Novel second generation analogs of eribulin. Part III: Blood–brain barrier permeability and in vivo activity in a brain tumor model
| Autor: | Boris M. Seletsky, Karen TenDyke, Sean Eckley, Bruce A. Littlefield, Huiming Zhang, Hong Du, Carlson Eric, Wanjun Zheng, Yimin Jiang, Sridhar Narayan, Murray J. Towle, Yongbo Hu, Edgar Schuck, Krista Condon, Vipul Kumar, Hongsheng Cheng, Bryan M. Lewis, Philip Saxton, Melvin J. Yu |
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| Rok vydání: | 2011 |
| Předmět: |
Eribulin Mesylate
Clinical Biochemistry Brain tumor Pharmaceutical Science Antineoplastic Agents Blood–brain barrier Biochemistry Inhibitory Concentration 50 Mice chemistry.chemical_compound In vivo Cell Line Tumor Drug Discovery medicine Animals Furans Molecular Biology P-glycoprotein Mice Inbred BALB C biology Brain Neoplasms Chemistry Organic Chemistry Biological activity Ketones medicine.disease In vitro Disease Models Animal medicine.anatomical_structure Blood-Brain Barrier Immunology biology.protein Cancer research Molecular Medicine Eribulin |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:1639-1643 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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