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Narayan S Carlson EM Cheng H Condon K Du H Eckley S Hu Y Jiang Y Kumar V Lewis BM Saxton P Schuck E Seletsky BM Tendyke K Zhang H Zheng W Littlefield BA Towle MJ Yu MJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1634-1638
Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with low susceptibility to PgP-mediated drug efflux. These compounds were active against MDR tumor cell lines in vitro and in xenograft models in vivo, in addition to being orally bioavailable. 相似文献
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Narayan S Carlson EM Cheng H Condon K Du H Eckley S Hu Y Jiang Y Kumar V Lewis BM Saxton P Schuck E Seletsky BM Tendyke K Zhang H Zheng W Littlefield BA Towle MJ Yu MJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1639-1643
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. 相似文献
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