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

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.