title: An Amino-Benzosuberene Analogue That Inhibits Tubulin Assembly and Demonstrates Remarkable Cytotoxicity.
abstract: The recent discovery of a small-molecule benzosuberene-based phenol that demonstrates remarkable picomolar cytotoxicity against selected human cancer cell lines and strongly inhibits tubulin polymerization (1-2 µM) inspired the design and synthesis of a variety of new, structurally diverse benzosuberene derivatives. An efficient synthetic route to functionalized benzosuberenes was developed. This methodology utilized a Wittig reaction, followed by a selective alkene reduction and ring-closing cyclization to form the core benzosuberone structure. This synthetic route facilitated the preparation of a 6-nitro-1-(3',4',5'-trimethoxyphenyl) benzosuberene derivative and its corresponding 6-amino analogue in good yield. The 6-amino analogue was a strong inhibitor of tubulin polymerization (1.2 µM), demonstrated enhanced cytotoxicity against the human cancer cell lines examined (GI50= 33 pM against SK-OV-3 ovarian cancer, for example), and exhibited a concentration dependent disruption of a pre-established capillary-like network of tubules formed from human umbilical vein endothelial cells.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas, 76798-7348, United States.
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Tanpure
authors.forename: Clinton S
authors.initials: CS
authors.lastname: George
authors.forename: Madhavi
authors.initials: M
authors.lastname: Sriram
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.forename: Justin K
authors.initials: JK
authors.lastname: Tidmore
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Charlton-Sevcik
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney