Design, synthesis and evaluation of human telomerase inhibitors based upon a tetracyclic structural motif.

Cancer Research Campaign Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, UK.
Anti-cancer drug design (Impact Factor: 2.38). 09/1999; 14(4):373-82.
Source: PubMed

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.

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