Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 6; pp. 1630 - 1633
• Main Authors: Narayan, Sridhar, Carlson, Eric M., Cheng, Hongsheng, Du, Hong, Hu, Yongbo, Jiang, Yimin, Lewis, Bryan M., 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: alcohols; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antitumor agents; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; bioavailability; Biological and medical sciences; Biological Availability; brain; breast neoplasms; cell culture; Cell Line, Tumor; drugs; European Union; Furans - chemistry; Furans - pharmacokinetics; Furans - pharmacology; General aspects; Humans; hydrophobicity; Ketones - chemistry; Ketones - pharmacokinetics; Ketones - pharmacology; macrolides; Medical sciences; Mice; Microtubule; Multi-drug resistance; multiple drug resistance; Oral bioavailability; P-glycoprotein; Pharmacology. Drug treatments; Structure-Activity Relationship; Xenograft Model Antitumor Assays; Xenograft models; United States; Japan; P-glycoprotein; Multi-drug resistance; Oral bioavailability; Xenograft models; Antitumor agents; Microtubule; Antineoplastic agent; Solid tumor; P Glycoprotein; Oxygen heterocycle; Macrocycle; Lipophilic compound; Hydroxyether; Multiple resistance; Tumor; Colon; Chemical synthesis; Tumor cell; Carrier protein; Human; Transmembrane protein; Eribulin; Ether; Rodentia; Melanoma; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Side chain; Cell line; Mouse; Animal; Pharmacokinetics; ABC transporter
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.111

Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models.