Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin Journal Article
| Authors: | Lecomte, N.; Njardarson, J. T.; Nagorny, P.; Yang, G.; Downey, R.; Ouerfelli, O.; Moore, M. A. S.; Danishefsky, S. J. |
| Article Title: | Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin |
| 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 (IC50: 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. |
| Keywords: | controlled study; unclassified drug; human cell; drug efficacy; nonhuman; mouse; animals; mice; animal tissue; metastasis; lung neoplasms; animal experiment; animal model; lung cancer; in vivo study; drug structure; in vitro study; xenograft model antitumor assays; cell line, tumor; drug synthesis; cancer inhibition; lung small cell cancer; tumor cell; neoplasm metastasis; cell movement; ic 50; small cell lung carcinoma; streptomyces; macrolides; piperidones; metastasis inhibition; ethers; migrastatin ether; antimetastatic agent; carboxymethyl migrastatin ether; ether derivative; migrastatin derivative |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 108 |
| Issue: | 37 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2011-09-13 |
| Start Page: | 15074 |
| End Page: | 15078 |
| Language: | English |
| DOI: | 10.1073/pnas.1015247108 |
| PROVIDER: | scopus |
| PMCID: | PMC3174672 |
| PUBMED: | 21808037 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2011" - "CODEN: PNASA" - "Source: Scopus" |
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