Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo

• Published in: Bioorganic & medicinal chemistry letters 2011-03, Vol.21 (6), p.1634-1638
• 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: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antitumor agents; bioavailability; Biological and medical sciences; Biological Availability; breast neoplasms; Drug Resistance, Neoplasm; drugs; Furans - administration & dosage; Furans - pharmacokinetics; Furans - pharmacology; General aspects; Humans; Ketones - administration & dosage; Ketones - pharmacokinetics; Ketones - pharmacology; Medical sciences; metastasis; Mice; Mice, Inbred BALB C; Microtubule; Multi-drug resistance; multiple drug resistance; Oral bioavailability; P-Glycoprotein; Pharmacology. Drug treatments; Xenograft Model Antitumor Assays; Xenograft models
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.097

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.