Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model
Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model
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DOI：
10.1016/j.bmcl.2011.01.096
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发表时间：
2011-03-15
影响因子：
2.7
通讯作者：
Yu, Melvin J.
中科院分区：
文献类型：
--
作者：
Narayan, Sridhar;Carlson, Eric M.;Yu, Melvin J.
新近批准用于治疗乳腺癌的微管蛋白制剂甲磺酸埃瑞布林的第二代新型类似物被报道。我们最近的工作重点是将这类化合物的目标适应症扩展到其他肿瘤类型。在此，我们描述了设计、合成和评价对体外脑肿瘤细胞系和相应的小鼠脑肿瘤模型有活性的伊瑞布林类似物。C32侧链区域氨基碱度的衰减导致化合物对P-gp介导的药物外排的敏感性降低，使这些化合物能够通过血脑屏障渗透。在临床前体内研究中，这些化合物在大脑和脑脊液中的含量明显高于艾瑞布林。此外，该系列的类似物在人类胶质母细胞瘤的原位小鼠模型中显示出抗肿瘤活性。(C) 2011 Elsevier Ltd.版权所有。
Novel second generation analogs of eribulin mesylate, a tubulin agent recently approved for the treatment of breast cancer, are reported. Our recent efforts have focused on expanding the target indications for this class of compounds to other tumor types. Herein, we describe the design, synthesis and evaluation of eribulin analogs active against brain tumor cell lines in vitro and corresponding brain tumor models in mice. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with lower susceptibility to P-gp mediated drug efflux, allowing these compounds to permeate through the blood-brain barrier. In preclinical in vivo studies, these compounds showed significantly higher levels in the brain and cerebrospinal fluid as compared to eribulin. In addition, analogs within this series showed antitumor activity in an orthotopic murine model of human glioblastoma. (C) 2011 Elsevier Ltd. All rights reserved.