title: Synthesis and Biological Evaluation of Benzocyclooctene-based and Indene-based Anticancer Agents that Function as Inhibitors of Tubulin Polymerization.
abstract: The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt ofCA4(referred to asCA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine andCA4led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to asKGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50< 5 μM), and benzocyclooctene phenol23was comparable toKGP18in terms of potency. The analogous indene-based compound31also functioned as an inhibitor of tubulin polymerization (IC50= 11 μM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue23, and it was converted to its water-soluble prodrug salt24to assess its potential as a VDA. Preliminaryin vivostudies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with24(120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies withCA4P, a clinically relevant VDA, were carried out as a positive control.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Herdman
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
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.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Prognostic Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9058, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Winters
authors.affiliation: Prognostic Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9058, United States.
authors.forename: Jeni
authors.initials: J
authors.lastname: Gerberich
authors.affiliation: Prognostic Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9058, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Prognostic Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9058, United States.
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Mason
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States; Mateon Therapeutics, Inc., 701 Gateway Boulevard, Suite 210, South San Francisco, California 94080, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
keywords: benzocyclooctene analogues; bioluminescence imaging (BLI); indene analogues; inhibitors of tubulin polymerization; small-molecule synthesis; vascular disrupting agents (VDAs)