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.
"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). "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Telomerase activity has been found in most cancer cells, but not in the majority of normal differentiated tissues. Therefore, telomerase has been considered a relatively selective and widely expressed tumor marker to be used as a diagnostic tool, and in some cases, as a potential prognostic indicator. Telomerase activity can also be used to evaluate chemosensitivity of neoplastic cells obtained from cancer patients, by measuring residual telomerase activity after drug treatment. Finally, telomerase has been considered to represent a suitable target for designing new anticancer strategies. This review focuses on present and future clinical applications of telomerase studies in cancer management. Copyright 2000 Harcourt Publishers Ltd.
Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 07/2000; 3(3):161-170. DOI:10.1054/drup.2000.0139 · 9.12 Impact Factor
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