title: Discovery of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a tubulin polymerization inhibitor with potent antiproliferative and tumor vascular disrupting properties.
abstract: A structure-activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).
authors.affiliation: Bionomics Ltd., 31 Dalgleish Street, Thebarton, South Australia, 5031, Australia. flynn@monash.edu
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Flynn
authors.forename: Gurmit S
authors.initials: GS
authors.lastname: Gill
authors.forename: Damian W
authors.initials: DW
authors.lastname: Grobelny
authors.forename: Jason H
authors.initials: JH
authors.lastname: Chaplin
authors.forename: Dharam
authors.initials: D
authors.lastname: Paul
authors.forename: Annabell F
authors.initials: AF
authors.lastname: Leske
authors.forename: Tina C
authors.initials: TC
authors.lastname: Lavranos
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Edmund
authors.initials: E
authors.lastname: Kostewicz
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Jung
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kremmidiotis
mesh_terms: D000840:Anisoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000840:Anisoles; C552092:BNC 105; D001572:Benzofurans; D050257:Tubulin Modulators