title: Structural interrogation of benzosuberene-based inhibitors  of tubulin polymerization.
abstract: The discovery of 3-methoxy-9-(30,40,50-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 lM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 lM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Herdman
authors.forename: Laxman
authors.initials: L
authors.lastname: Devkota
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Lin
authors.forename: Haichan
authors.initials: H
authors.lastname: Niu
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.forename: Ramona
authors.initials: R
authors.lastname: Lopez
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Clinton S
authors.initials: CS
authors.lastname: George
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Tanpure
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 / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D014404:Tubulin; D050257:Tubulin Modulators; C000594239:benzosuberone