title: Design, synthesis and evaluation of human telomerase inhibitors based upon a tetracyclic structural motif.
abstract: There is currently significant interest in the development of inhibitors of human telomerase for the treatment of cancer. We describe here the design and synthesis of a new class of mono-substituted small-molecule inhibitors of human telomerase based upon a tetracyclic structural motif. In contrast to the structurally related molecule 9-hydroxyellipticine, recently shown to inhibit telomerase activity in cell cultures but found to be inactive in a cell-free system, we demonstrate direct inhibition of the telomerase enzyme by the tetracyclic compounds in a modified cell-free TRAP assay. The most potent compounds exhibit activity in the low micromolar range and are thus comparable with some of the more active small-molecule telomerase inhibitors based on planar aromatic chromophores, previously described by ourselves and others. These compounds may represent useful leads for the development of more potent inhibitors of human telomerase.
authors.affiliation: Cancer Research Campaign Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Perry
authors.forename: S M
authors.initials: SM
authors.lastname: Gowan
authors.forename: M A
authors.initials: MA
authors.lastname: Read
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: S
authors.initials: S
authors.lastname: Neidle
mesh_terms: D020816:Amino Acid Motifs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D019914:Taq Polymerase / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D019914:Taq Polymerase; D019098:Telomerase