Novel second generation analogs of eribulin. Part III: Blood–brain barrier permeability and in vivo activity in a brain tumor model

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 6; pp. 1639 - 1643
• Main Authors: Narayan, Sridhar, Carlson, Eric M., Cheng, Hongsheng, Condon, Krista, Du, Hong, Eckley, Sean, Hu, Yongbo, Jiang, Yimin, Kumar, Vipul, Lewis, Bryan M., Saxton, Philip, Schuck, Edgar, Seletsky, Boris M., Tendyke, Karen, Zhang, Huiming, Zheng, Wanjun, Littlefield, Bruce A., Towle, Murray J., Yu, Melvin J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2011; Elsevier
• Subjects: Animal models; Animals; anticarcinogenic activity; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antitumor activity; Antitumor agents; Biological and medical sciences; Blood-Brain Barrier; Blood–brain barrier permeability; brain; Brain Neoplasms - drug therapy; Brain tumors; Breast cancer; breast neoplasms; Cell Line, Tumor; Cerebrospinal fluid; Disease Models, Animal; Drugs; Furans - pharmacokinetics; Furans - therapeutic use; General aspects; Glioblastoma; humans; in vivo studies; Inhibitory Concentration 50; Ketones - pharmacokinetics; Ketones - therapeutic use; Medical sciences; Membrane permeability; Mice; Mice, Inbred BALB C; Microtubule; Multi-drug resistance; Orthotopic brain tumor models; P-Glycoprotein; permeability; Pharmacology. Drug treatments; Tubulin; Tumor cell lines; Multi-drug resistance; Antitumor agents; JBFLNPIQVUSWKG-ZRAYEYSSSA-N; UFNVPOGXISZXJD-JBQZKEIOSA-N; Glioblastoma; Orthotopic brain tumor models; Microtubule; P-Glycoprotein; Blood–brain barrier permeability; Antineoplastic agent; Brain cancer; P Glycoprotein; Central nervous system; Morpholine derivatives; Oxygen heterocycle; Blood brain barrier; Macrocycle; Malignant glioma; Multiple resistance; Blood-brain barrier permeability; Chemical synthesis; Tumor cell; Carrier protein; Human; Transmembrane protein; Nervous system diseases; Eribulin; Rodentia; Malignant tumor; Permeability; Intracranial tumor; Biological activity; Cerebral disorder; In vivo; Vertebrata; Mammalia; Side chain; Cell line; Mouse; Animal; Central nervous system disease; Pharmacokinetics; ABC transporter; Ethylenic compound; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.096

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.