonstrates substantially higher levels of in vitro inhibitory activity, stability and synthetic accessibility when compared to the parent natural product. Herein, we describe two promising ether-derivative analogs, the migrastatin core ether (ME) and the carboxymethyl-ME (CME), which exhibit high efficacy in blocking tumor cell migration and metastasis in lung cancer. These compounds show an in vitro migration inhibition in the micromolar range (IC(50): ME 1.5 to 8.2 μM, CME 0.5 to 5 μM). In a human small-cell lung carcinoma (SCLC) primary xenograft model, ME and CME compounds were found to be highly potent in inhibiting overall metastasis even at the lowest dosage used (degree of inhibition: 96.2% and 99.3%, respectively). Together these very encouraging findings suggest that these analogs have promise as potent antimetastatic agents in lung cancer.

publication date

  • September 13, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3174672

Digital Object Identifier (DOI)

  • 10.1073/pnas.1015247108

PubMed ID

  • 21808037

Additional Document Info

start page

  • 15074

end page

  • 8

volume

  • 108

number

  • 37