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 (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.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lecomte
authors.forename: Jon T
authors.initials: JT
authors.lastname: Njardarson
authors.forename: Pavel
authors.initials: P
authors.lastname: Nagorny
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.forename: Robert
authors.initials: R
authors.lastname: Downey
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D004987:Ethers; D018942:Macrolides; D010881:Piperidones; C418199:migrastatin