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

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


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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    • "These agents are indirect telomerase inhibitors capable to stabilize the G-quadruplex structure and to interfere with telomere replication by blocking the elongation step catalyzed by telomerase (Zahler et al., 1991). Classes of G-quadruplex inhibitors described to date include anthraquinones (Sun et al., 1997; Perry et al., 1998), fluorenones (Perry et al., 1999a), acridines (Harrison et al., 1999), cationic porphyrins (Shi et al., 2001; Izbicka et al., 1999), a perylenetetracarboxylic diimide derivative (Fedoroff et al., 1998), indolo-quinolines (Caprio et al., 2000) and a benzonaphthofurandione tetracyclic compound (Perry et al., 1999b). "

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    ABSTRACT: The ends of chromosomes (telomeres) consist of tandem repeats of guanine-rich sequences. In eukaryotics, telomeric DNA is single stranded for the final few hundred bases. These single-stranded sequences can fold into a variety of four-stranded structures (quadruplexes) held together by quartets of hydrogen-bonded guanine bases. The reverse transcriptase enzyme telomerase is responsible for maintaining telomeric DNA length in over 85% of cancer cells by catalyzing the synthesis of further telomeric repeats. Its substrate is the single-stranded 3'-telomeric end. Inhibition of telomere maintenance can be achieved by stabilization of a quadruplex structure for the telomere end. A variety of small molecules have been devised to achieve this, ranging from anthraquinones to porphyrins, acridines, and complex polycyclic systems. Structural and mechanistic aspects of these quadruplex complexes are reviewed here, together with a discussion of the issues of selectivity/potency for quadruplex DNAs vs duplex DNA.
    No preview · Article · Nov 2000 · Biopolymers
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    ABSTRACT: The ribonucleoprotein telomerase is responsible for maintaining the length of telomeric ends of chromosomes in tumour cells. It is activated in over 85% of the tumour cells, and is emerging as a major target for cancer chemotherapy. A range of molecules containing tricyclic and tetracyclic aromatic chromophores has been shown to inhibit the telomerase enzyme system at the micromolar level. There is evidence that they do so via stabilisation of a guanine-quadruplex structure, which provides a stop signal for further telomere elongation. The known structure-activity relationships for these compounds are summarised, and pointers for the development of future molecules with enhanced selectivity are described.
    No preview · Article · Apr 2000 · Pharmacology [?] Therapeutics
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