Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15074-8. doi: 10.1073/pnas.1015247108. Epub 2011 Aug 1.
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.
美拉他汀是一种从链霉菌中分离出来的具有生物活性的天然产物，已被证明能抑制肿瘤细胞迁移。在完成美拉他汀的首次全合成后，制备了许多结构简化的类似物。经过广泛的体外筛选，发现了新一代的类似物，与母体天然产物相比，其在体外抑制活性、稳定性和合成可及性方面有显著提高。本文介绍了两种有前途的醚衍生物类似物，美拉他汀核心醚（ME）和羧甲基-ME（CME），它们在阻断肺癌肿瘤细胞迁移和转移方面具有很高的功效。这些化合物在体外具有抑制肿瘤细胞迁移的作用，其抑制活性在微摩尔范围内（IC50：ME 为 1.5 至 8.2 μM，CME 为 0.5 至 5 μM）。在人小细胞肺癌（SCLC）原代异种移植模型中，即使在使用的最低剂量下，ME 和 CME 化合物也能高度有效地抑制整体转移（抑制程度分别为 96.2%和 99.3%）。这些非常令人鼓舞的发现表明，这些类似物有望成为肺癌中有效的抗转移药物。
