title: Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo.
abstract: 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.
authors.affiliation: Eisai Product Creation Systems, Eisai Inc., Andover, MA 01810, USA. Sridhar_Narayan@eisai.com
authors.forename: Sridhar
authors.initials: S
authors.lastname: Narayan
authors.forename: Eric M
authors.initials: EM
authors.lastname: Carlson
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Cheng
authors.forename: Krista
authors.initials: K
authors.lastname: Condon
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Sean
authors.initials: S
authors.lastname: Eckley
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Vipul
authors.initials: V
authors.lastname: Kumar
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Lewis
authors.forename: Philip
authors.initials: P
authors.lastname: Saxton
authors.forename: Edgar
authors.initials: E
authors.lastname: Schuck
authors.forename: Boris M
authors.initials: BM
authors.lastname: Seletsky
authors.forename: Karen
authors.initials: K
authors.lastname: Tendyke
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhang
authors.forename: Wanjun
authors.initials: W
authors.lastname: Zheng
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Towle
authors.forename: Melvin J
authors.initials: MJ
authors.lastname: Yu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D019008:Drug Resistance, Neoplasm; D005663:Furans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin; D000095662:Polyether Polyketides