title: Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent.
abstract: The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI₅₀ = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC₅₀ = 1.1 μM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors.forename: Mallinath B
authors.initials: MB
authors.lastname: Hadimani
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Macdonough
authors.forename: Anjan
authors.initials: A
authors.lastname: Ghatak
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.forename: Ramona
authors.initials: R
authors.lastname: Lopez
authors.forename: Madhavi
authors.initials: M
authors.lastname: Sriram
authors.forename: Benson L
authors.initials: BL
authors.lastname: Nguyen
authors.forename: John J
authors.initials: JJ
authors.lastname: Hall
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kessler
authors.forename: Anupama R
authors.initials: AR
authors.lastname: Shirali
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Garner
authors.forename: George R
authors.initials: GR
authors.lastname: Pettit
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Mason
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000737:chemistry / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013267:Stilbenes; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D007211:Indoles; C584989:OXi8007 compound; D010755:Organophosphates; D011355:Prodrugs; D013267:Stilbenes; D014404:Tubulin; C040105:combretastatin; C058728:fosbretabulin; D003078:Colchicine
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